Metabolic Health

Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg’s hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg’s original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Full Paper https://doi.org/10.1007/s10863-025-10059-w

Introduction: For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit.

Areas covered: The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis.

Expert commentary: Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.

Full Paper: https://doi.org/10.1080/17512433.2018.1519391

Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20–93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Full Paper https://doi.org/10.1016/j.xcrm.2025.101968

TLDR: Resistance exercise is important for all stages of life.

The graphs tell the whole story, I'm not going to copy over the abstract.

Full paper: https://doi.org/10.1016/S0140-6736(24)02317-1

Despite intensive research, the causes of the obesity epidemic remain incompletely understood and conventional calorie-restricted diets continue to lack long-term efficacy. According to the carbohydrate-insulin model (CIM) of obesity, recent increases in the consumption of processed, high–glycemic-load carbohydrates produce hormonal changes that promote calorie deposition in adipose tissue, exacerbate hunger, and lower energy expenditure. Basic and genetic research provides mechanistic evidence in support of the CIM. In animals, dietary composition has been clearly demonstrated to affect metabolism and body composition, independently of calorie intake, consistent with CIM predictions. Meta-analyses of behavioral trials report greater weight loss with reduced-glycemic load vs low-fat diets, though these studies characteristically suffer from poor long-term compliance. Feeding studies have lacked the rigor and duration to test the CIM, but the longest such studies tend to show metabolic advantages for low-glycemic load vs low-fat diets. Beyond the type and amount of carbohydrate consumed, the CIM provides a conceptual framework for understanding how many dietary and nondietary exposures might alter hormones, metabolism, and adipocyte biology in ways that could predispose to obesity. Pending definitive studies, the principles of a low-glycemic load diet offer a practical alternative to the conventional focus on dietary fat and calorie restriction.

https://doi.org/10.1001/jamainternmed.2018.2933

Full Paper here

TLDR Only 7% of Adults have optimal metabolic health! 93% are compromised. This is the single largest health issue the world knows, costing us billions of dollars per day, and millions of lives needlessly cut short.

Background -Few studies have assessed U.S. cardiometabolic health trends—optimal levels of multiple risk factors and absence of clinical cardiovascular disease (CVD)—or its impact on health disparities.

Objectives -The purpose of this study was to investigate U.S. trends in optimal cardiometabolic health from 1999 to 2018.

Methods - We assessed proportions of adults with optimal cardiometabolic health, based on adiposity, blood glucose, blood lipids, blood pressure, and clinical CVD; and optimal, intermediate, and poor levels of each component among 55,081 U.S. adults in the National Health and Nutrition Examination Survey.

Results - In 2017-2018, only 6.8% (95% CI: 5.4%-8.1%) of U.S. adults had optimal cardiometabolic health, declining from 1999-2000 (P trend = 0.02). Among components of cardiometabolic health, the largest declines were for adiposity (optimal levels: from 33.8% to 24.0%; poor levels: 47.7% to 61.9%) and glucose (optimal levels: 59.4% to 36.9%; poor levels: 8.6% to 13.7%) (P trend <0.001 for each). Optimal levels of blood lipids increased from 29.9% to 37.0%, whereas poor decreased from 28.3% to 14.7% (P trend <0.001). Trends over time for blood pressure and CVD were smaller. Disparities by age, sex, education, and race/ethnicity were evident in all years, and generally worsened over time. By 2017-2018, prevalence of optimal cardiometabolic health was lower among Americans with lower (5.0% [95% CI: 2.8%-7.2%]) vs higher education (10.3% [95% CI: 7.6%-13.0%]); and among Mexican American (3.2% [95% CI: 1.4%-4.9%]) vs non-Hispanic White (8.4% [95% CI: 6.3%-10.4%]) adults.

Conclusions- Between 1999 and 2000 and 2017 and 2018, U.S. cardiometabolic health has been poor and worsening, with only 6.8% of adults having optimal cardiometabolic health, and disparities by age, sex, education, and race/ethnicity. These novel findings inform the need for nationwide clinical and public health interventions to improve cardiometabolic health and health equity.els of risk factors, even in low-risk groups, has serious implications for public health.

