Besides your unique biology, current condition and activities, the important decision for how much protein to consume depends on your age and the amino acid content of the protein choices. Older people need more, and too much methionine can be a significant problem.

Please note: There is strong evidence that both too little or too much protein can be deleterious in a variety of interconnected ways, and a person’s age and the protein source make a big difference. For longevity, the source of protein may have more of an impact even than caloric restriction. Recommended amounts stratified by age followed by a summary table for quick reference are at the bottom of this post, but please bear in mind that individual differences as reflected in multiple relevant lab values seen in the context of a complete clinical picture determine a personal recommendation.

Research published in EBioMedicine, part of the prestigious The Lancet portfolio of medical journals, offers helpful insight into how to choose the right amount of protein. This is an important consideration because, besides strength and locomotion, muscle is a major immunologic and metabolic ‘organ’ that contributes to immune system and metabolic regulation, especially blood glucose levels. While protein is crucial for maintaining or increasing muscle mass (and other protein structures in the body), too much can become a risk factor for chronic disease and mortality. At the same time, however, protein requirements go up with age and an insufficient amount results in sarcopenia, the loss of muscle mass, which is a biological calamity for aging that impacts multiple systems throughout the body due to the role of muscle tissue as an immunologic and metabolic organ.

The authors state:

“Lifespan and metabolic health are influenced by dietary nutrients. Recent studies show that a reduced protein intake or low-protein/high-carbohydrate diet plays a critical role in longevity/metabolic health. Additionally, specific amino acids (AAs), including methionine or branched-chain AAs (BCAAs), are associated with the regulation of lifespan/ageing and metabolism through multiple mechanisms. Therefore, methionine or BCAAs restriction may lead to the benefits on longevity/metabolic health. Moreover, epidemiological studies show that a high intake of animal protein, particularly red meat, which contains high levels of methionine and BCAAs, may be related to the promotion of age-related diseases. Therefore, a low animal protein diet, particularly a diet low in red meat, may provide health benefits. However, malnutrition, including sarcopenia/frailty due to inadequate protein intake, is harmful to longevity/metabolic health.”

The essential AAs (EAAs), such as BCAAs (branched chain amino acids) and methionine are especially involved in regulating aging process and metabolic health through multiple physiological and molecular mechanisms.

More important than caloric restriction

The authors note:

“Dietary interventions, including calorie restriction (CR), dietary restriction (DR), and protein restriction (PR), have been investigated for their effects on longevity or the prevention of age-related diseases through their effects on metabolic health. CR without malnutrition has been shown to extend the lifespan and improve metabolic health in organisms [1]. However, recent evidence indicates that the quantity, source and amino acid (AA) composition of proteins are more strongly associated with longevity and metabolic health than CR [2]. The macronutrient balance of diets, including low protein/high carbohydrate (LPHC) diets, has been shown to have the greatest significant impact on longevity and metabolic health [[3], [4], [5]].”

mTORC1, Gnmt and SAM, FGF21, GH, IGF-1, H2S

mTORC1

To understand protein metabolism it’s especially important to recognize the role of the Mechanistic target of rapamycin complex1 (mTORC1) and its importance to autophagy, the critical process by which worn out, damaged and senescent cells are removed by the immune system. As the authors note:

“mTORC1, a subunit of mTOR, is a serine/threonine kinase that acts as a central regulator of cell growth and metabolism in response to nutrients and growth factors [14]. mTORC1 is activated by various factors, including AAs [14,15] and is the primary modulator of protein, lipid, and nucleotide synthesis; autophagy; and insulin signalling [14]. The pharmacological inhibition of mTORC1 by rapamycin has been shown to extend the lifespan and exert beneficial effects on a set of ageing-related traits in mice, indicating that mTORC1 may be related to lifespan regulation [[16], [17], [18], [19], [20]]. Nutritional interventions, such as a LPD [low protein diet], also suppress mTORC1 because AAs promote mTORC1 activation [15].”

In particular, reduced levels of leucine and arginine lead to the suppression of mTORC1 activation. The suppression of mTORC1 is associated with the induction of autophagy and improvement of insulin resistance, resulting in longevity and metabolic health.

Glycine N-methyltransferase (Gnmt) and S-adenosylmethionine (SAM) metabolism

SAM is converted to S-adenosylhomocysteine by Gnmt…Recent reports have shown that SAM, rather than methionine, may be the main contributor to methionine restriction (MetR)-induced lifespan extension.

Fibroblast growth factor 21 (FGF21)

FGF21 is an endocrine signaling factor in PR and is associated with lifespan extension, metabolic control and organ protection. Levels increase on a LPD (low protein diet) regardless of the overall caloric intake in both rodents and humans [31]. The increased circulating levels of FGF21 play a role in the regulation of glucose/lipid homeostasis, mitochondrial activity, ketogenesis and energy expenditure (EE), which could be expected to be beneficial for age-related health.

Growth hormone/insulin-like growth factor-1 (GH/IGF-1)

“Reduced GH/IGF-1 signalling is linked to survival duration and decreased incidence of cancer and T2DM in humans [44,45]. Reducing IGF-1 signalling suppresses the ageing process…PR (protein restriction) or restriction of particular AAs such as methionine, may explain part of the effects of CR on longevity and disease risk because PR and AA restriction can sufficiently reduce IGF-1 levels and cancer incidence and extend the lifespan in model organisms independently of calorie intake [46].”

Hydrogen sulphate (H2S)

The restriction of dietary sulfur-containing AAs (SAAs), including methionine, leads to stress resistance and longevity by increasing H2S production.

“H2S can readily diffuse through tissues and has pleiotropic and beneficial effects at the cellular, tissue and organismal levels with the potential to contribute to stress resistance by exerting positive effects, including anti-oxidative/anti-inflammatory effects [53].”

Oxidative stress and inflammation

“Mitochondria are recognized as major source of reactive oxygen species (ROS), and the oxidative damage associated with mitochondria is involved in mitochondrial dysfunction and cellular ageing….A 40%PR (protein restriction) diet for 6–7 weeks without CR (calorie restriction) also decreases mitochondrial ROS (MtROS) production…Additionally, both 80% and 40% MetR (methionne restriction) without CR for 6–7 weeks decreased MtROS generation…BCAAs also cause oxidative stress and inflammation in peripheral blood mononuclear cells [61] and endothelial cells [62] via the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor-κB (NF-κB) and mTORC1.”

The protein source may be more important than the amount

The authors state:

“The protein source, including animal or plant protein, may be more important for mortality risk than the level of protein intake.”

Red meat, which high in branched chain amino acids and methionine, and especially processed red meat, did not do well in a prospective US cohort study involving 131,342 participants over 32 follow-up years [7].

“Among animal proteins, the consumption of red meat and processed meat is associated with the risk of developing chronic diseases, including CVD, CKD [chronic kidney disease], cancer and diabetes [8,9]. A meta-analysis indicated that a high consumption of red meat tends to increase the risk of CVD mortality and cancer and that a high consumption of processed meat significantly increases the risk of cancer and CVD mortality and diabetes [8]. Red meat is an important dietary source of EAAs and micronutrients, including vitamins, iron and zinc, that perform many beneficial functions. However, a high intake of red meat and processed meat results in an increased intake of saturated fat, cholesterol, iron, salt, and phosphate; oxidative stress/inflammation; elevation of by-products of protein or AA digestion by the gut microbiota, such as trimethylamine n-oxide or indoxyl sulfate; acid load; and protein/AA load, which are possibly associated with increased risks of CVD mortality and CKD.”

Branched Chain Amino Acids

BCAAs (valine, leucine, and isoleucine) have important benefits for mitochondrial function but excess levels may be harmful for longevity and metabolic health, particularly in the context of obesity, T2 diabetes, and cardiovascular disease (which are closely associated with each other).

“…the supplementation of BCAAs abolishes the effect of PR [protein restriction] on glucose metabolism and induces inflammation in visceral adipose tissue in mice [10]. In epidemiological studies, there is a positive relationship between increased circulating BCAA levels and insulin resistance in obese and diabetic patients [[75], [76], [77]] and CVD patients [[78], [79], [80], [81]]. Additionally, the increased circulating BCAAs are possibly due to abnormal BCAA metabolism associated with obesity resulting in an accumulation of toxic BCAA metabolites that, in turn, trigger mitochondrial dysfunction, which is associated with insulin resistance and T2DM [82].”

HOWEVER:

It’s a different story when we get older (recommended amounts of protein per day according to age groups are at the bottom of this post).

“…several clinical studies have also shown that BCAA supplements reduce sarcopenia in elderly people and exert beneficial effects on body fat and glucose metabolism, possibly by increasing mitochondrial biogenesis and muscle function [84].”

“Thus, the high intake of BCAAs due to excessive food intake in obese people is harmful in terms of insulin resistance and T2DM. However, a low level of BCAA intake in elderly people is also harmful in terms of sarcopenia. Therefore, the appropriate intake of BCAAs for individuals is necessary to maintain longevity and metabolic health.”

Methionine

“Met is directly involved in promoting the ageing process through multiple mechanisms.”

Dietary restriction of the amino acid methionine (methionine restriction = MetR) has shown a number of benefits across a range of organisms.

“MetR increases metabolic flexibility and overall insulin sensitivity and improves lipid metabolism while decreasing systemic inflammation [42,88,90]. …MetR produced a significant increase in fat oxidation and a reduction in intrahepatic lipid content [91]. Additionally, Virtanen et al. reported that the relative risk of an acute coronary event in individuals with a high methionine intake (>2.2 g methionine/day) was higher than that of individuals with a low methionine intake (<1.7 g methionine/day) in a prospective cohort study (1981 men, aged 42–60 years at baseline, average 14.0 years of follow-up) [92].

Additionally, plasma SAM [S-adenyl-methionine] concentrations were associated with higher fasting insulin levels, homeostasis model assessment of insulin resistance and tumour necrosis factor-α in a cross-sectional study involving 118 subjects with metabolic syndrome [93]. Another report demonstrated that plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity in a cross-sectional study involving 610 elderly people [94], while overfeeding increases serum SAM in proportion to the fat mass gained [95]. Thus, increased SAM related to overfeeding or metabolic dysfunction may be associated with whole body metabolic impairment.”

A balanced approach

The authors offer a balanced perspective in their conclusion:

“Among dietary interventions, MetR may be a candidate intervention for longevity and metabolic health (Fig. 4). Food sources of animal protein, such as beef, lamb, fish, pork and eggs, contain higher levels of methionine than plant food sources, including nuts, seeds, legumes, cereals, vegetables and fruits [96]. Therefore, an individual may need to eat less animal-based food to achieve MetR. For example, the Mediterranean diet [97] or the Dietary Approaches to Stop Hypertension (DASH) diet [98] may be useful for decreasing the consumption of animal protein, particularly red meat (Fig. 4). However, red meat is an important dietary source of micronutrients, including vitamins, iron and zinc; therefore, an appropriate intake is necessary to avoid malnutrition.”

And:

“…reduced protein intake does not decrease the potentially negative effects of certain types of carbohydrates and fats.”

“…methionine or BCAAs restriction may lead to the benefits on longevity/metabolic health. Moreover, epidemiological studies show that a high intake of animal protein, particularly red meat, which contains high levels of methionine and BCAAs, may be related to the promotion of age-related diseases. Therefore, a low animal protein diet, particularly a diet low in red meat, may provide health benefits. However, malnutrition, including sarcopenia/frailty due to inadequate protein intake, is harmful to longevity/metabolic health.”

Important

As always, there is no ‘one size fits all’. Individuals vary greatly in their metabolism, digestive capacity, GI microbiome, mitochondrial function, activity levels, immune regulation of inflammation, oxidative burden, glucose and insulin regulation, and a host of factors that can be measured with the appropriate tests to translate this information from a general perspective to an individual recommendation.

Recommended amounts by age

For healthy adults, peer‑reviewed position papers and meta‑analyses generally converge on about 0.7–0.8 g protein per pound per day to build muscle with resistance training, and somewhat less (≈0.45–0.6 g/lb) to maintain muscle and reduce sarcopenia risk, with higher intakes emphasized in older age groups. Scroll down to see the table below which converts leading evidence‑based recommendations (mostly in g/kg) into grams per pound of body weight.​

(Conversion used: 1 kg ≈ 2.2 lb, so g/kg ÷ 2.2 ≈ g/lb.)

Younger than 50 years

Evidence here mostly comes from general adult and sports‑nutrition literature, which does not show an increased baseline requirement solely due to age below ~50.canr.msu+3​

• To maintain muscle / reduce future sarcopenia risk

  • General adult minimum (RDA equivalent): ~0.36 g/lb (0.8 g/kg) – this prevents deficiency but is likely suboptimal for long‑term muscle preservation.nasm+1​

  • Evidence‑based “better than RDA” range from meta‑analyses and sports nutrition data: 0.45–0.55 g/lb/day (≈1.0–1.2 g/kg/day).pmc.ncbi.nlm.nih+1​

• To increase muscle with strength training

  • Sports nutrition and meta‑analytic data: 0.55–0.9 g/lb/day (≈1.2–2.0 g/kg/day) optimizes gains in lean mass and strength when combined with resistance training.pmc.ncbi.nlm.nih+3​

  • Many trials and position stands cluster most hypertrophy benefits around ~0.7–0.8 g/lb (~1.6–1.8 g/kg), with little additional benefit beyond ~0.82–0.91 g/lb for most lifters.pmc.ncbi.nlm.nih+1​

Age 50–65 years

From about midlife onward, sarcopenia risk rises and several expert groups and reviews advocate higher daily protein than the 0.8 g/kg RDA, even in healthy adults.mayoclinichealthsystem+5​

• To maintain muscle / protect against sarcopenia

  • Reviews and geriatric nutrition position papers: 1.0–1.2 g/kg/day is recommended as a baseline for older adults, which translates to ~0.45–0.55 g/lb/day.pmc.ncbi.nlm.nih+3​

  • Some analyses and expert reviews propose 1.2–1.6 g/kg/day to better counter anabolic resistance in this age band, i.e., ~0.55–0.73 g/lb/day.frontiersin+2​

• To increase muscle with strength training

  • Combining aging and resistance‑training data, many authors recommend staying toward the high end of the “athletic” range: 1.2–1.6 g/kg/day (~0.55–0.73 g/lb/day) as a practical target, with room up to about 2.0 g/kg/day (~0.9 g/lb/day) if tolerated and clinically appropriate.academic.oup+4​

  • This aligns with evidence that older adults often need higher per‑meal and total daily protein to stimulate maximal muscle protein synthesis compared with younger adults.pmc.ncbi.nlm.nih+3​

Age 66 years and older

In this group, sarcopenia and frailty become central concerns, and the strongest evidence base (PROT‑AGE and subsequent papers) supports substantially higher protein than the 0.8 g/kg RDA.pmc.ncbi.nlm.nih+5​

• To maintain muscle / protect against sarcopenia

  • PROT‑AGE Study Group and later reviews: 1.0–1.2 g/kg/day for generally healthy adults ≥65 years to maintain or regain lean mass and function: ~0.45–0.55 g/lb/day.researchexperts.utmb+3​

  • For those at risk of or with sarcopenia, or with chronic disease, recommended intakes commonly increase to 1.2–1.5 g/kg/day (sometimes up to ~2.0 g/kg), corresponding to ~0.55–0.68 g/lb/day (upper illness‑related targets ≈0.9 g/lb/day).espen+4​

• To increase muscle with strength training

  • Reviews on protein and aging plus sports‑nutrition data support ~1.2–1.6 g/kg/day (~0.55–0.73 g/lb/day) as a realistic, evidence‑supported range for hypertrophy and strength gains in older adults when combined with resistance training.pmc.ncbi.nlm.nih+5​

  • For sarcopenic or frail older adults engaged in supervised resistance programs, some clinical trials show benefit up to about 1.5 g/kg/day (~0.68 g/lb/day), with suggestions that 1.5–2.0 g/kg/day (~0.68–0.9 g/lb/day) may be appropriate in selected, medically monitored cases.espen+4​

Biology is a continuous process of responsiveness. All systems of the body, especially the brain, must have stimulation to thrive and maintain function. A research paper published in the respected journal Menopause brings attention to what is regrettably left out of menopause management and health care in general due to a prudish medical culture.

The authors conclude from their detailed study:

“Our findings suggest that self-pleasure is an important, but underused, self-help strategy for dealing with symptoms of menopause and, further, that nearly half of women in both earlier and later stages of menopause would be open to considering it. While managing menopause is something that necessitates a custom solution to each woman based on her unique health and needs, doctors and other health care providers should be cognizant of the valuable role that masturbation may play in symptom relief and communicate with their patients about the benefits of self-pleasure.”

For sexual wellness aids researched and designed by physicians, see Cerē.

“These patients often lack traditional cardiovascular risk factors, and as a result, their symptoms may not always trigger a full cardiac workup.”

Research recently published in the Journal of the American College of Cardiology that other pathologic mechanisms than atherosclerosis accounted for a large percentage of heart attacks in their study population, even more than half in women less that 65 years old.

“We sought to determine the incidence and outcomes of MI [myocardial infarction - heart attack] according to a unique pathophysiologic mechanism in a large community cohort aged ≤65 years, and to evaluate sex-differences in etiology.”

Atherothrombosis is the term for when a blood clot (thrombus) forms on a ruptured or eroded atherosclerotic plaque (a buildup of fat, cholesterol, and other substances in an artery wall.) There were five causes other than traditional atherothrombosis:

1. Spontaneous coronary artery dissection (SCAD)

2. Embolism [obstruction of an artery by a blood clot or bubble]

3. Vasospasm [spasmodic contraction of the blood vessel]

4. Myocardial infarction with non-obstructed coronary arteries of unknown cause (MINOCA-U) [unknown]

5. Supply-demand mismatch (SSDM). [an imbalance where the heart's need for oxygen exceeds the amount supplied by the blood, leading to myocardial ischemia (reduced blood flow to the heart muscle)]. Contributing causes can include hypertension increasing the heart’s workload, tachycardia (rapid heart rate) (e.g., from an arrhythmia), excess physical exertion beyond the individual’s tolerance when a sudden increase in activity raises the heart's oxygen needs; and other conditions including severe anemia, fever, or other systemic illnesses can increase the heart's demand for oxygen.

The data showed a preponderance of other causes for heart attack besides the typical atherothromotic.