Full Text - https://doi.org/10.1016/j.jacc.2022.04.046

Extremely promising results of the application of a strict ketogenic diet to glioblastoma survival rates.

Among the 18 patients participating in the study, 6 adhered to the ketogenic diet for more than 6 months. Of these patients, one patient passed away 43 months after diagnosis, achieving a survival of 3 years; another passed away at 36 months, narrowly missing the 3-year survival mark; and one is still alive at 33 months post-diagnosis but has yet to reach the 3-year milestone and is, therefore, not included in the final survival rate calculation. The remaining 3 are also still alive, completing 84,43 and 44 months of life, respectively. Consequently, the survival rate among these patients is 4 out of 6, or 66.7%. Of the 12 patients who did not adhere to the diet, only one reached 36 months of survival, while the rest have died in an average time of 15.7 ± 6.7 months, with a 3-year survival rate of 8.3%. Comparing the survival rates of the two groups, we see that the difference is 58.3% (66.7% versus 8.3%) and is statistically significant with p < 0.05 (0.0114) and X2 = 6.409.

Full Paper https://doi.org/10.3389/fnut.2024.1489812

A graduate of the University of Melbourne, Dr Sikaris trained at the Royal Melbourne, Queen Victoria, and Prince Henry's Heidelberg Repatriation Hospitals. He obtained fellowships from the Royal College of Pathologists of Australasia and the Australasian Association of Clinical Biochemists in 1992 and 1997 respectively.

Dr Sikaris was Director of Chemical Pathology at St Vincent's Hospital in Melbourne between 1993 and 1996. A NATA-accredited laboratory assessor, Dr Sikaris specialises in Prostate Specific Antigen, cholesterol and quality assurance and is currently chair of the International Federation of Clinical Chemistry Committee on Analytical Quality. His expertise is highly sought and he has presented extensively at national and international symposiums.

Great resource, that lists known DIAAS scores, and value per 100g of food, even links to the source papers for the values.

Summary (2 minute read): https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.27.1_supplement.127.4

Linked to the title is the full study. Image is figure 2 from the study.

TLDR - Saturated Fat is good for you. Linoleic acid (seed oils, vegetable oils) oils are bad for you.

https://doi.org/10.1136/bmj.i1246 (full paper)

The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted.

The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline −13.8% v −1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n=10 808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27).

Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes.

cross-posted from: https://sh.itjust.works/post/31544365

Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions.

TLDR: The current advice that LDL is "bad cholesterol", appears to be outdated, and the actual situation is more complex. In people over 60 high LDL appeared to be protective for mortality.

Conclusions: High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

Full Paper at https://pubmed.ncbi.nlm.nih.gov/27292972/

Related to, and following up on the LMHR paper from https://hackertalks.com/post/5835924

TLDR - Alternate day fasting leads to hair follicle damage in mice.

• Common intermittent fasting regimens inhibit hair follicle regeneration in mice
• Fasting selectively eliminates activated HFSCs, but not EpiSCs that maintain epidermis
• Activated adrenal gland-dermal adipocyte crosstalk mediates HFSC apoptosis
• Intermittent fasting inhibits human hair growth in a randomized clinical trial

https://www.cell.com/cell/abstract/S0092-8674(24)01311-4

Nick Norwitz did a great writeup https://staycuriousmetabolism.substack.com/p/fasting-will-make-you-bald-and-how

I haven't found the full paper in the usual places. So I'm relying on the writeup

In both mice and humans topical vitamin E proved to provide enough antioxidant protection to prevent the hair loss.

Globally, there is an increasing prevalence of non-communicable diseases. The morbidity and mortality from these conditions confer a greater economic societal burden. Epidemiological research associates insulin resistance in the etiology of these diseases, but there is limited evidence for the mechanism of damage. Emerging research suggests that hyperinsulinemia, a symptom of insulin resistance, may cause these pathological changes, and therefore be an independent contributor to these diseases. This review shows that hyperinsulinemia, or excessive insulin secretion, should be considered independently to insulin resistance, defined as glucose uptake rate, even though the two conditions are intertwined and will co-exist under normal conditions. Hyperinsulinemia directly and indirectly contributes to a vast array of metabolic diseases including all inflammatory conditions, all vascular diseases, gestational and type 2 diabetes, non-alcoholic fatty liver disease, obesity and certain cancers and dementias. The mechanisms include increased production of: insulin growth factor-1; reactive oxidative species and advanced glycation end-products; and triglyceride and fatty acids. Hyperinsulinemia also directly and indirectly affects many other hormones and cytokine mechanisms including leptin, adiponectin and estrogen. There is limited research standardizing the hyperinsulinemia diagnostic process. Methodological concerns and lack of standardized reference ranges preclude the use of fasting insulin. Most research has also focused on insulin resistance and it is unknown whether these methods translate to hyperinsulinemia.