“There were 4,116 myocardial injury events in 2,780 patients (36% women) over 15 years. Excluding periprocedural MI [heart attacks occurring during surgery, etc.], 1,474 events were classified as index MI [typcial heart attacks], of which 68% were caused by atherothrombosis [clots]. The population incidence of MI was much lower in women, particularly in MI caused by atherothrombosis (48 vs 137 per 100,000 person years and 23 vs 105 per 100,000 person-years). Incidence of SCAD was much higher in women (3.2 vs 0.9 per 100,000 person-years) with 55% of cases misclassified as MINOCA or atherothrombosis at index presentation. Women with atherothrombosis were similar in age to men (55 ± 8 years vs 54 ± 8 years), with similar disease extent at angiography but greater burden of risk factors. Proportionately, nonatherothrombotic causes comprised the majority of MI in women (atherothrombosis 47% vs 75%, secondary myocardial infarction [SSDM] 34% vs 19%, SCAD 11% vs 0.7%, embolism 2% vs 2%, vasospasm 3% vs 1%, MINOCA-U 3% vs 2%). The 5-year all-cause mortality was highest after SSDM (SSDM 33%, atherothrombosis 8%, embolism 8%, SCAD 0%) with low cardiovascular mortality in all groups.”

Doctors and other providers should to vigilant about these possibilities and willing to dig deeper and more comprehensively into the individual’s risk factors beyond atherosclerosis.

The authors conclude:

“This community-based study demonstrates nonatherothrombotic causes comprise an important burden of acute MI in persons age ≤65 years, particularly women. These cause-specific findings have implications for individualized management and risk stratification and provide epidemiologic benchmarking for future studies.”

Tiny particles in the blood, known as exosomes, are altered by diabetes in a way that reprograms immune cells in the tumor environment making them weaker, allowing the cancer to grow and spread more aggressively.

There is much evidence that metabolic disorders including insulin resistance, metabolic syndrome, and type 2 diabetes increase breast cancer risk and mortality. Excess glucose availability and higher levels of insulin are growth promoters for cancer cells. Research just published in Nature Communications Biology reveals how exosomes in type 2 diabetes suppress immune cells in the tumor microenvironment (TME).

“Metabolic disorders, particularly Type 2 diabetes (T2D), raise concerns for the management of breast cancer. Population studies have shown that women with T2D have 40% increased risk of developing breast cancer and 74% increase in overall mortality compared to non-diabetic (ND) women1... Recently, investigations into the immune phenotype of T2D have described subclinical chronic inflammation that induces insulin resistance and metabolic dysfunction that accompany the disease2. This inflammatory milieu ultimately leads to T cell dysfunction3, posing a significant clinical challenge for breast cancer patients. Cancer cells have adaptations that allow them to exploit this dysfunction, reprogramming immune cells to evade detection and clearance4. Traditional molecular diagnostics fall short in capturing these profound differences seen in the tumor microenvironment (TME) of T2D1, highlighting an urgent need for improved diagnostic and therapeutic approaches.”

Exosomes

An exosome is a tiny, membrane-bound extracellular vesicle carrying biomolecules such as proteins, lipids, DNA, and various types of RNA from their cell of origin that play a crucial role in intercellular communication by transferring their molecular cargo, thereby influencing the behavior and function of recipient cells. Changes in exosomes are associated with various diseases and some are used for diagnostic purposes, especially for cancer.

“Our group and others have recently highlighted the critical role of exosomes in linking metabolic dysregulation with cancer pathophysiology5,6,7. We demonstrated that exosomes isolated from T2D patient adipocytes promote a more aggressive tumor phenotype in cellular models of breast cancer, increasing epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) formation, compared to ND controls8. Similarly, plasma-derived exosomes from T2D patients enhanced EMT and CSC traits in prostate cancer cell lines9.”

The tumor microenvironment (TME)

The tumor microenvironment is the complex ecosystem surrounding a tumor, consisting of cancer cells, various stromal cells (such as immune cells, fibroblasts, and blood vessel cells), signaling molecules, and the extracellular matrix. This environment is dynamic and continuously interacts with the tumor, playing an active role in supporting tumor growth, invasion, and progression. Promoting a TME that is as inhospitable as possible for cancer cells is a cardinal intent of case management in the function medicine model. “Take away as much as possible what tumor cells like and give them, as much as possible, what they don’t like.” They especially like glucose and insulin, and they very much dislike immune cells that actively attack them. They deploy a number of tactics to suppress immune cells in the TME.

“Within the breast TME, exosomes have emerged as key mediators of cellular communication…that influence tumor behavior and progression5.”

“Using a novel patient-derived organoid (PDO) system that preserves native tumor-infiltrating lymphocytes (TILs), we show that T2D plasma exosomes induce a 13.6-fold expansion of immunosuppressive TILs relative to nondiabetic controls. This immune dysfunction may promote micrometastatic survival and resistance to checkpoint blockade, a known issue in T2D cancer patients. Tumor-intrinsic analysis revealed a 1.5-fold increase in intratumoral heterogeneity and 2.3-fold upregulation of aggressive signaling networks. These findings reveal how T2D-associated metabolic dysregulation alters tumor–immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression.”

Metabolic health must be a cornerstone of cancer managment

The authors discuss their important findings:

“T2D has long been established as a risk factor for poorer prognosis of breast cancer across numerous population studies1. Epidemiological data indicate that women with T2D have a higher incidence of breast cancer compared to ND and they often present with more aggressive tumor phenotypes27. Meta-analyses and large-cohort studies have reinforced these findings, suggesting that metabolic dysregulation in T2D may contribute to the pathogenesis and progression of breast cancer41. Much of the existing research has focused on tumor-intrinsic properties, including insulin-like growth factor signaling and excess glucose availability feeding tumor growth1. However, the role of the TME in this comorbidity has been largely overlooked. In this study, we aimed to investigate the impact of metabolic dysregulation in T2D on breast cancer aggressiveness and TME dynamics.”

Very interestingly…

“This reprogramming highlights a checkpoint-independent mechanism of T cell suppression, wherein ER [endoplasmic reticulum of the mitochondria] stress fundamentally redirects differentiation toward a dysfunctional state.”

Insulin resistance, metabolic syndrome, and type 2 diabetes all create persistent cellular stress that places a heavy burden on the endoplasmic reticulum (ER), disrupting its homeostasis and triggering maladaptive stress responses leading to insulin signaling impairment and cell dysfunction.

“Contrary to our expectations, we did not observe upregulation of checkpoint ligands on T cells, which would have indicated classical exhaustion. Immune exhaustion is a well-characterized mechanism of dysfunction in cancer, marked by sustained expression of inhibitory receptors and progressive loss of effector function4. While exhaustion phenotypes are known to worsen in T2D and contribute to poor clinical outcomes3, the immune profile observed here suggests a distinct, non-canonical pattern of T cell impairment. Our data instead point to ER stress as a central driver of T cell dysfunction.”

“These results have direct therapeutic implications. Standard immunotherapies that rely on checkpoint inhibition may be ineffective in this context, where T cells are not classically exhausted but rather reprogrammed by ER stress. This result is consistent with existing literature reporting a diminished response to immunotherapy in T2D cancer patients58,59.”

Moreover, the debris field resulting from cancer cell death from chemotherapy over time also induces a change in immune cells (macrophages) from an active ‘attack’ M1 type to a tolerant M2 type, adding to immunosuppression in the TME.

Clinical takeaway

The authors conclude:

“These findings reveal how T2D-associated metabolic dysregulation alters tumor–immune crosstalk through previously underappreciated exosomal signaling, impairing antitumor immunity and accelerating progression.”

“Our results suggest that metabolic status, particularly T2D, could be considered in the clinical management of estrogen receptor-positive breast cancer to improve therapeutic outcomes. Given the unique vulnerabilities of this population, we strongly advocate for the initiation of targeted clinical trials to explore the TME in these 120 million underserved and understudied patients. Addressing these gaps in knowledge and care could pave the way for more effective, personalized treatment strategies, ultimately improving survival and quality of life for this high-risk group.”

Technology Networks quotes corresponding author Gerald Denis, PhD, the Shipley Prostate Cancer Research Professor at Boston University:

“Breast cancer is already challenging to treat, and people with type 2 diabetes have worse outcomes, but clinicians don’t fully understand why,” said Denis. “Our study reveals one possible reason: diabetes changes the way the immune system works inside tumors. This could help explain why current treatments, like immunotherapy, don’t work as well in patients with diabetes. Knowing this opens the door to better, more personalized treatments for millions of people. Over 120 million Americans are diabetic or prediabetic, yet if they develop cancer, they are not treated differently in any significant way by the standards of treatment in oncology. Thus, this work addresses a serious public health challenge.”

PA means the adrenal gland over-produces the hormone aldosterone independently of renin, a common phenomenon with modern diets. This leads to kidney sodium retention, volume expansion, and elevated blood pressure (and some potassium loss). Excess aldosterone also causes direct damage to the entire cardiorenal system. 

The Endocrine Society recently announced a new clinical practice guideline, published in The Journal of Clinical Endocrinology & Metabolism, that goes into detail about how to diagnose and treat this very common disorder.

“Primary aldosteronism (PA), a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands, is a common cause of hypertension. It is associated with an increased risk of cardiovascular complications compared with primary hypertension. Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated.”

The guideline is widely endorsed by the American Association of Clinical Endocrinology, American Heart Association, European Society of Endocrinology, European Society of Hypertension, International Society of Hypertension, the Primary Aldosteronism Foundation, and the European Society of Cardiology

Primary Aldosteronism

“Primary aldosteronism (PA) is an adrenal disorder, either unilateral or bilateral, resulting in excess adrenal production of aldosterone. In PA, aldosterone production is at least partially autonomous of its normal major regulator, the renin–angiotensin system, circulating levels of which are suppressed. The excess aldosterone leads to renal sodium retention, volume expansion, elevated blood pressure (BP), and, in more severe forms, hypokalemia.”

Compared to high blood pressure without PA (primary hypertension), there are significantly higher risks for coronary artery disease, stroke, heart failure, kidney disease; and reduced psychological well-being and quality of life.

As noted in Medscape:

“Meta-analyses have shown that, compared to people with primary hypertension, those with PA have more than twice the risk for stroke and kidney disease, more than triple for atrial fibrillation, and twice the risk for heart failure.”

Quoting the lead author:

“The goal of this new guideline, Adler said, “is to make it easy to diagnose [PA] and to start appropriate aldosterone-targeted therapy to reduce the excess cardiovascular, stroke, and renal morbidity associated with [PA]. It’s so easy to treat. Part of the problem in the past is we made it so hard to diagnose.” 

Vastly under-recognized and under-treated

This condition is very common and hardly ever diagnosed.

“Despite its prevalence and the serious health risks it poses, PA remains largely underdiagnosed and undertreated. This under-recognition contributes significantly to the health care costs associated with hypertension, including the management of complications and related productivity losses.”

And:

“Screening for PA is critically low, often delayed until years after hypertension has been diagnosed, typically following the emergence of severe complications. This may in part be due to misconceptions that PA is only present in the setting of hypokalemia, adrenal macro-nodules, frankly elevated aldosterone levels, or severe hypertension. As a result, many individuals continue to be treated for primary hypertension, thus missing out on targeted treatments or potential cures, and enduring suboptimally managed BP and increased risks of cardiovascular and renal disease. The importance of this is emphasized in the latest major clinical guidelines on hypertension: The 2024 European Society of Cardiology (ESC) guidelines for the management of elevated BP and hypertension suggest screening for PA in all adults with diagnosed hypertension (6). The morbidity and mortality associated with PA are largely preventable.”

Also as noted in Medscape:

“Studies conducted over the past couple of decades suggest that PA prevalence is 5.9% among people with hypertension seen in primary care, 16.2% of younger adults aged 18-40 years with hypertension, 28.1% among adults with both hypertension and hypokalemia, 42% of those with hypertension and atrial fibrillation, and between 11.3% and 19.1% of those with hypertension and type 2 diabetes, according to the document.

Yet, in a study of US Veterans published in 2020, PA screening rates were less than 2% even among those with treatment-resistant hypertension. No improvements in screening rates were found in a more recent follow-up study from the same team.”

Screening and treatment guidelines

The Endocrine Society guideline goes into great detail on how to screen and treat primary aldosteronism, amounting to a state-of-the-art reference. It begins simply:

“PA screening includes measurement of serum/plasma aldosterone concentration and plasma renin (concentration or activity) with determination of the aldosterone to renin ratio (ARR). Potassium is also assessed—not for screening itself—but to aid in the accurate interpretation of aldosterone.”

It then can become more complex dependent on the specific case. Treatment guidelines are also detailed according to the case. When indicated, mineralocorticoid antagonists ( MRAs; aldosterone is a mineralocorticoid hormone) can be a much more effective treatment for hypertension than the usual medications when PA is involved.

Other medications to consider and surgery for certain adrenal tumors are also noted in the highly detailed recommendations offered in the new guideline. Most basically:

PA screening is suggested in all individuals with hypertension

1. In individuals with hypertension and PA, PA-specific therapy is suggested. Medical treatment with MRAs is preferable to nonspecific antihypertensive therapy. For individuals with lateralizing PA who are surgical candidates and desire surgery, unilateral adrenalectomy is preferred.

2. Screening for PA should include measurements of serum/plasma aldosterone concentration and plasma renin (concentration or activity).

   A positive screen is defined as both a low renin level with inappropriately high aldosterone and an elevated aldosterone to renin ratio. Cutoffs for both values differ by assay and are provided in the document. 

   Potassium should be measured with aldosterone to aid in interpretation since low potassium can lead to falsely low aldosterone readings. 

New medication that inhibits aldosterone is very effective

A trial just presented at the 2025 annual congress of the European Society of Cardiology, where it prompted spontaneous applause from the audience, was also simultaneously published online in The New England Journal of Medicine.

The authors state:

“Aldosterone dysregulation plays an important pathogenic role in hard-to-control hypertension. In several studies, baxdrostat, an aldosterone synthase inhibitor, reduced the seated systolic blood pressure of patients with uncontrolled or resistant hypertension.”

Quoted in Medscape, the senior researcher on the trial Bryan Williams, MD, chair of medicine at University College London, United Kingdom called the new class of drugs “a potential game changer” for patients:

“They target the core mechanism contributing to resistant/uncontrolled hypertension and should therefore reduce the future risk of heart disease, stroke, kidney disease, and potentially dementia in these patients,” he said.

Williams, the senior researcher on the BaxHTN trial, called the reduction in blood pressure with baxdrostat “very large” and “remarkably consistent across every subgroup.”

The decreases were observed with 24-hour ambulatory monitoring and at night and were maintained for “several weeks after drug withdrawal,” he said. “This is consistent with the hypothesis that aldosterone is playing a fundamental role in the generation of difficult-to-control hypertension in all of the patients, whatever their makeup, in both uncontrolled and resistant hypertension.” 

Baxdrostat was generally well tolerated with no unanticipated side effects, Williams said.

Despite the availability of many treatments, high blood pressure is hard to control. “Elevated blood pressure is still the single most important preventable cause of premature death globally, with about 50% of patients who are treated globally not reaching the recommended treatment targets, and this represents hundreds of millions of people,” Williams said.

The development of baxdrostat and related drugs is “a triumph of scientific discovery,” following the finding that disturbed aldosterone production to be a key driver of hard-to-control hypertension, he said.

“Aldosterone is the master regulator of how the body handles salt and water, and when the levels are inappropriately high, as they become as we age, this can make people less able to eliminate salt, and it drives up blood pressure and contributes to the development of heart failure, heart disease, stroke, and kidney disease,” Williams said.”

Chronic exposure to systemic inflammation is linked to a greater risk for mood disorders. For people with an autoimmune condition, the risk was nearly twice that of the general population.

Research recently published in BMJ [British Medical Journal] Mental Health demonstrates the need to be attentive to the role of chronic inflammation in the development of psychiatric disorders.

“Chronic inflammation is associated with psychiatric disorders. If inflammation is linked mechanistically to mental health, people living with chronic inflammatory conditions may experience mental health issues at higher rates than others.”

This study is particularly compelling in that the authors, using an autoimmune condition as an indirect indicator of chronic inflammation, examined data from a large cohort of 1,563,155 adult subjects from the general population to test their hypothesis.

Medscape quotes the lead author, Mudra Rakshasa-Loots, MD, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland:

“This study is the first to use data from the Our Future Health cohort, “which is already the world’s largest consented cohort study, so we were able to analyze the relationship between inflammatory conditions and mental health issues with unprecedented precision.”

Substantial increase in affective disorders

For all the affective/mood disorders considered—depression, anxiety, bipolar disorder—the risk was for people with autoimmune conditions was nearly twice that of the general population.

“Lifetime prevalence (95% CI) of self-reported lifetime diagnoses of any affective disorder (depression, bipolar disorder, anxiety) was significantly higher (p<0.001) among people with autoimmune conditions (28.8% (28.4% to 29.3%)) than in the general population (17.9% (17.8% to 18.0%)), with similar trends observed for individual affective disorders. Prevalence of current depressive symptoms (9-item Patient Health Questionnaire (PHQ-9) ≥10, 18.6% vs 10.5%) and current anxiety symptoms (7-item Generalised Anxiety Disorder Scale (GAD-7) ≥8, 19.9% vs 12.9%) was also higher among people with autoimmune conditions.…and these odds remained elevated when adjusting for the effects of age, sex, ethnicity (OR=1.75 (1.71 to 1.79), p<0.001) and additionally, for household income, parental history of affective disorders, chronic pain status and frequency of social interactions (OR=1.48 (1.44 to 1.52), p<0.001).”

This study adds to the body of evidence reminding clinicians to be attentive to the presence of brain-based disorders in there is chronic inflammation.

Vitamin B12 levels in the blood are managed differently than in the tissues and don’t accurately reflect B12 functional status.

B12 levels within the specified normal range may still be associated with neurological degeneration and dysfunction.

It’s well known among clinicians trained in clinical nutrition that serum vitamin B12 levels do not correlate reliably celluar tissue, and importantly, functional status. An excellent research article published in Annals of Neurology unpacks the chemistry that shows why in an especially lucid manner.

After reviewing the crucial importance of vitamin B12 for brain and nervous system function and prevention of anemia, they note:

“In addition to affecting general cognition and memory, vitamin B12 deficiency may even lead to dementia and psychosis, suggesting a broader dependence of the brain on B12.8-11”

Then they describe the historical problem of misleading lab results:

“In the United States, the cutoff value for B12 “deficiency” state is currently defined as below 148 pmol/L.1 This value was simply calculated as 3 standard deviations below the U.S. population average, independent of clinical observations.17 The American Society for Nutrition criticized this approach in 2010, arguing that more than 5% of patients who have a syndrome consistent with B12 deficiency and who respond to B12 supplementation have blood levels above that threshold.18 Other studies demonstrated that B-vitamins supplementation was beneficial in people with clinical features of cobalamin deficiency, regardless of the measured levels in the blood.13, 19 Selecting a cutoff value based on clinical observations would better reduce disparities in B12 deficiency diagnosis and management.”

Subclinical cobalamin (B12) deficiency

Vitamin B12 levels can be suboptimal with adverse effects in the absence of overt damage. Since B12 is required for myelin formation (nerve ‘insulation’), this can show up on MRI as abnormal brain white matter, or ‘white matter hyperintensities’ (WMH).

“Cases of biochemical B12 deficiency wherein suboptimal B12 levels have been reported without overt clinical manifestation have been reported as subclinical cobalamin deficiency (SCCD).20 SCCD is most prevalent in the elderly and is associated with greater WMH burden and cognitive decline over time.21, 22 In this context of B12 insufficiency, age might act as a vulnerability factor, accentuating the deleterious effects of low B12.”

Holo-TC versus Holo-HC

How cobalamin (B12) is ferried through the bloodstream turns out to be a vital determinant in whether or not the B12 measured in the blood is available to the tissues and cells.

“Distribution of the fractions of B12 measured in the blood adds another layer of complexity to understanding the neurological manifestation of B12 deficiency. Once cobalamin is absorbed, the transport proteins haptocorrin (HC) and transcobalamin (TC) bind it with great affinity and act as transporters in circulation.25, 26 Since only TC has a specific receptor (CD320) for cellular uptake, Holo-TC1 is usually considered to be biologically available for cells (“active”). On the other hand, Holo-HC hypothetically represents the fraction of B12 that is not immediately available to tissues (“inactive”); it can only bind non-specific asialoglycoprotein receptors on liver cells for reuptake, degradation and excretion in the bile.27"

The authors set out to determine if lower total B12 levels within the typical ‘normal range’ may still permit subtle functional and structural neurological deficits if the active fraction of plasma B12 (Holo-TC) is too low to sustain adequate cellular B12 needs.

“To that end, we evaluated the association of B12 concentrations with markers of myelin integrity (multifocal VEP; mfVEP), cognitive performance, blood biomarkers of neuronal and glial integrity, as well as quantitative brain MRI analyses across a spectrum of measurable B12 levels as well as the active fraction of the plasma B12.”

Even high levels of B12 if unavailable are associated with neurodegeneration

They were able to demonstrate how even though serum B12 was ‘over the top’, when much of it was unavailable to the cells it resulted in neurodegeneration.

This graphic explains how high levels of B12 in the currently defined normal range can be associated with neurodegeneration because the available B12 (Holo-TC) is relatively small compared to the unavailable Holo-HC B12. These are not distinguished in the clinically available blood tests for B12.

Rethinking the “biologically sufficient” B12 levels

Key findings of this research include:

• Lower B12 associates with a delay in VEP latency, and that it is specific to the biologically available fraction of serum B12 bound to transcobalamin (Holo-TC). They also associate with slowed spatial processing speed.

• On MRI, participants with lower Holo-TC have a higher burden of T2 WMH.

• High levels of Holo-HC, the biologically unavailable fraction of B12, associate with an increase in the levels of T-Tau proteins in the serum, a biomarker for neurodegeneration.

• The observed detrimental effect of low B12 on the CNS is likely related to myelin integrity.

“These findings suggest that current parameters for defining adequate B12 levels may be inappropriate when considering neurophysiological, neuropsychological, serological, and neuroradiological outcomes.”

Further research investigating the adverse effects of high levels of the unavailable holo-haptocorrin (Holo-HC) is needed.

Especially, having a clinical lab step to make the Holo-TC blood test available to practitioners outside of a research setting is an urgent need.

Summarizing their findings, the authors state:

“Our findings are of critical importance for rethinking the “biologically sufficient” B12 levels. The population-based studies that defined healthy micronutrient levels may have missed the subclinical manifestations of low or high B12 at the extremes of the population distribution that can affect people without causing overt symptoms.”

“Notably, during and following B12 repletion therapy, patients often request higher dosing of B12 to treat their neurological symptoms, even after their hematological symptoms have resolved.62 Our findings support the idea that subtle neurological deficits manifest at higher levels than the current threshold defined for deficiency, and most importantly, it could provide an explanation for the often-reported discrepancy between hematological and neurological symptoms.63, 64”

“This slow progression toward deficiency could be better described by a sliding scale of insufficiency, wherein the tissue levels decline until Holo-TC falls below what is necessary to supply critical cells for biochemical reactions in the nervous system, and then the bone marrow. Revisiting the definition for healthy B12 levels could promote earlier intervention and prevention of cognitive decline, especially in the elderly carrying increased risk for B12 malabsorption and insufficiency.67, 68

“…inadequate amounts of vitamin B12 could induce neurological deficits at a threshold that is higher than the one in current use (Graphical abstract). Moreover, we should work on defining a cutoff for higher B12 and study how haptocorrin might be associated with or could induce neuro-axonal damage.”

For an earlier study of the inadequacy of serum B12 testing in the prestigious journal Neurology, see Serum levels of vitamin B12 are not accurate for brain health and cognition.

Metabolic conditions like type 2 diabetes and pre-diabetes foster a pro-metastatic tumor microenvironment, reducing survival. Patients should always be monitored for this and appropriate metabolic interventions made part of the treatment plan.

A research article just published in Molecular Cancer Research explores how insulin resistance of adipose tissue drives worse outcomes for breast cancer. The authors state:

“Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival.”

They further note:

“Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology…”

Spread via Exosomes

Exosomes are tiny vesicles formed inside cells that contain cellular proteins, DNA, and RNA. They get released into the blood by cells, including cancer cells, and travel to other parts of the body where they can transfer the proteins, DNA, and RNA they contain into other cells. This is how they promote the spread of cancer and can also keep immune cells from killing cancer cells.*

The authors set out to investigate how exosomes secreted by the TME breast adipocytes might drive epithelial-to-mesenchymal transition (EMT) [malignant transformation] and metastasis in TNBC via miRNAs. It’s difficult to over emphasize the importance of their results:

“EMT, proliferation and angiogenesis [growth of tumor-feeding blood vessels] were elevated in IR [insulin resistant] vs. control and IS [insulin sensitive].”

Moreover:

“Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR- 145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis.”

Implications

Highlighting their conclusions, they emphasize:

“IR [insulin resistant] adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis—likely via miRNA pathways—suggesting that metabolic diseases like T2D foster a pro-metastatic TME, reducing survival, warranting close monitoring and potential metabolic interventions in TNBC patients with T2D.”

It is crucially important for providers to be aware that clinically significant insulin resistance is a major factor prior to worsening to the point of crossing the line into type 2 diabetes, and that this pertains to other cancers as well as breast cancer. For more on this see The Triglyceride–Glucose Index is a powerful biomarker for cardiovascular disease, depression, dementia, cancer and much more.

How widespread is this? Consider that approximately 40% of the United States population has fatty liver disease which is driven by insulin resistance—and very few know it.

Quoted in Technology Networks Cancer Research, the lead author states:

“Our study highlights the growing understanding that cancer does not develop in isolation—it is influenced by a person’s overall health, including metabolic conditions like diabetes. This problem is urgent because the epidemic of obesity-driven diabetes is worsening and now affects over 537 million adults worldwide. This finding adds to the idea that treating underlying conditions, not just cancer itself, could improve patient outcomes,” said Denis, who also is co-director of the BU-BMC Cancer Center.”

*Exosome science is already used in the ExoDx Prostate Test, a urine test for more accurate risk assessment of prostate cancer when PSA is elevated.

Supine hypertension is a greater hazard for cardiovascular disease with or without seated hypertension.

An original investigation published in JAMA (Journal of the American Medical Association) Cardiology provides evidence that supine blood pressure measurement reveals risks for cardiovascular disease that are missed by taking blood pressure while seated. The authors state:

“Nocturnal hypertension while asleep is associated with substantial increases in risk of cardiovascular disease (CVD) and death. Whether hypertension while supine is a risk factor associated with CVD independent of seated hypertension remains unknown.”

They set out to determine if high blood pressure is present while simply supine is a risk factor independent of seated hypertension. They measured supine and seated blood pressure in more than 13,000 middle-aged adults with surveillance for CVD over 27 years. Hypertension was defined as systolic blood pressure ≥130 or diastolic blood pressure ≥80 mm Hg.

The results are worthy of attention by clinicians when evaluating CVD risk:

“In this cohort study of 11 369 middle-aged adults, supine hypertension without seated hypertension was associated with incident coronary heart disease, heart failure, stroke, fatal coronary heart disease, and all-cause mortality.”

Moreover…

“Results did not differ by antihypertensive medication use, and supine hypertension alone without seated hypertension was associated with cardiovascular outcomes similarly to having hypertension in both positions.”

Quoted in Medscape Family Medicine, the authors stated:

"While hypertension in both seated and supine positions was associated with the highest risk of adverse events, having supine hypertension without seated hypertension and independent of seated BP [blood pressure] was also a potent risk factor associated with CVD [cardiovascular disease]. For most outcomes, the risk was quite similar to that associated with having hypertension in both positions," the authors wrote.

"Given the simplicity of performing a supine BP in the clinic and the opportunity to detect occult hypertension, supine hypertension warrants greater attention," they added.

The Cardiovascular-Kidney-Metabolic model corresponds more closely to heart attack pathogenesis than the outdated cholesterol dogma and predicts risk for a number of biologically related disorders.

There is a growing wealth of evidence supporting the Cardio-Kidney-Metabolic model (aka the Cardio-Renal-Metabolic model) as a more accurate description and predictor of cardiovascular disease than the scientifically flawed cholesterol dogma. Not surprisingly given the vital importance of insulin resistance as a major cause of chronic inflammation and tissue damage, it is relevant for multiple other diseases as well.

A novel biomarker in the era of cardiometabolic medicine

In a paper published this month in the International Journal of Cardiology the authors introduce this topic of the Triglyceride-Glucose Indes (TyG) by stating:

“…an accurate global assessment of insulin resistance is of utmost importance…This narrative review article aims to provide a comprehensive evaluation of the credibility of TyG as a surrogate marker of insulin resistance…”

They highlight these points:

• The TyG index is increasingly recognized as a promising new biomarker for evaluating insulin resistance and cardiometabolic risk.

• Extensive research has highlighted the robust link between elevated TyG index and heightened risk of cardiometabolic conditions.

• The TyG index has demonstrated comparable or even superior efficacy to traditional markers like HOMA-IR in forecasting cardiometabolic outcomes, positioning it as a valuable tool for risk assessment.

Cardiovascular-Kidney-Metabolic (CKM) Syndrome

In this study, the authors conclude:

“In conclusion, there is a significant positive association between the risk of the TyG index and advanced CKM syndrome. Our findings suggest that the TyG index may serve as a practical tool for early risk identification, stratification, and management guidance for CKM syndrome, particularly in primary care settings.”

In this paper, one of many highlighting the connection with CKM (chronic kidney disease), the authors noted that diabetes (DM) does not have to have developed yet for the kidney damage to be occurring.

“Among individuals with CKM syndrome, the study suggested a non-linear U-shaped relationship between the baseline TyG index and the deterioration of kidney function, regardless of whether the patient had DM. Furthermore, the TyG index with the lowest risk of deterioration of kidney function ranges from 8.65 to 9.15, with an inflection point at 8.88. Therefore, this study indicates that maintaining optimal TyG index levels in patients with CKM syndrome may be of great significance in delaying the kidney function decline. Deviations from the appropriate range, either higher or lower, may lead to an elevated risk of deterioration of kidney function in patients with CKM syndrome.”

Unstable plaque is also known as ‘vulnerable plaque’ because it is vulnerable to rupture and formation of a clot that plugs a downstream vessel. If it’s a coronary vessel (going to the heart), that’s a heart attack. If a cerebral vessel (going to the brain), that’s a stroke. The calcified plaque as shown in a CAC scan (carotid artery calcium scan) has been stabilized by calcification. It shows that there’s some history of vascular inflammation, but it is not a ‘hanging sword’ like the unstable plaque.

In a research article published in the Journal of the American Heart Association, the authors investigated the association between the TyG index and unstable carotid plaque. They concluded:

“The TyG index has a significant association with unstable carotid plaque. The association between the TyG index and unstable carotid plaque is similar between men and women, and the association in older patients is higher than that in middle‐aged patients.”

This makes it a very important independent risk factor because it is associated with the most proximal risk for a heart attack or stroke.

Here’s how they summarize their findings:

• This is the first large‐scale study to explore the relationship between the triglyceride–glucose index and unstable carotid plaque in different glycemic statuses.

• The research revealed a strong association between the triglyceride–glucose index and unstable carotid plaque; this relationship is similar for both men and women, but it is notably stronger in older patients compared with middle‐aged patients.In different glycemic status, those with diabetes exhibit the most significant connection between the triglyceride–glucose index and unstable carotid plaque.

• In different glycemic status, those with diabetes exhibit the most significant connection between the triglyceride–glucose index and unstable carotid plaque.

• The results of this study emphasize the need for risk management strategies for different sexes, ages, and glycemic statuses to prevent patients from developing unstable carotid plaque.

And The role of the triglyceride-glucose index as a biomarker of cardio-metabolic syndromes in the journal Lipids in Health and Disease:

“Overall, our findings support the use of the TyG index as a valid biomarker to assess the risk of developing MetS, T2DM, as well as atherosclerotic cardiovascular disease.”

In the paper Comparison of triglyceride-glucose index and HOMA-IR for predicting prevalence and incidence of metabolic syndrome, the authors demonstrated:

• HOMA-IR and TyG index are commonly used insulin resistance index.

• TyG index is superior to HOMA-IR for predicting the prevalence of metabolic syndrome.

• The predictive power for incident metabolic syndrome is significant only for the TyG index, not HOMA-IR.

• TyG index is a useful surrogate marker for the management and prevention of metabolic syndrome.

The authors of this paper note:

“Insulin resistance can be assessed by the Triglyceride-Glucose Index (TyG), a simple, low-cost, and easy-to-apply method.”

And they found it to a very effective predictor of cardiovascular risk:

“Elevated TyG values ​​(≥9.04) were positively associated with cardiometabolic risk factors (total cholesterol, LDL, VLDL, uric acid, alanine aminotransferase, aspartate aminotransferase, waist-hip ratio, systolic blood pressure, HOMA-IR, smoking, metabolic syndrome, diabetes, and hepatic steatosis)…The TyG index showed a good predictive capacity for cardiovascular risk in ten years assessed by the FRS [Framingham risk score].

Their research of the TyG Index as a metric for insulin resistance found it to be closely associated with all-cause mortality and life expectancy in middle-aged and older patients in primary care.

“TyG-BMI and TyG-WC demonstrated a U-shaped* association with total and premature all-cause mortality. Low and high levels of TyG-BMI and TyG-WC were associated with reduced life expectancy.”

*The first are of the U-curve would be seriously underweight.

Carotid intima-media thickness (c-IMT) refers to the thickness of the carotid artery's inner layers. A c-IMT test uses ultrasound imaging to detect plaque buildup in the carotid arteries, an indicator of cardiovascular risk. In this paper, the data showed:

“There was a significant association between the TyG index and all c-IMT measurements. Those in the highest TyG index quartiles had significantly higher IMTmean and IMTmax compared to those in the lower quartiles. These associations were consistent across all vascular sites examined and remained significant after adjusting for all potential confounders.”.

Summarizing their conclusions:

“The triglyceride-glucose (TyG) index is now widely recognized as a marker of insulin resistance and has been linked to the development and prognosis of atherosclerotic cardiovascular diseases (ASCVD) in numerous populations…TyG index is a sensitive marker of risk in a European population with moderate ASCVD risk, as assessed by c-IMT measurements, in a large cohort of Lipid Clinic patients.”

And from the same journal, the connection with vascular stiffness and calcification: Association between triglyceride glucose index and arterial stiffness and coronary artery calcification: a systematic review and exposure-effect meta-analysis.

“TyG is an independent risk factor for hypertension across different thresholds, showing a clear dose-response relationship. BMI may influence this association, emphasizing the importance of managing insulin resistance early to aid hypertension prevention.”

Importantly, the TyG Index can predict subclinical coronary disease that is brewing but not yet apparent and traditional risk factors are not evident as shown in this study.

“TyG index is an independent marker for predicting subclinical CAD in individuals conventionally considered healthy.”

The TyG Index and Afib (Atrial Fibrillation)

In The association of the triglyceride-glucose index with the risk of atrial fibrillation: Analysis of the UK Biobank, the authors demonstrate:

• “The triglyceride-glucose index is U-shapedly associated with the risk of atrial fibrillation, with higher risk at both low and high levels.

• The U-shaped association between the triglyceride-glucose index and atrial fibrillation risk remains significant regardless of genetic predisposition.

• The U-shaped association between the triglyceride-glucose index and atrial fibrillation risk remains significant regardless of glucose metabolism, or heart valve disease.”

And concluded:

“This study demonstrates a U-shaped association between the TyG index and the risks of AF, underscoring the index's potential utility in identifying individuals at elevated risk for these conditions.”

It is also predictive for how well radiofrequency ablation for afib will work. In Association between triglyceride–glucose index trajectories and radiofrequency ablation outcomes in patients with stage 3D atrial fibrillation:

“The TyG trajectories in patients with stage 3D AF are significantly linked to the outcomes of AF recurrence. Continuous monitoring of TyG levels during follow-up may help in identifying patients at high risk of AF recurrence, enabling the early application of effective interventions.”

And in Clinical predictive model of new-onset atrial fibrillation in patients with acute myocardial infarction after percutaneous coronary intervention in Scientific Reports, the TyG Index is an indicator of new-onset afib (NOAF) after recovery from a heart attack.

A paper published in the same journal found the TyG Index was effective at detecting higher risk for all-cause mortality after PCI treatment for a heart attack.

The TyG + NLR predict death from all causes

In this superlative research, the investigators found that risk prediction of death from all causes can be sharpened and rendered invulnerable to confounders by combining the TyG with the NLR (neutrophil-lymphocyte ratio). Clinicians should always be keenly observing the NLR already since it’s such an important biomarker for systemic inflammation.

”IR [insulin resistance] and inflammation are closely associated with various metabolic diseases and adverse outcomes (24, 25). NLR reflects the systemic inflammatory status of the body and has been shown to be related to poor outcomes and prognosis in several studies (26, 27). Therefore, in this study, we combined the TyG index with NLR, an indicator of the degree of inflammatory response, to construct a new index, TyG-NLR...

In our study, the TyG index showed an association with all-cause mortality before adjusting for confounders. However, this association became non-significant after adjusting for confounders, which is consistent with previous studies, demonstrating the instability of the TyG index when used alone (33). However, when we utilized the combined TyG-NLR index, our results showed that TyG-NLR was significantly associated with all-cause mortality. After adjusting for all confounders, participants in the highest quartile of the TyG-NLR index had a 1.63-fold increased risk of all-cause mortality compared to those in the lowest quartile. Additionally, we observed that participants with TyG-NLR indices in the second and third quartiles had 1.05-fold and 1.19-fold increased mortality risks, respectively, compared to those in the lowest quartile. These characteristics not only establish the TyG-NLR index as an effective tool for evaluating the risk of all-cause mortality but also further support the central role of insulin resistance and inflammation in adverse health outcomes, providing a crucial theoretical basis for future risk stratification, prediction, and intervention strategies.