Full Paper at https://doi.org/10.15562/diabesity.2015.19

TLDR - Justifying the TG/HDL ratio as a measure of insulin resistance. The importance of this cannot be over stated, since TG and HDL are part of standard lipid panels it means we have a readily available way to determine people's insulin sensitivity right now without needing special tests. (93% of USA people have insulin resistance)

Atherosclerosis is an immunoinflammatory pathological procedure in which lipid plaques are formed in the vessel walls, partially or completely occluding the lumen, and is accountable for atherosclerotic cardiovascular disease (ASCVD). ACSVD consists of three components: coronary artery disease (CAD), peripheral vascular disease (PAD) and cerebrovascular disease (CCVD). A disturbed lipid metabolism and the subsequent dyslipidemia significantly contribute to the formation of plaques, with low-density lipoprotein cholesterol (LDL-C) being the main responsible factor. Nonetheless, even when LDL-C is well regulated, mainly with statin therapy, a residual risk for CVD still occurs, and it is attributable to the disturbances of other lipid components, namely triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Increased plasma TG and decreased HDL-C levels have been associated with metabolic syndrome (MetS) and CVD, and their ratio, TG/HDL-C, has been proposed as a novel biomarker for predicting the risk of both clinical entities. Under these terms, this review will present and discuss the current scientific and clinical data linking the TG/HDL-C ratio with the presence of MetS and CVD, including CAD, PAD and CCVD, in an effort to prove the value of the TG/HDL-C ratio as a valuable predictor for each aspect of CVD.

https://doi.org/10.3390/diagnostics13050929

Full paper at url

Indispensable amino acid (IAA) composition and standardized ileal digestibility (SID) of five animal- and 12 plant-based proteins were used to calculate their respective Digestible Indispensable Amino Score (DIAAS) according to the three age categories defined by the Food and Agriculture Organization (FAO). Mean IAA content and mean SID obtained from each protein dataset were subsequently used to simulate optimal nutritional quality of protein mixtures. Datasets revealed considerable variation in DIAAS within the same protein source and among different protein sources. Among the selected protein sources, and based on the 0.5- to 3-year-old reference pattern, pork meat, casein, egg, and potato proteins are classified as excellent quality proteins with an average DIAAS above 100. Whey and soy proteins are classified as high-quality protein with an average DIAAS ≥75. Gelatin, rapeseed, lupin, canola, corn, hemp, fava bean, oat, pea, and rice proteins are classified in the no quality claim category (DIAAS <75). Potato, soy, and pea proteins can complement a broad range of plant proteins, leading to higher DIAAS when supplied in the form of protein mixtures and at specific ratios. Such complementarity highlights the potential to achieve an optimal nutritional efficiency with plant proteins alone.

Direct PDF here

The focus of this discussion is the impact on ketones, even in the presence of a high carbohydrate diet. i.e. as a drug people consume.

It is a really interesting area of research. A metabolite can function like a epigenetic drug

https://youtu.be/QJEdToMDWZw

25% of these trails are just using supplementation, not dietary interventions.

A Great talk on science literacy, and how even well intended professionals can get mislead by incomplete research. I highly encourage you to watch this video if your curious about reading science literature, and especially in "interpreting' media summaries of flawed papers.

Consider cherry picking by agenda motivated papers

Notice how the One Blue RCT that supported one position was cited exclusively by many more papers then the THREE other RCTs that contra indicated that position?

https://doi.org/10.1136/openhrt-2021-001680

Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet

The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.

Apologies, I had to butcher the title, it was too long for lemmy.

TLDR - Women who had a high omega-6 to omega-3 ratio in their fat where at elevated risk for developing breast cancer.