…chronic insulin resistance is not only highly correlated with systemic inflammation but also leads to lipid metabolism disorders…NLR, as a sensitive indicator of systemic inflammatory status, can assess the body’s immune response capacity. Chronic inflammation may suppress normal immune function, making individuals more susceptible to infections or malignant diseases, which may directly or indirectly increase the risk of mortality. Additionally, the interaction between insulin resistance and inflammation may exacerbate tissue and organ damage and functional decline through elevated pro-inflammatory cytokines (such as TNF-α and IL-6) and oxidative stress levels, playing a critical role in the progression of various chronic diseases (36, 37).”

The TyG Index and Urinary Incontinence

Essentially, the data in this study shows that the TyG Index, stress urinary incontinence, and the CKM syndrome are all connected.

“Higher CMI was significantly associated with increased SUI risk in women (P < 0.001). RCS analysis revealed a nonlinear relationship, with a threshold at 1.64….Mediation analysis showed that the TyG index completely mediated the relationship between CMI and SUI, accounting for 97.67% of the total effect. Sensitivity analyses using PSM confirmed the robustness of these results.”

More on the association between the TyG Index and urinary incontinence:

• Associations between metabolic syndrome and female stress urinary incontinence: a meta-analysis

• Association between triglyceride glucose body mass index and urinary incontinence: a cross-sectional study from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2018

• Association between triglyceride-glucose index and its correlation indexes and stress urinary incontinence in postmenopausal women

The TyG Index - Depression, Cognitive Dysfunction, & Dementia

The authors of this paper state:

“In conclusion, our study suggests that the triglyceride-glucose (TyG) index may serve as an important indicator of psychocognitive health in older adults. The NHANES-based analysis highlights significant associations between the TyG index, depression, and cognitive function, emphasizing its potential role in identifying individuals at risk. Additionally, machine learning models demonstrated strong predictive performance, suggesting potential clinical applications for assessing depression risk.”

In this important study, the authors state:

“Insulin resistance (IR) has been proposed as a potential risk factor for depression, a major common disorder affecting a significant proportion of adults worldwide. Based on this premise, this study systematically investigated all the studies examining the triglyceride-glucose (TyG) index, a surrogate marker of IR, in patients with depression or suicidal ideas/attempts.”

Their data showed:

”The present study analyzed seven studies involving 58,981 individuals to investigate the association between the TyG index and depression. The key findings of this study implied that a high TyG index is associated with depression. Moreover, the TyG index can act as a predictor of depression-related events such as suicidal ideation and attempts.”

“In conclusion, our study provides evidence for a significant association between the TyG index and depression, supporting the hypothesis that disturbances in glucose and lipid metabolism may contribute to the rise of depression and related events, such as suicidal ideation and attempts. The TyG index holds promise as a clinically relevant tool for assessing metabolic abnormalities and identifying individuals at risk for depression and other IR-related disorders.”

More on depression and the TyG Index:

The central role of pro-inflammatory cytokines (PICs)—which are associated with the TyG Index—in depression: Pro-inflammatory cytokines in stress-induced depression: Novel insights into mechanisms and promising therapeutic strategies

• PICs affects symptom, development, severity, and treatment outcome of depression.

• PICs may be a potential biomarker of depression.

• Anti-inflammatory therapy is a promising treatment for depression.

• Regulating PICs may represent a promising therapeutic strategy for depression.

And The association between insulin resistance and depression in the Korean general population in which the authors state:

• Increased insulin resistance was associated with depressive symptoms in the Korean general population (N=165,443).

• These findings suggest that early management of insulin resistance may prevent progression toward depressive symptoms.

Higher insulin levels in response to insulin resistance are responsible for damage to the brain as well for the rest of the body. This paper unpacks the mechanisms involved.

“Insulin signaling, as well as insulin resistance (IR), is a major contributor in the regulation of mood, behavior, and cognition. Recent evidence showed that both peripheral and central insulin resistance play a role in the pathophysiology, clinical presentation, and management of neuropsychiatric disorders like Cognitive Impairment/Dementia, Depression, and Schizophrenia. Many human studies point out Insulin Resistance/Metabolic Syndrome can increase the risk of dementia especially Alzheimer’s dementia (AD). IR has been shown to play a role in AD development but also in its progression.”

“IR has been shown to precede neurodegeneration…Early identification and management of IR may help as a strategy to potentially alter neuropsychiatric disorders onset as well as its progression.”

“…insulin resistance in otherwise healthy young and middle-aged adults was found to be associated with preclinical signs of neuropsychiatric impairment (cognition and mood).”

““Insulin resistance is defined as an impaired response to insulin stimulation in peripheral tissues, which leads to increased peripheral insulin levels” [44]. Brain insulin resistance is defined as the reduced physiological actions of insulin in the brain. In the nerve cells, insulin modulate neurotransmitters like N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid (GABA) as well as catecholamines [45]. There is a bidirectional relationship between peripheral and brain insulin resistance, with each one influencing the other [17,46]. Since the pancreas is the main source of CSF Insulin levels, its level correlate with peripheral levels [47] and altered transport across BBB has been shown in IR [48]. Brain insulin resistance can induce activation of microglia and astrocyte and impair intracellular signaling leading to mood disorders and cognitive impairment [46,49] (Table 2). A decrease in the cerebrovascular cell’s cytoplasmic insulin receptors along with defective coupling are seen in BIR as well as in AD [50,51].”

This original article assesses the association of the TyG Index (indicating insulin resistance) and cognitive decline.

“Our study supports a significant association between cognitive decline and high TyG index values. We revealed the heightened risk of cognitive decline with an increased TyG index and underscored the potential diagnostic capability of this surrogate marker of IR. The assessment of the TyG index's predictive capacity for cognitive decline yielded promising outcomes and highlighted its diagnostic potential with an impressive overall AUC of 0.74, a sensitivity of 0.695, and a specificity of 0.68. Moreover, our multivariate meta-regression analysis revealed a significant association between the observed pooled estimate and the publication year, sample size, and male ratio.”

The connection reported in this research article can hardly be over-emphasized.

“Triglyceride-glucose index (TyG) is a reliable surrogate marker of insulin resistance, and insulin resistance has been implicated in Alzheimer's disease pathophysiology…This study showed that moderately elevated TyG index was independently associated with a higher incidence of Alzheimer's disease. TheTyG index might be used to define a high-risk population of Alzheimer's disease.”

In this systematic review:

“Our study found that a higher TyG index was significantly associated with an increased risk of cognitive impairment and dementia. When the TyG index was regarded as a categorical variable, the risk of cognitive impairment and dementia in the high TyG index group was 2.32 and 1.14 times higher than that in the low TyG index group, respectively. For each additional unit of the TyG index, the risk for cognitive impairment and dementia increased by 3.39 and 1.37, respectively.”

“Our study found a link between an elevated TyG index and the risk of cognitive impairment and dementia. The TyG index values can be easily obtained in clinical practice by measuring plasma glucose and TG levels. Several studies have suggested that the TyG index has the potential to serve as an indicator of cognitive impairment.”

And in this research article:

“The results of this study reveal a notable association between elevated TyG index levels and the occurrence of cognitive impairment among the elderly Chinese demographic. The initiation of targeted intervention strategies may effectively mitigate cognitive impairment, potentially decreasing the prevalence of dementia.”

The authors of this paper state:

“Compared to those with the low TyG index, subjects with the high TyG index were significantly associated with the risk of cognitive impairment…The association was consistent for Alzheimer’s disease and vascular dementia…In conclusion, a high TyG index may be associated with higher risk of cognitive impartment and dementia in adult population.”

Not surprisingly, this research article demonstrates the association of the TyG Index with brain atrophy. This is in keeping with the loss of autophagy described above.

“Insulin resistance, as indicated by a high TyG index, was associated with poor function in multiple cognitive domains and global brain atrophy.”

The TyG Index and Cancer

The TyG Index has been shown to be associated with a number of cancers. This is to be expected given how significant a biomarker it is for major drivers of malignancy: chronic inflammation and excessive growth hormone (insulin) proliferation of abnormal cells.

This research confirms:

• Insulin resistance markers TyG index and TyG-BMI index can play a predictive role in the long-term prognosis of breast cancer patients undergoing NACT [neoadjuvant chemotherapy].

• TyG and TyG-BMI show a linear correlation with disease-free survival [DFS] and overall survival by restricted cubic spline analyses.

“This study suggests that the TyG index level before NACT is an independent prognostic factor for DFS and OS and can serve as a promising biomarker to predict the long-term prognosis of breast cancer patients undergoing NACT. Moreover, the TyG index and TyG-BMI show a linear correlation with DFS and OS [overall survival].”

This research arrives at very important conclusions of great practical relevance:

“This study found that the TyG index is a risk factor for prostate cancer, and the interaction between the TyG index and different risk factors may increase the risk of prostate cancer. There is a linear dose-response relationship between the TyG index and the risk of prostate cancer, and the TyG index has a certain predictive value of the risk of prostate cancer, and the risk of prostate cancer can be reduced by controlling the levels of blood lipids and blood glucose. By controlling blood lipid and blood glucose levels, the risk of prostate cancer can be reduced.”

Remember that insulin is what drives higher triglyceride levels.

In Association of triglyceride-glucose index with the risk of prostate cancer: a retrospective study:

“Prostate cancer is the most common malignancy in men, and its incidence is increasing year by year. Some studies have shown that risk factors for prostate cancer are related to insulin resistance. The triglyceride-glucose (TyG) index is a marker of insulin resistance. We investigated the validity of TyG index for predicting prostate cancer and the dose-response relationship in prostate cancer in relation to it.”

“TyG index may be a more accurate and efficient predictor of prostate cancer.”

In this paper:

“Association between TyG index and prostate cancer may facilitate to predict unfavorable prognostic factors of radical prostatectomy. Increased TyG index may used as a predictive marker of positive surgical margin status before radical prostatectomy, BCR, advanced cT and pT stages after radical prostatectomy or worse biopsy gleason score in clinical practice.”

This paper highlights how the TyG Index reveals what is not disclosed by other biomarkers used for insulin resistance.

“The results of this study showed no associations of insulin resistance markers with the risk of clinically relevant PCa, but higher glucose and TyG index were associated with poorer survival from PCa.”

In fact, fasting glucose and HgA1c may often not reveal spiking of insulin during the day, which is why we use 1,5-Anhydroglucitol (Glycomark) as a blood biomarker for glucose instability and CGMs (continous glucose monitors) to overcome those limitations.

And in this paper in the prestigious British Journal of Cancer:

“In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01–1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14–1.35, of which 28%; 4%–52%, mediated)…Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.”

Of course, it’s insulin resistance that accelerates visceral obesity. Importantly, there can be fatty liver disease and other depredations of visceral obesity without being ‘fat’.

Clinical Notes

How to calculate the TyG Index? To do it manually, it’s TyG index = Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL) / 2]. But who wants to do that? Instead, there are a number of online medical calculators. The TyG Index calculator I use is here.

‘Moving the ball’ in case management including the TyG Index and what drives it is a complex matter and addressed on an individual basis. But because it’s often overlooked, the role of the vitamin D effect is worth mentioning here.

“The results demonstrated that the TyG index was positively associated with all-cause and cardiovascular mortality in diabetic patients, whereas vitamin D levels were negatively associated with mortality, exhibiting an overall U-shaped association. The results indicated that vitamin D partially mediated the association between TyG and all-cause mortality…

This finding underscores the necessity of evaluating the influence of vitamin D on survival outcomes in individuals with disparate levels of the TyG index.”

Note: It’s not enough to know the serum level of 25-OH Vitamin D which, for the purposes of immune system and metabolic health should be in the upper end of the reference range. Because of genetic variations in sensitivity of the VDR (vitamin D receptor) and the binding affinity of DBP (vitamin D binding protein), these must be evaluated by observing 25-OH Vitamin D, 1,25-OH Vitamin D, and PTH (parathyroid hormone) in the same serum specimen.

Cognitive age was calculated to be 6.7 years younger among those who drank the most coffee compared to those who drank the least (not popular coffee-based drinks with added sugar).

Previous research has shown that coffee can be well tolerated, even helpful, for afib (see Coffee helps atrial fibrillation with high blood pressure) and abstaining from coffee does not benefit*. Since afib can be a cause of cognitive impairment, the authors of a study published in the Journal of the American Heart Association determined to see if coffee could benefit cognition in afib.

“Atrial fibrillation is an independent risk factor for the development of cognitive impairments. Regular coffee consumption has shown cognitive benefits in healthy individuals. Whether regular consumption reduces cognitive decline in vulnerable patients is controversial. We investigated the association in elderly people with atrial fibrillation.”

The lead author was quoted in Technology Networks Applied Sciences:

““The most frequent cardiac arrhythmia, atrial fibrillation, is known to independently increase the risk of dementia,” said Massimo Barbagallo, M.D., lead author of the study and a resident in the neuro intensive care unit at the University Hospital Zürich. “Thus, the question is whether coffee might offset the increased risk of cognitive impairment in people with AFib.”

The investigators combined an array of neurocognitive tests to construct an overall cognitive performance indicator. Consumption of less than one cup per day was the reference group, while the highest intake group was more than five cups per day. More coffee was clearly best.

“The <1 cup/day consumers (reference group) reached a cognitive construct score of −0.24, and the group with the highest consumption (>5 cups/day) was at −0.10. Montreal Cognitive Assessment score in the reference group was 24.58 ; the group with the highest intake achieved 25.25.”

Coffee also reduced inflammation

The authors included two key biomarkers of inflammation in their assessment, hs‐CRP (high‐sensitivity C‐reactive protein) and IL‐6 (interleukin‐6). Both showed improvement with higher coffee consumption.

Inflammatory markers decreased with higher coffee consumption (hs‐CRP with 5 compared with <1 cup/day by factor 0.78, IL‐6 significantly by factor 0.73.

It makes sense that reducing inflammation and cognitive impairment would occur together.

The authors conclude:

“Coffee consumption in patients with atrial fibrillation may be associated with improved cognitive performance and reduced inflammatory markers. Further research is needed to confirm these findings and to consider implementation in dietary counseling for atrial fibrillation management.”

* “Atrial fibrillation is the most common heart rhythm disorder in adults, affecting more than 5 million people in the U.S., according to the American Heart Association. The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation noted that abstaining from caffeine to prevent heart rhythm disturbances is of no benefit to people with AFib,” also noted in Technology Networks Applied Sciences.

N-terminal pro–B-type natriuretic peptide (NT-proBNP, also a key biomarker for diagnosing heart failure), easily included in a routine blood test, when elevated shows a nearly fourfold increase in risk for atrial fibrillation in at-risk populations.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is commonly used in clinical practice to detect abnormalities in cardiac function, especially heart failure. A systematic review recently published in the journal Heart (the international peer reviewed cardiology journal, the the flagship of BMJ's cardiology portfolio and an official journal of the British Cardiovascular Society) showed that NT-proBNP serum testing can be used to detect risk for afib (atrial fibrillation).

The authors note:

“N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in clinical practice…This meta-analysis aimed to evaluate the association between NT-proBNP levels and AF incidence, and to explore the potential of NT-proBNP in enhancing AF risk prediction models.”

Their analysis of searched databases (PubMed, Embase, Cochrane Library, Web of Science and Scopus) up to August 2024 included 136,089 participants from 16 cohorts, with 8017 incident AF cases, showed a strong relationship:

“Elevated NT-proBNP levels were associated with a higher risk of developing AF... A significant non-linear dose-response relationship was observed, and stronger associations were noted in older populations and when serum samples were used.”

The risk increased by 9% for each 10 pg/mL increase in NT-proBNP.

The study had documented limitations, but the authors conclude:

“NT-proBNP levels are strongly associated with an increased risk of AF, particularly in older adults. Incorporating NT-proBNP into risk prediction models may enhance early identification of individuals at risk of AF, with potential implications for population-based screening…”

The ketogenic diet is a medical diet that can improve certain conditions and, for some people, promote weight loss. But it should be managed on an individual basis and applied intermittently with breaks.

The ketogenic diet, high in fat and low in carbohydrates causes the body to break down fat into molecules called ketones. These become the main source of energy for many cells in the body. A ketogenic diet has been recognized for years to be helpful in some forms of treatment resistant epilepsy. (This was assumed to be due to a neuronal stabilizing effect, but more recent research suggests the mechanism may be changes in the gut microbiome.) The drop in insulin triggered by the ketogenic diet can also be beneficial for a number of conditions. But research just published in Science Advances (AAAS) shows that the ketogenic diet can also backfire if administered without sufficient care.

The authors note:

“Multiple publications provide evidence that the primary ketone produced in ketogenesis, β-hydroxybutyrate (β-HB), may be anti-inflammatory (14, 66), suggesting that this could play a mechanistic role in the beneficial effects of KDs (8, 10). In contrast, others have shown KDs are pro-inflammatory and lead to organ disorders, including cardiac fibrosis and kidney damage (15–19, 67)…””

Keto diet effects are complex and can cause cellular senescence

This study adds to the evidence that a prolonged ketogenic diet can induce cellular senescence, a form of aging in which the cell is in a state of irreversible growth arrest but can still promote chronic inflammation throughout the body. The authors of this study used enzyme-linked immunosorbent assay (ELISA) to measure biomarkers of the SASP including tumor necrosis factor–α (TNFα), interleukin-1β (IL-1β), and IL-6, important pro-inflammatory signaling agents.

“Senescent cells can adversely affect adjacent cells and the tissue microenvironment by secreting pro-inflammatory cytokines (37)…While these cytokines are produced by various cells and have pleiotropic effects, they are frequently produced by senescent cells and have been shown to be pro-inflammatory (61). All were significantly increased in mouse sera following a 21-day KD (Fig. 6A). We also found similar up-regulation of SASP [senescence-associated secretory phenotype] biomarkers in the heart, kidney, and liver tissue samples collected after 7- and 21-day KDs (fig. S6, D to F).”

These effects are independent of age:

“All mice, regardless of age, showed a significant increase in p53, p21, and SA-β-gal [promoters of senescence] in both heart and kidney tissue on KD, compared to age-matched controls (Fig. 7, A to F), and comparable to mice starting the 21-day KD at 6 weeks of age.”

Interestingly, they also demonstrated that the effects were independent of the form of fats used:

“These data support that cellular senescence can be induced by sustained KD, independent of age or lipid composition, and is not an artifact of reduced dietary protein.”

Translation to humans subjects

These findings were replicated in human subjects:

“We next examined the relevance of these observations to humans by analyzing plasma samples from a published clinical trial by our institution (62) in which patients of varying age, sex, and health condition were assigned to a KD, with fasting blood samples collected at the start of the trial (baseline) and after 3 and 6 months. Patients in this trial were monitored to confirm that they were in ketosis (62). In both male (Fig. 6B) and female patients (Fig. 6C), samples obtained after 6 months KD showed a significant increase in both TNFα and IL-1β compared to baseline. We saw a similar trend in IL-6, with a significant increase in female patients after 6 months KD (Fig. 6C). In contrast, there was no change or only a modest increase in these pro-inflammatory biomarkers after 3 months on KD. These data support that a long-term KD can induce SASP in humans of varied age, sex, and health, similar to what we observed in mice on a 21-day KD.

It appears to be the lipids, not the ketones, that are responsible.

“Last, we used a NIH 3T3 cell culture model that suggests it may be the increased lipids or lipoproteins, rather than the increase in ketone levels, that play a role in p53-induced cellular senescence on a KD (fig. S8A).”

Ketogenic diet benefit or harm is influenced by multiple factors

“It is increasingly evident that the effects of a KD are complex, and the health-related outcomes of its use likely depend on multiple factors (65). Some of the conflicting reports appear to revolve around whether a KD is pro- or anti-inflammatory. Multiple publications provide evidence that the primary ketone produced in ketogenesis, β-hydroxybutyrate (β-HB), may be anti-inflammatory (14, 66), suggesting that this could play a mechanistic role in the beneficial effects of KDs (8, 10). In contrast, others have shown KDs are pro-inflammatory and lead to organ disorders, including cardiac fibrosis and kidney damage (15–19, 67) perhaps due to the increase in lipids or lipoproteins, which have been shown previously to be detrimental (68). An important study suggests that diet duration may be key in determining this outcome by showing a short-term KD improved murine metabolism through activation of tissue-specific resident immune cells, while a long-term continuous KD induced systemic inflammation, obesity, and glucose intolerance (9).”

Duration of the ketogenic diet may be the key

The good news is that the ketogenic diet-induced cellular senescence is time-dependent and reversible, and that an intermittent ketogenic diet (IKD) does not induce cellular senescence. Moreover:

“An important study suggests that diet duration may be key in determining this outcome by showing a short-term KD improved murine metabolism through activation of tissue-specific resident immune cells, while a long-term continuous KD induced systemic inflammation, obesity, and glucose intolerance (9).”

This has great practical significance:

“Several recent studies have reported benefits from various IKD protocols. An alternate-day KD improved cardiac function in a murine model of heart failure (64), while an alternate-week KD reduced midlife mortality, age-related memory loss, and other health issues in male mice (10). To evaluate whether an IKD would avoid p53 activation and cellular senescence, we placed mice on alternating 4-day KD and 7-day standard diet for three cycles (IKD), a 31-day KD (positive control), or a standard diet (negative control). In contrast to the sustained KD, the IKD did not increase p53 or cellular senescence (Fig. 8, G and H, and fig. S8, D and E), nor did IKD increase SASP biomarkers in the tissues (fig. S8, F and G). These data potentially have important clinical application because they suggest that IKD may have fewer side effects than sustained KD while still potentially having a positive influence on health-related end points (10, 64).”

Summary of clinical implications

“Because we observed that these changes in key organs such as the heart and kidneys, where the accumulation of senescent cells can contribute to systemic inflammation and toxicity (3, 18, 19), we believe that they have important clinical implications. In this regard, two publications showed a long-term KD promoted cardiac fibrosis and dysregulated mitochondrial function, due to chronic inflammation (18, 67)… Furthermore, it was recently published that KD-fed mice develop hepatic injury, steatosis, inflammation, glucose intolerance, and insulin resistance (22). In light of all these data and that our mice on a KD also showed reduced glucose tolerance, it could be hypothesized that metabolic dysfunction on a KD may lead to increased cellular senescence in specific conditions. There is an increasing consensus that the buildup of senescent cells, whether by increased induction or impaired clearance, contributes to age-related diseases and even aging itself (28, 29, 60, 69). Our analyses of SASP pro-inflammatory cytokines in patients suggest that cellular senescence may also be associated with sustained KD in humans.”

Intermittent application of the ketogenic diet is a crucial point:

“Our study showed that an IKD can prevent the accumulation of senescent cells induced by sustained KD. This observation builds on that of others (10, 64), suggesting that an IKD may be more beneficial than a long-term continuous KD, perhaps by avoiding eventual pro-inflammatory activation (9). These data may be of clinical relevance because it could be surmised that the accumulation of senescent cells in children on a continuous KD, as used for refractor seizures, could play a role in the documented long-term side effects (71–73)… Our results showed a significant reduction in p53, p21, and SA-β-gal after returning to a normal diet for 1-week, suggesting an IKD may be a potential alternative clinical intervention to a continuous KD.”

An alternate week or alternate day application may be better and easier.

“An IKD could be especially relevant in the clinic, as this type of KD may be easier for patients to adhere to and could potentially offer many of the benefits of weight loss and improved health parameters without the risk of cellular senescence from sustained KD. In this regard, both an alternate-day and an alternate-week IKD have been reported to improve health parameters over a continuous KD in different murine models (10, 64), while a third study using a 3-day/week IKD reported attenuated improvements relative to continuous KD (74). Further research is clearly needed to determine whether and for what conditions an IKD could be beneficial in humans, as well as the optimum regimen.”

The authors conclude with a sound recommendation:

“The results of our in vivo murine experiments in this study, as well as those from other laboratories, reinforce that the effects of KD are complex, with both potential benefits and side effects likely due to multiple factors, including the timing, composition of the diet and the genetics, endocrine factors, and health conditions of the individual. As such, it is proposed that the use of a KD should be considered within the overall scope of personalized medicine, where the variables for each patient are taken into consideration to determine who will, and who will not, benefit from this dietary intervention as well as the specific regimen to follow.”

“Our findings point to an at-risk population that may warrant early intervention and prevention efforts to reduce cardiovascular and neurocognitive risk at midlife and beyond.”

Research recently published in JAMA Network Open / Psychiatry titled ‘Posttraumatic Stress Disorder Symptoms and Cardiovascular and Brain Health in Women’ reports on a study involving a large, well-characterized community sample of midlife women that draws attention to the adverse effects of chronic inflammation generated by unresolved trauma. As the authors note, this issue concerns a large percentage of the population:

“Cardiovascular disease (CVD) and Alzheimer disease (AD) are major women’s health issues. CVD is the leading cause of death among US women, with 45% of women developing CVD in their lifetime.1 AD is the fourth leading cause of death among US women.2 Furthermore, approximately two-thirds of individuals with AD and related disorders are women.3….

Most women in the US will experience at least 1 major traumatic event in their life,4 and 10% will develop PTSD. Women have double the risk of PTSD relative to men.5 PTSD is associated with a 50% to 60% increased risk of incident CVD and elevated stroke and dementia risk.

The significance of menopause

They draw attention to the complications of menopause which fortifies my conviction of the importance of thorough testing of postmenopausal hormone and hormone metabolite levels.

“Midlife is a critical time for women’s cardiovascular and brain health, as it occurs directly before the onset of clinical CVD12 and is when initial hallmarks of AD and related disorders (eg, amyloid β, hyperphosphorylated tau) begin.13 Midlife includes menopause, a time of accelerating vascular risk,14 decreased memory,15 and potential emergence of effects of earlier stress exposure.16.”

And few studies prior to this one have considered unresolved PTSD in tandem with the effect of the APOEε4 genotype which increases the risk for poor cardiovascular health, cognitive decline, and dementia.

Accelerated brain and vascular degenerative changes

Evaluation of the 274 community-based women ages 45 to 67 years without a history of CVD, stroke, or dementia included questionnaires (PTSD Checklist–Civilian Version), physical measures, phlebotomy, neuropsychological testing, a carotid ultrasonographic examination, and 3-Tesla brain magnetic resonance imaging.

“We tested whether higher PTSD symptoms would be associated with higher carotid IMT, greater brain white matter hyperintensity (WMH) or volume (WMHV), and poorer cognition among midlife women who underwent vascular imaging, neuroimaging, and a comprehensive neuropsychological battery.

Carotid IMT, or ultrasonographically assessed thickness of the intimal and medial layers of the carotid artery, is an established subclinical CVD indicator associated with future CVD events and useful for assessing cardiovascular health among midlife women among whom other subclinical indicators (eg, coronary calcification) may lack sensitivity.20,21

WMHs are lesions in the [brain] white matter apparent on magnetic resonance imaging (MRI) that reflect, in part, small vessel disease and are linked to later dementia, cognitive decline, and mortality.22

Collectively, IMT and WMHs help identify women at risk for future disease. Furthermore, we tested a modifying role of the APOEε4 genotype, hypothesizing that women who were APOEε4 carriers would be at particularly elevated cardiovascular and neurocognitive risk with PTSD symptoms.”

PTSD symptoms → adverse cardiovascular and neurocognitive outcomes

They found that women with greater PTSD symptoms had higher carotid intima and media thickness which persisted when controlling for other CVD risk factors. Interestingly, associations between PTSD and IMT did not significantly vary by APOEε4 status.

For brain lesions (white matter hyperintensity on MRI), interactions between PTSD symptoms and APOEε4 status were observed in the primary outcome of whole-brain WMHV, as well as periventricular and parietal WMHV in multivariable models. Among women who were APOEε4 carriers, PTSD symptoms were associated with greater whole-brain, periventricular, deep, and frontal WMHV.

They determined that:

“In this cross-sectional study among midlife women, higher PTSD symptoms were associated with greater carotid atherosclerosis. Furthermore, among women who were APOEε4 carriers, PTSD symptoms were associated with greater WMHV (whole brain, periventricular, deep, frontal) and poorer cognitive performance across multiple domains. These findings point to the adverse outcomes associated with PTSD symptoms for cardiovascular and neurocognitive health at midlife, particularly for women who are APOEε4 carriers.”

They further concluded:

“The findings of this cross-sectional study underscore the important implications of PTSD and its symptoms for women’s cardiovascular and brain health, with women who were APOEε4 carriers particularly at risk. PTSD is a major women’s health issue, affecting 10% of women in their lifetime. Our findings point to an at-risk population that may warrant early intervention and prevention efforts to reduce cardiovascular and neurocognitive risk at midlife and beyond.”

For how unprocessed trauma generates inflammation from the central nervous system throughout the body and the profound benefits of Brainspotting, see Stress-linked mental disorders, systemic inflammation, and Brainspotting.

Traumatic or emotionally charged experiences can get ‘stored’ in our nervous system, leading to emotional distress and physical symptoms. When physiological or emotional issues remain unprocessed, we can become stuck in a maladaptive biological and/or cognitive-emotional homeostasis. Brainspotting activates the trauma or stress-related emotions, and memories that persist in the deeper, subcortical brain in a way that permits spontaneous processing and resolution.

An insightful paper, Central regulation of stress-evoked peripheral immune responses, just published in the respected journal Nature Reviews Neuroscience (Volume 24 | October 2023 | 591–604) is an excellent introduction to how Brainspotting works within the functional medicine model to ameliorate the stress-driven biological dysfunction resulting from unprocessed trauma and other chronic stress. The authors note:

“Contemporary neuroscientists now have a growing understanding that psychological states can indeed impact physiological processes in the periphery such as metabolism, host defence and cardiovascular function . In turn, somatic states are sensed by the CNS to shape and guide behaviour . Underlying many of these processes are cells of the immune system, which have diverse inflammatory and regulatory roles and are embedded in all tissues throughout the body.”

They add specific detail to how the specific neuronal populations involved in the brain-to-body circuits regulate immune system responses.

“Here, we review the current literature to discuss how a negative affective state brought upon by psychological stress can control peripheral immunity. Specifically, we highlight stress-responsive brain regions that innervate immunologically relevant tissues, such as the bone marrow, spleen, gastrointestinal tract, adipose tissue and liver, largely through the autonomic nervous system and hypothalamic-pituitary–adrenal (HPA) axis.”

The immune cells distributed throughout the body respond in ways that contribute to the stress-relevant disorders such as anxiety and depression in a mutually interacting feedback loop:

“In addition, we address how immune cells in these tissues respond to stress and how these responses contribute to physiological and behavioural changes associated with stress-relevant psychiatric disorders such as anxiety and depressive disorders. These studies reveal a feedback loop between the nervous and immune systems that becomes hijacked during chronic stress to propagate psychiatric illness and inflammatory co-morbidities.

The link between chronic stress and inflammation

It’s become increasingly recognized that individuals with trauma or stress-related disorders show signs of chronic, non-resolving inflammation, the common denominator of most chronic diseases. This can show up in ways that include elevated pro-inflammatory cytokines, dysregulated myelopoiesis and lymphopoiesis (immune cell formation), and disruption of the body barrier systems including the gut epithelium and blood–brain barrier; and more.

“A pivotal study in 1987 reported that a subpopulation of people with viral hepatitis treated with interferon-α (IFNα; a pro-inflammatory anti-viral cytokine) developed depression, demonstrating that a pro-inflammatory molecule in the periphery could directly influence mood. Consistent with this finding, individuals with prior hospitalizations for infections or autoimmune diseases display greater odds of subsequently developing depression, with multiple infections having additive effects.”

“…animals that are exposed to chronic stress are predisposed to the development of inflammatory conditions such as experimental autoimmune encephalitis, colitis, atherosclerosis and diabetes. Thus, the experience of psychological stress — independent from any prior or concurrent immune challenge — exerts whole-body immunomodulatory activity, provoking inflammation and vulnerability to inflammatory diseas..”

Brain-to-body neurocircuits

The authors detail brain-body regulating loops including brain-to-bone marrow, brain-to-spleen, and brain-to-gut neurocircuits that have substantial effects on inflammation and mood. The first two directly influence the formation and type of white blood cells produced, while it’s hard to think of anything that brain-gut dysregulation doesn’t potentially affect.

“Our systematic review and meta-analysis suggests that phototherapy is a promising intervention, as it can improve cognitive function in older patients with dementia…further well-designed studies are needed to explore the most effective clinical implementation conditions, including device type, duration, frequency, and time.”

Special role of the gut

It’s well-known that the gastrointestinal system with its bulk of immune tissue and the enteric nervous system (the “gut brain”) has a tremendous influence on other systems in the body and a big impact on the brain, including mood, and inflammation.

“With constant exposure to pathogenic and food-related antigens and as the home of many lymphoid follicles, the gastrointestinal tract represents another immunologically relevant tissue that is sensitive to stress. Substantial research has investigated the communication between the central and enteric nervous systems (also known as the gut–brain axis) and its impact on local and systemic inflammation…

Growing evidence suggests that chronic stress impairs healthy gastrointestinal function presenting as dysregulated intestinal motility, dysbiosis of the microbiota and initiation of low-grade inflammation.”

Clinicians and the informed public will recognize the vital role of the vagus nerve in regulating these systems.

The brain and immunometabolism

Insulin resistance, hyperglycemia, weight gain and aberrant appetite are all susceptible to the effects of stress and unprocessed trauma.

“Metabolic dysfunction is another common consequence of chronic stress in both humans and animals, with significant co-morbidity existing between MDD and metabolic syndrome . Moreover, metabolic inflammation — leukocyte infiltration and pro-inflammatory signalling in insulin-responsive tissues — promotes systemic hyperglycaemia…

Both chronic stress and metabolic syndrome have also been associated with hepatic steatosis and markers of liver inflammation such as macrophage infiltration and expression of stress-relevant brain regions…chronic psychosocial stress dampens orexin signalling in the brain, leading to hepatic inflammation, macrophage infiltration, hyperglycaemia, and depression-like and anxiety-like behaviour. From the LH [lateral nucleus of the hypothalamus], these effects may be exerted through parasympathetic neurons in the DMV [dorsal motor nucleus of the vagus] as LH orexin neurons project to the DMV and parasympathetic input from the vagus nerve dampen hepatic inflammation.”

Unresolved stress and immunosuppression

Chronic, unresolved stress due to trauma or other factors renders us more susceptible to opportunistic and chronic infections.

“While acute stressors or infections activate the HPA axis, which stimulates the immune system to facilitate the clearance of pathogens, chronic stress has immunosuppressive effects. This exemplifies how stress is a context-dependent adaptation that is necessary for the body to appropriately respond to threats but becomes maladaptive and pathological when left unresolved…It is hypothesized that chronic stress leads to persistent activation of the HPA axis, resulting in glucocorticoid resistance and subsequent over-production of pro-inflammatory cytokines and impairment in adaptive immune responses. Together, these maladaptations worsen the outcomes of infectious disease.”

“These studies demonstrate bi-directional communication between the brain and body, whereby chronic stress suppresses host defence against pathogens and these infections subsequently activate brain regions that promote anxiety-like or depression-like behaviour.”

Brainspotting and its profound value in Functional Medicine

Our bodies and brains are trying the best they can to keep functioning in the face of a multitude of adversities. Homeostasis is the biological drive to maintain a stable equilibrium. When physiological or emotional issues are unable to be fully resolved, we can become stuck in an adaptation that entrenches unresolved issues—a maladaptive biological and/or cognitive-emotional homeostasis. The intent in functional medicine is to migrate the system from this entrenched, maladaptive biology to a healthier one. It entails recognizing the strong bidirectional relationship between the emotional and physical systems in the body. Emotional distress can manifest as physical symptoms and physical symptoms can exacerbate emotional distress. This interplay can create a cycle of symptoms that is difficult to break without addressing unprocessed trauma.

Trauma can have profound and lasting effects on both the brain and the body, and caring for these mechanisms can be necessary for a comprehensive approach to patient care, especially in the bioconscious functional medicine model.

Biological effects of unprocessed trauma

1. Stress Response and the HPA Axis: Trauma can trigger the body's stress response, leading to the dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and a chronic stress response. This results in the release of stress hormones like cortisol. Chronic activation of the HPA axis due to unresolved trauma can drive stress chemistry with widespread biological consequences including immune disorders, hormonal imbalances, muscle tension, pain, and gastrointestinal disturbances.

2. Dysregulation of the Autonomic Nervous System (ANS): Traumatic experiences can lead to a dysregulation of the autonomic nervous system (ANS), which controls all involuntary bodily functions such as heart rate, digestion, and breathing. When someone experiences trauma, the ANS can become overactive or underactive, leading to a range of physical symptoms.

3. Inflammatory Response: Unprocessed trauma can promote chronic inflammation in the body. The continuous activation of the stress response system can increase the production of pro-inflammatory cytokines. Prolonged inflammation is associated with various biological disorders, including cardiovascular disease, metabolic disorders like diabetes, and autoimmune conditions.

4. Altered Brain Structure and Function: Trauma can cause structural and functional changes in the brain, particularly in regions such as the amygdala, prefrontal cortex, hippocampus, and persistent subcortical activation. These changes can affect emotional regulation, memory processing, and the ability to cope with stress. Altered brain function can contribute to mental health disorders like depression, anxiety, and post-traumatic stress disorder (PTSD), which in turn can impact physical health through mechanisms such as sleep disturbances, appetite changes, and reduced physical activity.