Seed oils (vegetable oils) are the major dietary driving source of omega-6s. It seems reasonable that seed oils have a outsized cancer risk.

The ratio of omega-3 to omega-6 fatty acids, especially the long-chain eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) to arachidonic acid (AA) ratio, is inversely associated with breast cancer risk. We measured the association between cytologic atypia, a biomarker for short-term risk of breast cancer development, and omega-3 and omega-6 fatty acid intake and levels in blood and breast tissue. Blood and benign breast tissue, sampled by random periareolar fine-needle aspiration (RPFNA), was obtained from 70 women at elevated risk for breast cancer. Self-reported dietary intake was assessed by the NCI's Food Frequency Questionnaire. The fatty acid composition of five lipid compartments, red blood cell, plasma and breast phospholipids, and plasma and breast triaclyglycerides (TAG), was analyzed by gas chromatography as weight percent. Median daily intakes of EPA+DHA and total omega-3 fatty acids were 80 mg and 1.1 g, respectively. The median total omega-3:6 intake ratio was 1:10. Compared with women without atypia, those with cytologic atypia had lower total omega-3 fatty acids in red blood cell and plasma phospholipids and lower omega-3:6 ratios in plasma TAGs and breast TAGs (P < 0.05). The EPA+DHA:AA ratio in plasma TAGs was also lower among women with atypia. This is the first report of associations between tissue levels of omega-3 and omega-6 fatty acids and a reversible tissue biomarker of breast cancer risk. RPFNA cytomorphology could serve as a surrogate endpoint for breast cancer prevention trials of omega-3 fatty acid supplementation.

Full paper at above link

Conclusions: A meta-analysis of prospective epidemiologic studies showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD or CVD. More data are needed to elucidate whether CVD risks are likely to be influenced by the specific nutrients used to replace saturated fat.

General Paper Analysis - This is a meta-analysis of epidemiology. While the meta aspect gives great confidence in the results, we have to be mindful that epidemiology is the weakest of scientific data. A pyramid built on sand - as it were.

But as the paper itself says

such studies have caveats, including a reliance on nutritional assessment methods whose validity and reliability may vary (25), the assumption that diets remain similar over the long term (26) and variable adjustment for covariates by different investigators. Nonetheless, a summary evaluation of the epidemiologic evidence to date provides important information as to the basis for relating dietary saturated fat to CVD risk.

Full paper at the link.

TLDR - as insulin resistance goes up, diseases increase.

2001!!!!! Full paper here

The current study was initiated to evaluate the ability of insulin resistance to predict a variety of age-related diseases. Baseline measurements of insulin resistance and related variables were made between 1988-1995 in 208 apparently healthy, nonobese (body mass index < 30 kg/m2) individuals, who were then evaluated 4-11 yr later (mean +/- SEM = 6.3 +/- 0.2 yr) for the appearance of the following age-related diseases: hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. The effect of insulin resistance on the development of clinical events was evaluated by dividing the study group into tertiles of insulin resistance at baseline and comparing the events in these 3 groups. Clinical endpoints (n = 40) were identified in 37 individuals (18%) of those evaluated, including 12 with hypertension, 3 with hypertension + type 2 diabetes, 9 with cancer, 7 with coronary heart disease, 4 with stroke, and 2 with type 2 diabetes. Twenty-eight out of the total 40 clinical events were seen in 25 individuals (36%) in the most insulin-resistant tertile, with the other 12 occurring in the group with an intermediate degree of insulin resistance. Furthermore, insulin resistance was an independent predictor of all clinical events, using both multiple logistic regression and Cox's proportional hazards analysis. The fact that an age-related clinical event developed in approximately 1 out of 3 healthy individuals in the upper tertile of insulin resistance at baseline, followed for an average of 6 yr, whereas no clinical events were observed in the most insulin-sensitive tertile, should serve as a strong stimulus to further efforts to define the role of insulin resistance in the genesis of age-related diseases.

This graph is all you need to know, as insulin resistance goes up, more diseases increase.

• CVA - Cerebrovascular accident
• Type 2 - Diabetes Type 2
• CHD - Coronary Heart Disease
• CA - Cancer
• HT - Hyper Tension