5. Immune System Dysfunction: Trauma can impair the functioning of the immune system. Stress hormones like cortisol suppress innate and Th1 lymphocytes (white blood cells), making individuals more susceptible to infections, impair cancer surveillance, and promote autoimmunity and autoinflammatory disorders including chronic low-grade inflammation. It can also increase susceptibility to infections, allergies, and autoimmune diseases.

6. Somatization: What’s in the brain is in the body and vice versa. Unprocessed trauma can express as functional physical symptoms associated with a wide array of disorders and altered pain perception, often an unconscious process. These symptoms can include headaches, fatigue, and gastrointestinal issues.

7. Altered Pain Perception: Trauma can affect the perception of pain. Some individuals may have a heightened sensitivity to pain, while others may be less aware of pain. This altered pain perception can contribute to somatic symptoms and disorders.

8. Psychological Factors and Unhealthy Coping Mechanisms: Unprocessed trauma can lead to persistent psychological distress which can indirectly affect physical health by disrupting sleep patterns, appetite, and overall well-being. We may turn to unhealthy coping mechanisms, such as substance abuse or overeating, to deal with emotional distress. These behaviors can contribute to the development of biological disorders.

9. Epigenetic Changes: Emerging research suggests that trauma can alter gene expression patterns. These changes may even increase the risk of various health conditions being passed down to future generations since epigenetic modifications can be hereditary.

In summary, trauma that has not been fully processed can have deep effects on the body's biological systems. Chronic activation of the stress response, alterations in brain structure and function, immune system dysfunction, epigenetic modifications, and unhealthy coping strategies can all contribute to the development or exacerbation of biological disorders. In the functional medicine model, it's necessary to consider the impact of unresolved trauma when diagnosing and treating patients for comprehensive and effective care.

Brainspotting to resolve unprocessed trauma

Brainspotting is a therapeutic approach developed by Dr. David Grand in 2003 and has grown in resources and effectiveness since then. It has gained popularity in the field of trauma therapy and has been found effective for various psychological and brain-body connection issues.

How Does Brainspotting Work?

1. The Brain-Body Connection: Brainspotting is based on the understanding that our brains and bodies are interconnected, and that our eye positions can help access and process unprocessed trauma, emotions, and memories in the brain. Traumatic or emotionally charged experiences can get stored in our nervous system, leading to emotional distress and physical symptoms. The central concept is that there are "brainspots" in our field of vision which are connected to specific emotional or physiological experiences. These spots are activated when we focus our gaze on them.

2. The Visual System: Brainspotting recognizes the relationship between our visual system and our brain's processing of emotions and memories. The human brain has a vast network of connections between the visual cortex (responsible for processing visual information) and the limbic and subcortical systems (involved in regulating emotions, memory, and their somatic manifestations). It draws on the concept that specific eye positions can activate different neural networks and access deep emotional and traumatic material.

3. Identification of Brainspots: In a Brainspotting session, the practitioner helps you identify what are known as "brainspots." These are specific points in your visual field that are associated with your emotional or traumatic experiences, corresponding to a specific issue, trauma, or emotion. These spots are linked to the activation of subcortical neural networks related to those experiences.

4. Focused Attention: The practitioner guides you in maintaining focused attention on the brainspot while simultaneously being aware of your bodily sensations, thoughts, and emotions. This sustained focus allows for deep processing of the stored trauma or emotional distress.

5. Dual Attunement: One of the unique aspects of Brainspotting is the concept of "dual attunement." This means that both you and the practitioner are attuned to your inner experiences during the session. The practitioner observes your non-verbal cues and helps you navigate your emotions without requiring you to verbally describe them (you are free to remain silent or express whatever you wish).

6. Processing and Integration: As you maintain your focus on the brainspot, your brain is activated to process and integrate the traumatic or distressing memories, emotions, and sensations. This can lead to the release of stored tension, new insights, and a reduction in emotional distress. Brainspotting aims to promote the integration of these experiences into your psyche, fostering healing and growth.

The exact neurological mechanisms at play are still the subject of ongoing research. The field of neuropsychology is continually advancing, and our understanding of how therapies like Brainspotting affect the brain may become clearer with further research and exploration. See Brainspotting: Recruiting the midbrain for accessing and healing sensorimotor memories of traumatic activation and Brainspotting: Sustained attention, spinothalamic tracts, thalamocortical processing, and the healing of adaptive orientation truncated by traumatic experience.

Benefits of Brainspotting

1. Effective for Trauma: Brainspotting has been particularly effective in treating trauma-related issues, such as post-traumatic stress disorder (PTSD), without requiring detailed verbal recounting of traumatic events.

2. Neuroplasticity: change from Brainspotting is based on the concept of neuroplasticity, which is the brain's ability to reorganize and form new neural connections throughout a person's life. The therapeutic process is believed to tap into this capacity for change by helping the brain reprocess and reframe traumatic or emotionally charged experiences through the identified brainspot, by which the brain may gradually reorganize itself, leading to symptom relief and emotional healing.

3. Deep Emotional Processing: Brainspotting can access and process emotions and memories that may be difficult to reach through traditional talk therapy because unprocessed trauma is ‘stored’ at the subcortical level, deeper than the verbal cerebral level. It allows for a deeper activation of subconscious material and allows access to early, preverbal phenomena. It taps into the brain's natural healing mechanisms.

4. Reduction in Symptoms: Many patients report a significant reduction in symptoms like anxiety, depression, and PTSD after Brainspotting sessions.

5. Reduced Re-traumatization: Because it doesn't require you to verbalize traumatic experiences, it can be less re-traumatizing compared to some other therapies.

6. Faster Results: Some individuals have reported quicker and more lasting results with Brainspotting than with traditional talk therapy, which may take longer to uncover and address underlying issues.

7. Individualized Approach: Brainspotting is highly individualized, adapting to your unique experiences and needs. The practitioner maintains a discipline of refraining from imposing interpretations or analyses.

How Brainspotting can be adjunctive to or preferable to verbal therapy

While verbal therapy, such as cognitive-behavioral therapy (CBT) or psychoanalysis, is valuable and effective for many people, Brainspotting can be superior in certain situations:

1. Limited Access to Subcortical Regions: While talk therapy can provide valuable insight and cognitive restructuring, it may have limited direct access to the subcortical regions where traumatic memories are often stored. Processing preverbal trauma through talk therapy may rely on the individual's ability to create a verbal narrative from nonverbal experiences.

2. Less Verbal Pressure: Some individuals struggle to express their emotions or find talking about their problems difficult, Brainspotting offers an alternative, non-verbal way to access and address these issues.

3. Physical Manifestations: When emotional issues manifest primarily as physical symptoms or sensations, Brainspotting can be particularly effective in addressing both the emotional and physical components simultaneously without relying on verbal communication.

4. Faster Progress: The focused approach of Brainspotting can lead to faster therapeutic progress, especially for trauma-related issues. 

5. Less Emotional Labor: For those who find it emotionally taxing to repeatedly discuss traumatic experiences in verbal therapy, Brainspotting can offer relief.

6. Unique Experience: Brainspotting offers a unique therapeutic experience that can complement traditional talk therapy or stand alone as a powerful approach when indicated.

It's essential to note that the effectiveness of Brainspotting, like any therapy, depends on the individual and their specific needs. In many cases, a combination of Brainspotting and traditional talk therapy can be desirable. The two approaches can complement each other; Brainspotting can help individuals access and process subcortical trauma, while talk therapy can provide cognitive understanding and support for integrating these experiences into one's overall narrative.

For a brief and highly digestible video introduction to Brainspotting see Brainspotting Therapy - Developed by David Grand (PhD) - A sketch animation by Dr Mark Grixti.

Brainspotting and Primal World Beliefs

Primal world beliefs, or “primals” for short, are extremely basic beliefs about the world as a whole, such as the belief that the world is dangerous. Our primal world beliefs impact us constantly and influence health, depression, success, optimism, well-being, extroversion…most life outcomes people care about. Maladaptive primal beliefs could be a consequence of trauma, but primals may be installed when there is no remembered or suspected acute trauma, elicited by experiences that are never identified. It is particularly significant to note that primals are very durable—research has shown that they tend not to be changed by dramatically negative or positive experiences.

All primal world beliefs are:

• Stable: Primals can change but in practice they are as stable across time as personality traits like extraversion. This means many people likely spend decades holding the same world beliefs.

• Hidden: Primals are not that related to demographic factors. For example, people who are rich do not see the world as more abundant than people who are poor. Men don’t see the world as safer than women. This means you can’t tell someone’s primals by looking at them.

• Correlated: Primals are correlated to how we live our lives and our mental health. For example, Safe world belief is very strongly correlated to trust and less depression. Enticing is very strongly correlated to curiosity, gratitude, and happiness. Alive is strongly correlated to spirituality and having purpose in life. This means that, across a wide range of behaviors, humans act rationally given their primals.

Primal world beliefs do not presuppose a history of traumatic events, but maladaptive primals may have negative health consequences comparable to the chronic stress of unresolved trauma and may likewise be accessible to remediation by Brainspotting.

Focus on relative risk coupled with insufficient disclosure of absolute in the reporting of randomized controlled trial outcomes misleads healthcare providers and the public to overestimate concerns about high cholesterol and the benefits of cholesterol-lowering therapy.

An important paper, Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy, recently published in the Cureus Journal of Medical Science presents how the use of statistics obscures the correct import of RCT (randomized controlled trial) outcomes, inflating the risk of having high cholesterol and the amount of benefit from treatment to lower cholesterol levels.

The disturbing problem of credibility in general

The authors note that skepticism over the credibility of much published research in all areas is warranted.

“Richard Horton, editor of the Lancet, expressed the opinion that “much of the scientific literature, perhaps half, may simply be untrue” [1]. A similar sentiment was expressed by John Ioannidis, professor of medicine, epidemiology, and population health at Stanford, who stated, “There is increasing concern that in modern research, false findings may be the majority or even the vast majority of published research” [2]. Marcia Angell, former editor of The New England Journal of Medicine (NEJM), disclosed, “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines” [3]. The skepticism over the credibility of much of the published research may have occurred, in part, from decades of misleading presentations of research findings by clinical trial directors.”

In this paper, the authors focus on how a key aspect of data analysis has been used by trial directors to obscure the objective findings to promote their agenda:

“While these eminent leaders of medical establishments have lamented over a range of flaws in the conduct of medical research, we have focused on one aspect of data analysis that has been deployed by many trial directors to promote their agenda, rather than to present their findings in the most objective manner possible. Specifically, directors have deployed a statistical strategy that can amplify a modest benefit of drug treatment to appear as if the effect is of great clinical significance. This statistical strategy focuses on the use of relative risk (RR) reduction and the exclusion or minimization of absolute risk (AR) reduction, which are two different ways to express the same raw data.”

For example, if 2 per cent mortality occurs in the placebo group and 1 per cent in the treatment group, a 50 per cent relative mortality reduction sounds great, but the absolute mortality reduction that has actually occurred is only 1 per cent, which is clinically trivial.

“Skolbekken [5] also illustrated this issue…in his critique of how the benefits of cholesterol-lowering therapy had been portrayed. The following is our summary of the data from hypothetical studies in his research: In one randomized controlled trial (RCT), 2,000 people die out of 10,000 in a placebo group, and 1,000 people die out of 10,000 in a treated group, resulting in an AR reduction of 10% (1,000/10,000=10%). In another RCT, two people die out of 10,000 in a placebo group, and one person dies out of 10,000 in a treated group, resulting in an AR reduction of 0.01% (1/10,000=0.01%). Despite the vast difference in the ARs between the two studies (10% and 0.01%), in both, the RR reduction was 50% (1,000 is 50% of 2,000, and one is 50% of two).

Skolbekken asserted that the “real impact of treatment … can only be seen by also reviewing the absolute risk reduction.” He also noted that reporting only the relative risk gives “a more favourable impression of the effectiveness of a drug than absolute risk estimates.” Numerous investigators have emphasized the importance of this issue; surveys have shown that lay people, as well as healthcare providers, overestimate the benefit of a treatment, such as cholesterol reduction, when the findings are presented solely as the RR [6-16].”

Misleading presentation of the data in cholesterol-heart disease research

The authors conducted an in-depth analysis of the five landmark randomized controlled trials (RCTs) that assessed heart disease monitoring and prevention over the past four decades. These well known studies are, in 1984, “Lipid Research Clinics Coronary Primary Prevention Trial” (LRC-CPPT) [17,18]; 1986, “Multiple Risk Factor Intervention Trial” (MRFIT) [19]; 2008, “Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin” (JUPITER) [20]; 2017, “Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk” (FOURIER) [21]; and 2023, “Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen” (CLEAR) [22].

“These five clinical trials have been selected because they played a key role in implicating high total serum cholesterol, in general, and low-density lipoprotein cholesterol (LDL-C), in particular, in causing heart disease and in promoting the pharmacological reduction of cholesterol to prevent coronary heart disease (CHD). Our review addresses how the findings in each of these clinical trials were presented to all audiences primarily in the RR format, which exaggerated the role of cholesterol in CHD and amplified the modest benefits of lipid reduction.”

For each of these famous studies the authors conduct a detailed analysis that discloses how the emphasis on RR obfuscates the true conclusions that should be drawn from the data. I’ll mention a few here.

Miscommunication of the benefits of a lipid-lowering therapy

The LRC-CPPT (Lipid Research Clinics Coronary Primary Prevention Trial) addressed the hypothesis that “long-term reduction of serum cholesterol in hypercholesterolemic men initially free of CHD will lead to a lowered incidence of coronary heart disease”. Half a million middle-aged males with the highest (top 5%) cholesterol levels were put on a low-cholesterol diet for 7.4 years; about half were given a placebo and the remainder were given a bile-sequestering agent (cholestyramine), which reduced cholesterol levels. It’s amazing to see how this study established the dogma of cholesterol and heart disease on a misapprehension of the evidence.

“The authors reported that cholesterol reduction resulted in “a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction.”

There was widespread praise for the LRC-CPPT findings, as exemplified by an editorial in the British Medical Journal (BMJ), which stated, “At long last we have clear evidence that reducing very high plasma concentrations of cholesterol and low density lipoprotein (LDL) cholesterol lowers the incidence of coronary heart disease” [23]. Similar views were expressed in a lead article in the Medical Journal of Australia entitled “The lipid hypothesis is proven,” which declared “the incidence of death from definite CHD was reduced by 24% in the cholestyramine group” [24].”

In the same year in which the LRC-CPPT findings were published, the National Institutes of Health (NIH) convened a panel of experts on diet, cholesterol, and heart disease. The panel published a consensus statement, which was based, in large part, on the LRC-CPPT findings [25]. The NIH panel concluded, “It has been established beyond a reasonable doubt that lowering definitely elevated blood cholesterol levels … will reduce the risk of heart attacks caused by coronary heart disease. This has been demonstrated most conclusively in men with elevated blood cholesterol levels ….”

The NIH consensus panel and others failed to address the ensuing controversy over numerous irregularities that were found in the LRC-CPPT statistical methods. Most importantly, when absolute risk was considered instead of relative risk, the results become practically meaningless.

“Specifically, commentators accused the LRC-CPPT investigators of changing how they analyzed the data because the initial data analysis, based on their prespecified method paper [17], failed to support the hypothesis that cholesterol reduction would reduce CHD events or mortality….In Figure ​Figure1,1, we have illustrated the data in the original publication (from their Table 3) to highlight the difference between the magnitudes of the absolute risk reduction and the relative risk reduction.”

“More objective assessments of flaws with the LRC-CPPT and the NIH consensus panel were provided at the time by two acknowledged experts. The first was from Dr. Thomas Chalmers of Mount Sinai Medical School, who commented, “I think they made an unconscionable exaggeration of all the data” [32]. The second was from Dr. George Mann, professor of biochemistry and medicine at Vanderbilt University Medical School [30]: “They have held repeated press conferences bragging about this cataclysmic breakthrough which the study directors claim shows that lowering cholesterol lowers the frequency of coronary disease. They have manipulated the data to reach the wrong conclusion. This is plain for any student of elementary statistics to see. The managers at NIH have used Madison Avenue hype to sell this failed trial in the way media people sell an underarm deodorant. The (NIH Consensus Panel) has failed to acknowledge that the LRC trial, like so many before it, is saying firmly and loudly ‘No, … the drug you generously tested for a pharmaceutical house does not work …’.”

MRFIT: Misrepresenting evidence to assert that small increases in cholesterol are harmful

The observational component of the MRFIT (Multiple Risk Factor Intervention Trial) assessed the hypothesis that there would be a positive association between serum cholesterol and CHD deaths in middle-aged males. It was promoted as demonstrating that small increment of total cholesterol, increased one’s risk of dying of CHD. It concluded that “of all CHD deaths, 46% were estimated to be excess deaths attributed (solely) to serum cholesterol 180 mg/dl or greater.”

“The data from Table 3 of the original publication are provided here as Figure ​Figure2,2, which illustrates the relation between serum cholesterol levels (in deciles) and CHD mortality. The same raw data generated the RR (red bars) and the AR (blue bars) for CHD death rates. The data presented as RR seem alarming, since they appear to strongly support the authors’ conclusion that small increments in cholesterol are associated with substantial increases in CHD risk. The graph illustrates that people with total cholesterol levels of 216 mg/dl, 246 mg/dl, and >290 mg/dl have two, three, and four times the risk, respectively, of dying of CHD, compared to people whose total cholesterol level is 150 mg/dl. This dramatic increase in CHD death supported the authors’ conclusion that cholesterol levels above 180 mg/dl “powerfully affects risk for the great majority of middle-aged American men.”

A proper analysis of absolute risk tells an entirely different story, where the difference in the rate of heart disease mortality between the lowest and highest levels of cholesterol was no more than 1%.

Again, the authors did not mention the absolute risk which nullified their contention based on relative risk that elevated levels of cholesterol are implicated “in the causation of premature CHD.” This was instrumental in countering the trend that was building at the time that debunked the assertion that cholesterol causes heart disease.

“To put the MRFIT findings into historical perspective, by the 1980s, the hypothesis that cholesterol caused heart disease was falling out of favor. Clinical trials of different agents, such as corn oil [40], clofibrate [41], and cholestyramine [18], had all failed to demonstrate a significant clinical benefit of cholesterol reduction on coronary events and mortality. Had the trial directors focused on AR instead of RR, MRFIT should have served as the death knell for the cholesterol hypothesis. Cardiovascular research would have shifted its focus in subsequent decades on more traditional CHD risk factors, including smoking, stress, hypertension, hyperglycemia, and insulin resistance. Instead, MRFIT, as well as LRC-CPPT, provided the impetus for the expansion of cardiovascular disease (CVD) treatments to new approaches to reduce cholesterol, including the development of statins.”

The famous JUPITER trial purporting to show the benefit of statins

Statins have become so fervently advocated by many providers that to investigate the evidence invites castigation as a fear-mongering denial cultist.

“Statins reduce cholesterol levels by blocking the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol synthesis. Statins have been considered so successful in preventing coronary events that William Roberts, MD, editor of the American Journal of Cardiology, described statins as “miracle drugs,” which “are to atherosclerosis what penicillin was to infectious diseases” [42]. Praise for statins has been so strong that critics have been labeled as members of a “statin denial cult” [43], who disseminate “fake medical news and fearmongering … through relentless attacks on statins” [44].

We suggest that statins are promoted as “miracle drugs” largely because statin advocates have often publicized their RR reduction while failing to highlight their modest AR reduction. Moreover, the adverse effects of statins have been minimized or ignored entirely. Diamond and Ravnskov [45] provided a critique of this strategy in their assessment of clinical trial outcomes for statin treatment in primary and secondary prevention of CHD.”

JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) was a landmark study that was the major ‘game-changer’ for the use of statins in cardiovascular prevention. The intent was to prove whether a statin (rosuvastatin aka Crestor) would reduce vascular events in people without hyperlipidemia. At that time, the reference range for cholesterol was much higher.

“JUPITER was a landmark trial with findings that were embraced by many healthcare providers because it appeared to demonstrate substantial benefits for people without high cholesterol and with a low risk for CHD. In two representative comments on JUPITER outcomes, Dr. Steven E. Nissen, director of cardiology at the Cleveland Clinic, proclaimed, “It’s a breathtaking study. It’s a blockbuster. It’s absolutely paradigm-shifting,” and Dr. W. Douglas Weaver, president of the American College of Cardiology, was equally emphatic: “This takes prevention to a whole new level. Yesterday you would not have used a statin for a patient whose cholesterol was normal. Today you will” [46].”

It appeared to be so successful that it was stopped prematurely. But as with the two previous trials, the results were misrepresented by emphasizing RR (relative risk) benefit with “little to no mention of the AR (absolute risk)".”

However, the extensive adverse effects were reported as AR rather than RR, making them appear far smaller!

“Although the AR reduction with rosuvastatin treatment was modest, a small benefit could be of value if statins had very few and only minor adverse effects. However, the adverse effects of statins are extensive [45,48-59], including an increased risk of new-onset type 2 diabetes [20,60-65], an increase in fasting blood glucose in patients with and without diabetes [66], mitochondrial dysfunction [67-69], tendinopathy [70], myopathy [71,72], acute kidney injury/renal failure [73-75], and cognitive deficits [54,76-83].

The JUPITER trial documented a significant increase in the incidence of new-onset diabetes with rosuvastatin treatment compared to placebo (their Table 4). In reporting this adverse effect of statins, the authors presented the data only in terms of its AR, without transforming it into the RR. According to Gigerenzer et al. [84], the portrayal of the RR without including the AR provides “incomplete and misleading information,” which they referred to as “mismatched framing.”

If the authors had used the RR, they would have reported a 25% increase in new-onset diabetes on the statin. The trial director described it as a “play of chance”.

“However, the significant increase in the incidence of diabetes with statin treatment has been reported in numerous subsequent publications [60-64,85], including an RCT that characterized the mechanistic basis as to how statins increase the susceptibility of users to develop diabetes [65]. This finding is relevant to why RCTs have demonstrated an increase in fasting blood glucose in patients with and without diabetes [66], as well as a meta-analysis that suggested females are more susceptible than males to develop type 2 diabetes with statin treatment [60].”

When the JUPITER trial findings were first reported, the manipulation did not go unnoticed:

“The findings of the JUPITER trial were subject to widespread criticism, similar to the controversy generated in response to LRC-CPPT. According to Curtiss and Fairman [86], “Criticism of the JUPITER trial results began immediately” and developed into “an avalanche” of published critiques [87-90]. Criticisms were raised at multiple levels, including questionable justification for terminating JUPITER in less than two years despite the plan to run the trial for four years. There were also concerns that the premature termination was influenced by the pharmaceutical company sponsoring the trial. There was also criticism of the efforts by the authors to downplay the increased incidence of diabetes with drug treatment. It is noteworthy that Serebruany [91] asserted that “the medical community does not uniformly accept the results of the JUPITER trial, engaging in heavy, somewhat personal debates over the validity of the JUPITER findings” including “commercial interests of the principal investigator” and a “fundamental problem with trial integrity.”

The biggest issue was how emphasizing the RR and ignoring the AR made the statin intervention appear, falsely, beneficial:

“Critics commented that the study outcomes emphasized the RR and ignored the AR reduction. For example, Vaccarino et al. [90] expressed concerns regarding the lack of attention to the modest AR benefit in JUPITER. These authors stated that the trial was terminated prematurely based on the 44% RR reduction in events, but they echoed the concerns of others by stating, “what really matters for dictating changes in clinical practice is the absolute risk reduction…Despite the appearance of an impressive 54% RR, the modest AR led Vaccarino et al. to conclude that “the treatment benefits achieved in the JUPITER trial are not large enough to advocate an expansion in the clinical indications for statins.”

But the FDA granted approval for prevention anyway.

Cholesterol-lowering benefits misconstrued in recent research

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial reported that the antibody-based drug evolocumab reduced LDL-C by 59%, but the benefit was again misrepresented by mentioning only the RR and not the AR.

“According to Sabatine, “Evolocumab reduced the risk of cardiovascular events, a 15% reduction in the primary endpoint, a 20% reduction in the risk of cardiovascular death, MI or stroke” [92]. The 15%-20% benefits of evolocumab treatment were highlighted, as well, in the opening paragraph of the Discussion section of the publication [21].

Sabatine’s approach to data presentation followed the now routine practice of mentioning only the RR, without including the AR. The impact of the FOURIER findings may have been less impressive had the reduction in the risk of the composite of cardiovascular death, MI, or stroke been expressed as the AR, which was only a 1.5 percentage point difference between treatment and placebo (5.9% versus 7.4%).”

Moreover, there was no statistically significant difference in death due to any cardiovascular condition and no effect on all-cause mortality.

And it’s a similar story for the recent CLEAR (Cholesterol Lowering via Bempedoic Acid) trial which tested bempedoic acid (reduces hepatic cholesterol synthesis and raises LDL receptor expression, thereby increasing the clearance of LDL cholesterol from the circulation) on statin-intolerant patients. Although it reduced LDL-C levels by 26.1%, the actual benefit was nil and outweighed by side effects:

“The group-administered bempedoic acid exhibited a 26.1% reduction in LDL-C levels (compared to a 10.6% reduction in the placebo group). The AR reduction with bempedoic acid for combined major coronary adverse events was 1.5 percentage points (13.3% versus 11.7%), with no benefit in fatal or nonfatal stroke or death from any cause, including cardiovascular causes. Bempedoic acid treatment produced adverse effects not seen with statins, including a significant increase in hyperuricemia (10.9% versus 5.6%), gout (3.1% versus 2.1%) and cholelithiasis (gall stones) (2.2% versus 1.2%), renal impairment (11.5% versus. 8.6%), and elevated hepatic enzyme level (4.5% versus. 3.0%).”

And as usual now, in discussion the RR was used to exaggerate benefit while the AR was brought up only to downplay the side effects:

“In a discussion of the CLEAR outcomes, Dr. Ann Marie Navar did not mention the AR 1.6 percentage point difference in the benefits of bempedoic acid treatment. Instead, she presented the benefits of bempedoic acid in terms of the RR data, by stating that there was a 13% RR reduction in events [95]. In contrast, when Dr. Navar addressed the adverse effects of the treatment, she mentioned only the AR data, stating that there was only a 1% increase in the incidence of gout and cholelithiasis (the formation of gallstones), with no mention of the increased incidence of renal impairment, elevated hepatic enzyme level, and near doubling of the incidence of hyperuricemia with bempedoic acid treatment versus placebo. Gigerenzer et al. [84] considered this form of data presentation to be the second “sin” against transparent reporting, that is, deliberately reporting benefits as relative risk reductions while reporting harms as absolute risk increases.”

Healthcare providers misled by exclusive presentation of data as RR

Healthcare providers are far more likely to prescribe lipid-lowering medication when informed only of the RR (relative risk) and way less likely to prescribe when the AR (absolute risk) has been communicated.

“As an example of how healthcare providers can be misled by an exclusive presentation of data as RR, Bucher et al. [97] demonstrated that physicians were more inclined to prescribe cholesterol-lowering medication for hypercholesterolemia when the trial results for identical endpoints were expressed as RR reduction, compared to AR reduction. Sackett and Cook [98] commented on this finding by stating that “restricting the reporting of efficacy to just relative risk reductions can lead to greater - and at times - excessive zeal in decisions about treatment for patients with low susceptibilities.”

For clinical decision making, the data reported in absolute terms should always be the benchmark:

“Stegenga [103] emphasized that “Effectiveness always should be measured and reported in absolute terms (using measures such as ‘absolute risk reduction’)” and he further stated that “people’s comparative understanding of relative versus absolute outcome measures is dubious. Relative measures … fundamentally mislead patients into overestimating effectiveness.” Nevertheless, peer-reviewed medical publications and the media exhibit a high prevalence of bias toward reporting the RR and ignoring the AR.”

“…this strategy by clinical trial investigators to amplify the appearance of the magnitude of their intervention is unacceptable scientific behavior. We concur with Gigerenzer et al. [84] that journal editors should enforce transparent reporting of data, including the requirement that papers include the AR and RR in the abstracts. In addition, an education on the miscommunication of risk and benefits in research should be included in the training of healthcare workers and students of public health.”

Distraction from important causes of vascular disease—and the benefits of LDL-C

The atherogenic modifications in plasma, including glycation—binding with excess glucose (hyperglycemia) which is associated with heightened inflammation, insulin resistance with elevated levels of insulin that are destructive to the glycocalyx (protective sheath of the inner lining of the blood vessel), that permits vascular inflammation, and atherogenic modifications of sdLDL leading to the formation of vulnerable plaque are then typically ignored. Moreover, it obscures the importance of LDL-C for health.

“…the exaggeration of the putative harms caused by elevated LDL-C [104] and the benefits of lipid-lowering medications has detracted from an appreciation of the physiological relevance of elevated levels of LDL-C in optimal health. For example, LDL-C is an important component of the immune system [105-107]. Chronically elevated LDL-C levels may enhance aspects of immune functioning, which is potentially relevant to the finding that elderly people with familial hypercholesterolemia (FH) have lower rates of mortality from cancer and infection compared to the general population [108-110].”

Moreover, we know that LDL-C is a very poor predictor of MACE (major adverse cardiovascular events) and more than half of heart attacks occur with low LDL-C.

“The importance of LDL-C to overall health may explain why LDL-C is such a poor marker of risk for CVD [34-38], as well as cardiovascular and all-cause mortality [39]. Coronary artery calcification (CAC), in contrast to LDL-C, is the single best predictor of future fatal and nonfatal coronary events [111-121]. Moreover, among those with genetically confirmed FH [familial hypercholesterolemia], approximately half showed no detectable CAC and had a favorable prognosis, despite significantly elevated LDL-C levels [122]. These observations help to explain why FH individuals do not face an increased risk of CVD mortality with advanced age, as well as the greater longevity of people in the general population with high LDL-C, compared to those with low LDL-C [39].”

And this tracks with the diminished benefits of statins when examining the correct metric, AR (absolute risk):

“Finally, the overestimation of the involvement of LDL-C in producing CHD based on RR statistics is confirmed by the modest AR benefits of statins…This finding was quantified recently by Byrne et al. [132] in a systematic review and meta-analysis of statin RCTs. These investigators reported that the AR reduction of statins was only 0.6% for all-cause mortality, 0.7% for MI, and 0.3% for stroke and 0.9%, 2.2%, and 0.7%, respectively, in primary and secondary prevention…This finding of limited benefits of statins is further confirmed by the work of Kristensen et al. [133] who reported that overall, statin treatment delayed death in primary and secondary prevention trials by only 3.2 and 4.1 days, respectively. These findings support the conclusions of Byrne et al. [132] that “when considering the ARR of statins, the benefits are quite modest, and most trial participants who took statins derived no clinical benefit.”

This all makes it fair to say that LDL-C has simply gotten a ‘bad rap’:

“Hence, the pejorative view of LDL-C as the “bad cholesterol,” which has been perpetuated by the disproportionate emphasis on RR statistics, is not supported by a balanced review of the literature. The characteristic of this perspective is the opinion that “evidence falsifying the hypothesis that LDL drives atherosclerosis has been largely ignored” [134], and the opinion of three cardiologists that “LDL cholesterol risk has been exaggerated” [135] (see also Ravnskov et al. [34] and Diamond et al. [136] for related reviews and discussion).”

Other scientists have attempted to spotlight this problem

The authors of this paper (‘Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy’) state:

“We are not the first to object to the preferential use of RR, without sufficient attention to AR, in clinical trial reporting. For decades, academicians have deplored the strategy taken by some clinicians to promote their findings by emphasizing RR to the exclusion of reporting the AR [6-16]. In one example, Gigerenzer et al. [84] considered this form of data presentation to be “the first ‘sin’ against transparent reporting.”

Another study published last year in JAMA Internal Medicine also scrutinized this problem with regard to cholesterol and statins in a systematic review and meta-analysis and came to the same conclusions:

They too noted that the association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of outcomes, such as all-cause mortality, heart attacks, and strokes was not being made clear. So they set about to…

“…assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy.”

They included twenty-one large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes, comparing treatment with statins and reduction of LDL-C to placebo (and no change in LDL-C). Three independent reviewers assessed the quality of the evidence, extracted the data, resolved their decisions by consensus, conducted the meta-analyses. What did they conclude?

The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Stated succinctly:

“The study results suggest that the absolute benefits of statins are modest, may not be strongly mediated through the degree of LDL-C reduction, and should be communicated to patients as part of informed clinical decision-making as well as to inform clinical guidelines and policy…

The transparent communication of RRR (relative risk reduction) and ARR (absolute risk reduction) by clinicians, as well as the potential for harm, to their patients may lead to more informed decision-making about the true benefits and risks of statins.31 In addition, our findings have implications for future clinical guideline development and for policy makers and payers considering the opportunity cost of statin therapy.”

Bottom line

The authors of the first paper cited, ‘Historical Review of the Use of Relative Risk Statistics in the Portrayal of the Purported Hazards of High LDL Cholesterol and the Benefits of Lipid-Lowering Therapy’, conclude:

“We have reviewed the findings of five landmark clinical trials conducted over the past four decades that have supported the current consensus that high LDL cholesterol causes CVD and that the pharmacological reduction of LDL produces substantial CVD benefits. Our assessment of these trials demonstrates that the association of cholesterol with CVD is far more modest than has been portrayed. We also assert that the promotion of statins as “miracle drugs” has been based on an emphasis on their RR reduction, which amplifies the appearance of their modest AR benefits.”

Sadly…

“The biased approach to data analysis in the five trials we have reviewed is representative of the now common practice of highlighting RR over AR in data presentation and in the media, which has been referred to as a “miscommunication of risk.” A consequence of this biased approach to the reporting of CVD clinical trial findings explains in large part why healthcare providers and the public have overestimated the purported hazards of high cholesterol and the benefits of cholesterol reduction.”

When will this scientifically unacceptable and misleading practice change?

In conclusion, for the past four decades, academics have repeatedly asserted that the portrayal of clinical trial findings as the RR, while disregarding the AR, is a deceptive practice. In the cardiovascular disease field, a consequence of this strategy has resulted in the exaggerated appearance of the purported hazards of high cholesterol and an amplification of the magnitude of benefits of cholesterol-lowering medications. This strategy appears to have been deployed for the first time with the publication of the LRC-CPPT trial in 1984 but has now become commonplace. To counter this trend of scientific misconduct, we assert that publications and media reports of clinical trial findings should always portray the benefits, as well as harms, of interventions in terms of both absolute and relative risks.

Readers may also be interested in this study in the journal Circulation showing evidence that higher levels of cholesterol are associated with less atrial fibrillation in their female cohort.

Phototherapy, therapeutic exposure to light, is an effective, safe, noninvasive way to boost cognition in dementia; making it a desirable option compared to drug treatments with adverse effects and limited efficacy.

A review, Phototherapy improves cognitive function in dementia: A systematic review and meta-analysis, just published in the journal Brain and Behavior examined a variety of therapeutic light applications for measurable improvements in cognition.

“This study aimed to investigate the effectiveness of phototherapy intervention on cognitive function in older adult patients with dementia. PubMed, Ovid MEDLINE, Web of Science, EMBASE, Cochrane Central Registry of Controlled Trials, PsycINFO, and Clinical Trials were searched from their inception to August 10, 2022, for randomized controlled trials involving patients with dementia who received phototherapy interventions. We used the weighted mean difference (MD) or standard weighted mean difference to generate the pooled estimates. The primary outcome was cognitive function as measured by the Mini-Mental State Examination (MMSE) score.”

The authors included studies on elderly adults with dementia, including Alzheimer's disease (AD), vascular dementia (VD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), mixed dementia (MD), or dementia due to other causes who had phototherapy interventions to controls that received no intervention but only routine care or health education.

There is a great need for safe and effective interventions…

“As drug treatment for dementia has limitations such as medical contraindications, limited efficacy, and adverse effects (Azhar et al., 2022; Wong, 2016), non-pharmacological therapy has been increasingly regarded as a critical part of comprehensive dementia care (Li et al., 2021; Sink et al., 2005). Phototherapy, which utilizes full-spectrum bright light usually above 600 lux (Onega et al., 2016; Zou et al., 2022) or wavelength-specific lights, such as blue-enriched (Cremascoli et al., 2021) or blue-green (Nowak, 2008) lights, is a promising non-pharmacological therapy that has the advantages of non-invasiveness, inexpensive, and high safety (Forbes et al., 2014; C.-R. Liu et al., 2021; Scales et al., 2018).”

A variety of interventions showed efficacy

Even though a third of the subjects had intermediate or high-risk disease at diagnosis, the great majority did well:

“Phototherapy interventions of all forms, frequencies, and durations were included in this review. In most (eight of 12) studies (Burns et al., 2009; Dowling et al., 2007; Figueir, 2019; Fontana Gasio et al., 2003; Graf et al., 2001; McCurry et al., 2011; Onega et al., 2016; Zou et al., 2022), phototherapy intervention was implemented using bright light, while two (Kolberg et al., 2021; Nizamutdinov et al., 2021) studies used LED light, and the remaining two (Cremascoli et al., 2021) used blue or blue-green light. Phototherapy duration generally ranged from 6 to 120 min. Half (six of 12) of the studies implemented phototherapy interventions at specific times of day, three (Burns et al., 2009; Nowak, 2008; Zou et al., 2022) in the morning, one (Graf et al., 2001) in the afternoon, one in (Fontana Gasio et al., 2003) the dawn-dusk period, and one (Dowling et al., 2007) consisting of two intervention groups in the morning and afternoon. Besides, four studies (Cremascoli et al., 2021; McCurry et al., 2011; Nizamutdinov et al., 2021; Onega et al., 2016) did not report a specific intervention time, and two (Figueir, 2019; Kolberg et al., 2021) utilized a 24-h lighting sequence. The frequency ranged from twice a day to five times per week, while most (nine of 12) studies used phototherapy once a day.”

A light box is the most commonly used modality:

“The light box was the most classic and commonly used device in phototherapy, and it provides full-spectrum bright light usually over 2500 lux, with a duration of at least 30 min in the daytime, lasting 4–8 weeks (Fetveit et al., 2003; Graf et al., 2001; C.-R. Liu et al., 2021; McCurry et al., 2011; Onega et al., 2016; Zou et al., 2022). It should be noted that the light box was placed 60 cm away from the patient at or above the patient's eye level…In recent years, helmets and glasses have also been used as phototherapy devices, which usually employ light of a specific wavelength with a duration of approximately 15 min (Cremascoli et al., 2021; Nizamutdinov et al., 2021). Such portable devices allow for better control of light intensity and are ergonomic without interfering with patients’ normal activities.”

In summary, the authors conclude:

“Our systematic review and meta-analysis suggests that phototherapy is a promising intervention, as it can improve cognitive function in older patients with dementia…further well-designed studies are needed to explore the most effective clinical implementation conditions, including device type, duration, frequency, and time.”

Keeping Aging Brains Healthy - Battling Alzheimer’s Disease with Light and Sound, researchers at MIT’s Aging Brain Initiative are demonstrating how non-invasive modalities can support brain biology to protect and promote cognitive health.

“The Aging Brain Initiative is an interdisciplinary effort combining faculty expertise, knowledge, and technical resources from across MIT to solve the mysteries of the aging brain. MIT scientists are opening doors to an entirely new direction of brain research, building new tools to address the challenges of brain aging, and creating a better future for millions..”

Retraining the brain with sensory stimulation

MIT neuroscientists in the lab of Professor Li-Huei Tsai at The Picower Institute for Learning and Memory are studying how retraining brainwaves with lights flickering at appropriate wavelengths can reverse the effects of Alzheimer's and other diseases on the aging brain. Brain wave entrainment with gamma frequencies appears particularly helpful for reducing Alzheimer's disease pathology and improving memory.

“A growing body of evidence, including Aging Brain Director Li-Huei Tsai’s findings, hint at a meaningful connection between modulating brainwaves and affecting neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug."

Brain Photobiomodulation (PBM)

Brain photobiomodulation can be applied with low level laser therapy (LLLT) and LED light sources. Devices worthy of consideration that use potent LEDs at specific wavelengths and frequencies to promote healthy brain biology include the Auragen™ Light & Sound System and the Neuronic Neuroradiant 1070.

“Autoimmune diseases (ADs) affect approximately 10% of the world's population. Because ADs are frequently systemic disorders, cardiac involvement is common…In Cardiac Arrhythmias in Autoimmune Diseases we focus on typical arrhythmias and their pathogenesis…among selected ADs (sarcoidosis, systemic lupus erythematosus, scleroderma, type 1 diabetes, Graves' disease, rheumatoid arthritis, ankylosing spondylitis [AS], psoriasis, celiac disease [CD], and inflammatory bowel disease [IBD]).”

“Various autoimmune diseases targeting different organs showed associations with new-onset AF in the general population.

Autoimmune diseases are significantly associated with the risk of new-onset AF in this prospective population-based study, comprising almost half a million participants.

Inflammation may underlie atrial remodeling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF…”

“The requirement of substantial fibrosis of the right atrium may well be a consequence of autoimmune activation...”

Elicited findings support the notion of enhanced proinflammatory state coupled with an autoimmune process in which apoB, presumably aggregated to SHBG, emerge as a basic mechanism in the development of AF…this is alike the dynamics for type-2 diabetes and inflammatory rheumatic disease.”

“Inflammatory pathways contribute to both electrical and structural atrial remodelling and thrombogenesis in patients with AF.

…the presence of inflammation in the heart or systemic circulation can predict the onset of AF and recurrence…after cardiac surgery, cardioversion, and catheter ablation.

…thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity.”

“…a significant role played by inflammation in the occurrence and continuation of AF, and inflammatory markers such as CRP…and IL-6 are associated with AF, failure of cardioversion, and associated thrombogenesis.29 …higher baseline CRP levels in the patients with more AF recurrence postablation.30 …increased CRP levels associated with recurrence of AF.31 …increased markers of inflammation such as IL-6 and CRP associated with increased AF in the general population…”

…insulin resistance, a major risk factor for CV disease.11 The metabolic syndrome (MetS) is associated with increased pro-inflammatory cytokines…There is much evidence for an association of periodontal disease with increased CV risk with atherosclerosis triggered by resultant systemic inflammation and endothelial dysfunction.18

“Different cardiac receptors and ion channels were identified as targets for autoantibodies, the binding of which either initiates a signaling cascade or serves as a biomarker of underlying remodeling process. Consequently, the wide spectrum of heart rhythm disturbances may emerge, ranging from atrial to ventricular arrhythmias as well as conduction diseases, irrespective of concomitant structural heart disease or manifest autoimmune disorder.”

“Several types of antibodies are associated with atrial fibrillation (Figure 2). The first antibody detected in atrial fibrillation was that against myosin heavy chain 24…. patients with paroxysmal atrial fibrillation…showed the presence of immunoreactivity against cardiac myosin heavy chain...Subsequently, antibodies against the Na/K ATPase 24, 25, the M2-muscarinic cholinergic receptors, the β1 adrenergic receptors, and the heat shock protein (HSP) 65 26…promoting the development of atrial fibrillation...Recent clinical studies have included autoantibodies against β1-adrenergic receptors as an independent variable… 38, 39”

“Autoantibodies known to contribute to the development of bradyarrhythmias (red) and tachyarrhythmias (green) are illustrated here.

The significance of autoantibodies in the pathogenesis of cardiovascular abnormalities …is receiving increasing attention. In particular, there is substantial evidence that autoantibodies play an important role in the development of cardiac arrhythmias in a wide range of disease conditions.”

“Serum concentrations of various autoantibodies have been proven to be significantly increased in patients with different types of AF when compared to healthy people. Most scientific attention has been applied to activating autoantibodies against receptors of the autonomous nervous system. Moreover, a growing number of studies has shown that other autoantibodies may affect pathogenetic pathways leading to AF.”

“A major characteristic of AF-related structural remodelling is atrial fibrosis, a process closely related to inflammation…

A vicious cycle exists in which inflammation leads to a higher prevalence of structural cardiovascular disease, which in turn leads to more inflammation and AF; in fact, inflammation is known to affect signalling pathways that lead to the development of AF.

Therapy must first target systemic inflammation, since decreasing the inflammatory burden has consistently shown to positively ameliorate the prognosis.

New mapping techniques allowing the characterization of the arrhythmic substrate have opened new perspectives and may help in the treatment of AF in these patients, since atrial tissue is the target of inflammation-induced arrhythmic alterations.”

“Several epidemiological studies have shown that psoriasis increases the risk of developing atrial fibrillation…

In subgroup analysis, the greater risk was found in studies from North America, RR 1.482 (95% CI: 1.119-1.964, P < 0.05), whereas a moderate risk was observed in studies from Europe RR 1.43 (95% CI: 1.269-1.628, P < 0.0001)…

Therefore, physicians should monitor patient's physical condition on a timely basis.”

“This large‐scale population‐based study is the first to analyze the role of autoimmune vasculitis in the development and prognosis of atrial fibrillation (AF).

…autoimmune vasculitis was significantly associated with incident AF cases compared with non‐AF controls.

AF was more strongly associated with overall mortality in the presence than the absence of autoimmune vasculitis.

…a preexisting autoimmune process may be a potential mechanistic link to the development of new‐onset AF.”

“There is a 38% increased risk of atrial fibrillation in patients with celiac disease as compared to individuals without celiac disease used as controls.

Early identification, lifestyle modification, adherence and compliance to gluten-free diet, could slow the risk of AF…”

Inflammation and oxidative stress have been found to be responsible of many molecular mechanisms of CD including activation of immune cells such as macrophages, T and B cells, neutrophils and inflammatory cytokines (IL-6, TNF-α). These cytokines and activated immune cells could affect the contractility and electrical myocytes stability inducing fibroblast activation and cellular fibrosis [24-26]. These atrial changes provide reentrant arrhythmias confirmed clinically and electrocardiogram [27].

This study would be considered global research because it includes countries around the world such as USA, UK, Sweden, and others.”

“Our findings support a role of autoimmune disease in the pathophysiology of AF, potentially acting through systemic inflammation, which has consistently been linked to AF risk.

More profound systemic inflammation (at the time of diagnosis before a gluten-free diet is introduced reducing the inflammation) could be one interpretation of why the HR is so much higher around the time of diagnosis. We also found a positive association before diagnosis of CD when inflammation caused by undiagnosed CD is likely to have been most intense.”

“The presented findings support that chronic oral inflammations likely affect the pathogenesis of AF by multiple pathways, suggesting the existence of an oral-heart-axis.”

“Chronic oral inflammation induced by bacterial biofilm (gingivitis, periodontitis, and apical endodontic lesions) cause a localized inflammation, which affects cardiac structural and electrophysiological remodeling linked to atrial fibrillation by:

“One of the many responses of the body to an infection is activation of the autonomic nervous system. An important functional component of this system is the inflammatory reflex, a sensory pathway to detect and localize the presence of inflammation by the body’s autonomic nervous system [84].

…inflammation is also regulated in a complex manner by its antagonist, the sympathetic nervous system [86]. Its activation leads, among others, to the release of catecholamines, such as norepinephrine and epinephrine…”

It’s far more than just the gut, of course, but the GI component should never be overlooked.

“The application of the FMM identifies the gene--environment interactions that facilitate the patients nodal points and corrects them with emphasis on personalized diet, nutrition, and lifestyle changes.”

“The importance of addressing the proximal causes of atrial fibrillation is recognized, yet frustration with the currently applied preventive measures is high…the functional medicine model (FMM), which identifies the proximal causes of atrial fibrillation at the level of gene-environment interaction.

The pathological processes leading to atrial fibrillation sustaining disorder have been elucidated in translational studies and are described as ‘nodal points.’ Examples are inflammation, oxidative stress, autoimmune mechanisms, and visceral adiposity. These same nodal points also cause disorder that results in atrial fibrillation-related complications and the development of atrial fibrillation-associated diseases. These nodal points vary from patient to patient and can be identified by careful evaluation of the patients clinical phenotype.”

Tachycardia (abnormally rapid heart rate)

Supraventricular tachycardia can occur with afib undergoing catheter ablation.

“The IgG fractions from patients with inappropriate sinus tachycardia exerted a positive chronotropic action with a high prevalence of anti-beta receptor antibodies (52%)…The IgG fractions from healthy volunteers did not contain antiautonomic receptor antibodies.

Our results suggest, for the first time, a link between inappropriate sinus tachycardia and circulating anti-beta adrenergic receptor antibodies... This finding offers new insight…potential therapeutic consequences.”

Red blood cells have always been thought to be immunologically inert. Research published in Science Translational Medicine reveals that red blood cells have receptors that bind DNA in circulation triggering an inflammatory response during which they are ‘eaten’ by immune cells, resulting in anemia.

Anemia of inflammation and immune cell activation by pathogen DNA (PAMPs = pathogen-associated molecular patterns) are both well-known phenomena, but until now it was not known that red blood cells also have receptors that activate an inflammatory process resulting in their own destruction.

“Red blood cells (RBCs) have historically been considered immunologically inert. In this study, however, Lam et al. demonstrated that RBCs promote inflammation through expression of Toll-like receptor 9 (TLR9) on the cell surface. The authors observed that RBC-expressed TLR9 bound DNA from bacteria, plasmodia, and mitochondria in vitro, and RBC-bound DNA was enriched in humans and mice during sepsis.”

Debris in the battle zone of infection

DNA from bacteria and other pathogens, including coronavirus, are present as debris in circulation to the immune system as it fights infection. Immune cells possessing receptors that bind this DNA help to organize and direct the immune response.

“Here, we showed that RBCs serve as critical immune sensors through surface expression of the nucleic acid–sensing Toll-like receptor 9 (TLR9). Mammalian RBCs expressed TLR9 on their surface and bound CpG-containing DNA derived from bacteria, plasmodia, and mitochondria…In vivo, CpG-carrying RBCs drove accelerated erythrophagocytosis [‘eating up’ of the red blood cells] and innate immune activation characterized by increased interferon signaling.”

Red blood cells acted to drive inflammation and disease severity

Reacting to the nucleic acids in the battlefield debris…

“TLR9-expressing RBCs regulated red cell clearance and inflammatory cytokine production, demonstrating that RBCs function as immune sentinels during pathologic states.”

The authors conclude:

“Consistent with these findings, RBC-bound mitochondrial DNA was elevated in individuals with viral pneumonia and sepsis secondary to coronavirus disease 2019 (COVID-19) and associated with anemia and severity of disease. These findings uncover a previously unappreciated role of RBCs as critical players in inflammation distinct from their function in gas transport.”

Clinical Note

As discussed above, the nucleic acid–sensing Toll-like receptors (TLR9) on the red blood cells bind DNA and mitochondrial debris from the killing off of pathogens and death of the neutrophils that kill them. In autoimmune and autoinflammatory disorders, when there is a deficiency of pro-resolving mediators, it can take too long for monocytes (turning into macrophages) to gobble up the apoptotic (dying neutrophils), in which case they transition in to secondary necrosis and release more debris that exceeds the clearance ability of the monocytes, resulting in an influx of yet more neutrophils along with, as this paper shows, activation of TLR9 receptors on RBCs. This is where agents such as the pro-resolving lipid mediator fractions of fish oils can be used to reduce inflammation and tip the balance of toward more monocyte recruitment away from additional neutrophil recruitment.

Higher pressures required by masks covering both the nose and mouth cause the airway to collapse more than with nasal masks, significantly increasing airway resistance and reducing CPAP effectiveness. And mouth versus nasal breathing is deleterious across the board.

A study recently published in the journal Chest, Oronasal vs Nasal Masks, The Impact of Mask Type on CPAP Requirement, Pharyngeal Critical Closing Pressure (Pcrit), and Upper Airway Cross-sectional Areas in Patients With OSA, reveals a big difference between the oronasal masks that cover both the nose and mouth and nasal masks that cover only the nose.

The authors note:

“OSA [obstructive sleep apnea] is a common sleep disorder associated with long-term health consequences.1 CPAP therapy remains the gold standard treatment for patients with OSA. CPAP [continuous positive airway pressure] is highly effective and works by pneumatically splinting the upper airway2 during sleep. However, CPAP is often poorly tolerated3,4 because of patient characteristics, disease severity, psychological factors, side effects, and the type of mask used (ie, nasal vs oronasal masks). Nasal masks are recommended for patients referred for CPAP treatment,5 but oronasal masks are still frequently used in clinical practice despite the common difficulty of maintaining a good fit or seal. As such, oronasal masks are often associated with a higher CPAP level, higher residual apnea-hypopnea index (AHI), and poorer adherence than nasal masks,6 according to a meta-analysis of both randomized and nonrandomized controlled trials. However, the physiological mechanisms underlying the differences in mask performance are currently unknown.”

Moreover…

Imaging techniques (ie, cine-MRI or endoscopy) during wake or drug-induced sleep have found that CPAP applied via oronasal masks can lead to the posterior displacement of the tongue and an increase in upper airway resistance.7,8 The increase in upper airway resistance may increase the collapsibility of the airway, explaining the need for higher optimal CPAP with an oronasal mask. However, to date, no study has successfully quantified how these different CPAP interfaces alter an individual’s airway collapsibility during natural sleep.

So they used cine-MRI (MRI ‘video’) plus digital manometry (pressure measurement) and a MRI-compatible respiratory effort sensor to investigate investigate the dynamic changes within the upper airway with CPAP therapy during sleep and wake, using the two most common commercial oronasal and nasal CPAP mask types rather than specialized research masks.

Airway collapse with oronasal masks

Higher CPAP pressures with oronasal masks are a clear factor:

“The current study demonstrated that oronasal masks require higher therapeutic CPAP levels and that this increase in CPAP requirement was strongly associated with increased airway collapsibility (higher Pcrit)…During nasal breathing, the oronasal mask was associated with smaller retroglossal and retropalatal cross-sectional area than the nasal mask.”

They suggest that having to increase the CPAP pressure setting can be a surrogate marker for airway collapse:

“Taken together, these data provide further evidence that a patient’s therapeutic CPAP level may be a reasonable surrogate marker of airway collapsibility19 and that oronasal masks cause measurable anatomical compromise that may offset some degree of CPAP efficacy.”

Additionally, the oronasal mask straps may push the mandible backward, further constricting the airway:

“The tightening of the oronasal mask straps may push the mandible posteriorly20 #0166EF. Accordingly, we found that the cross-sectional area of the retroglossal/retropalatal region when using an oronasal mask was slightly reduced compared with the nasal mask at low pressures (ie, 4 cm H2O).”

Breath through the nose, not the mouth

And, importantly, they observed the significant difference between mouth and nose breathing as observed in other contexts:

“Another possible mechanism is the route of breathing (ie, whether patients are breathing nasally or orally). Studies using a specialized dual compartment (nasal/oral) oronasal mask interface in which PAP delivery was switched between the nasal or the oronasal (both) compartments without changing the interface found a +2- to 3-cm H2O difference in therapeutic CPAP levels.8,21 These analyses further show that patients with a greater percentage of oral breathing (relative to nasal breathing) required greater pressures to induce stable breathing with oronasal PAP.”

Mouth taping can help, even without obstructive sleep apnea:

“More recently, Madeiro et al21 have shown increased airway resistance during oronasal PAP delivery. This increase in airway resistance could be eliminated by application of tape to the mouth to prevent mouth breathing, mouth opening, or transmission of pressure to the oral cavity. More broadly, mouth opening during the application of nasal CPAP increases collapsibility (Pclose) by a magnitude similar to that found in the current study (approximately +2 cm H2O).23 Moreover, oral breathing has been shown to increase airway resistance during sleep in non-OSA patients.24…the available evidence would suggest that the oronasal masks are associated with more mouth opening/breathing, which in turn increases the airway resistance/collapsibility and therefore drives the higher therapeutic CPAP requirement.”