Metabolic Health

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 - 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 Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators.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.

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

TLDR - Fat is good for you, sugar/carbs not so much

Full paper can be found here

Higher carbohydrate intake was associated with an increased risk of total mortality

Intake of total fat and each type of fat was associated with lower risk of total mortality

Higher saturated fat intake was associated with lower risk of stroke

Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality.

Global dietary guidelines should be reconsidered in light of these findings.

Ben Bikman does a deep dive into hormonal roots of male infertility! This is part of his excellent "Metabolic Classroom series"

TLDR - Stay active and exercise into old age. Sarcopenia is not inevitable.

DOI: 10.3810/psm.2011.09.1933

Aging is commonly associated with a loss of muscle mass and strength, resulting in falls, functional decline, and the subjective feeling of weakness. Exercise modulates the morbidities of muscle aging. Most studies, however, have examined muscle-loss changes in sedentary aging adults. This leaves the question of whether the changes that are commonly associated with muscle aging refl ect the true physiology of muscle aging or whether they reflect disuse atrophy. This study evaluated whether high levels of chronic exercise prevents the loss of lean muscle mass and strength experienced in sedentary aging adults. A cross-section of 40 high-level recreational athletes (“masters athletes”) who were aged 40 to 81 years and trained 4 to 5 times per week underwent tests of health/activity, body composition, quadriceps peak torque (PT), and magnetic resonance imaging of bilateral quadriceps. Mid-thigh muscle area, quadriceps area (QA), subcutaneous adipose tissue, and intramuscular adipose tissue were quantified in magnetic resonance imaging using medical image processing, analysis, and visualization soft- ware. One-way analysis of variance was used to examine age group differences. Relationships were evaluated using Spearman correlations. Mid-thigh muscle area (P = 0.31) and lean mass (P = 0.15) did not increase with age and were significantly related to retention of mid-thigh muscle area (P  0.0001). This occurred despite an increase in total body fat percentage (P = 0.003) with age. Mid-thigh muscle area (P = 0.12), QA (P = 0.17), and quadriceps PT did not decline with age. Specific strength (strength per QA) did not decline significantly with age (P = 0.06). As muscle area increased, PT increased significantly (P = 0.008). There was not a significant relationship between intramuscular adipose tissue (P = 0.71) or lean mass (P = 0.4) and PT. This study contradicts the common observation that muscle mass and strength decline as a function of aging alone. Instead, these declines may signal the effect of chronic disuse rather than muscle aging. Evaluation of masters athletes removes disuse as a confounding variable in the study of lower-extremity function and loss of lean muscle mass. This maintenance of muscle mass and strength may decrease or eliminate the falls, functional decline, and loss of independence that are commonly seen in aging adults.

Despite concerted efforts to improve diet quality and reduce malnutrition, micronutrient deficiencies remain widespread globally, especially in low- and middle- income countries and among population groups with increased needs, where diets are often inadequate in iron, zinc, folate, vitamin A, calcium, and vitamin B12. There is a need to understand the density of these micronutrients and their bioavailability across diverse foods and the suitability of these foods to help meet requirements for populations with high burdens of micronutrient malnutrition

Full paper available at the above URL

a 2021 paper on bioavailability of nutrients needed per day from different whole food sources. I.E. It's not just the macronutrients in the food, it's not just the micronutrients in the food, its how much of the nutrients are bioavailable (absorbed) when consumed.

If you eat 100g of protein but only absorb 4g, your still deficient, etc.

"we provide a direct molecular mechanism for the regulation of misfolded proteins by ketone bodies and related metabolites."..."Given that proteostatic mechanisms like autophagy are known to be activated by nutrient deprivation, it is unsurprising that evolutionary pressures would encourage the clearance of patho- genic proteins during ketosis to promote cellular health in organisms seeking additional substrate for ATP production. In this situation, ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness. This mechanism can be leveraged for therapeutic development in aging and NDDs,"

Summary:

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.

Full paper available at Cell.com

https://youtu.be/jpNU72dny2s

Robert H. Lustig, M.D., M.S.L. is Professor emeritus of Pediatrics, Division of Endocrinology at the University of California, San Francisco (UCSF). He specialises in the field of neuroendocrinology, with an emphasis on the regulation of energy balance by the central nervous system. His research and clinical practice has focused on childhood obesity and diabetes. Dr. Lustig holds a Bachelor’s in Science from MIT, a Doctorate in Medicine from Cornell University. Medical College, and a Master’s of Studies in Law from U.C. Hastings College of the Law.

Dr. Lustig has fostered a global discussion of metabolic health and nutrition, exposing some of the leading myths that underlie the current pandemic of diet-related disease. He believes the food business, by pushing processed food loaded with sugar, has hacked our bodies and minds to pursue pleasure instead of happiness; fostering today’s epidemics of addiction and depression. Yet by focusing on real food, we can beat the odds against sugar, processed food, obesity, and disease.

Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener1. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel2,3. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.

TLDR - "In all cases, diets supplemented with HFCS resulted in faster tumour growth compared with control diets"

I'm having trouble finding the full text of the paper, normal avenues 🦜 are a little behind

https://pubmed.ncbi.nlm.nih.gov/39633044/

Comparing biomarker profiles measured at similar ages, but earlier in life, among exceptionally long-lived individuals and their shorter-lived peers can improve our understanding of aging processes. This study aimed to (i) describe and compare biomarker profiles at similar ages between 64 and 99 among individuals eventually becoming centenarians and their shorter-lived peers, (ii) investigate the association between specific biomarker values and the chance of reaching age 100, and (iii) examine to what extent centenarians have homogenous biomarker profiles earlier in life. Participants in the population-based AMORIS cohort with information on blood-based biomarkers measured during 1985-1996 were followed in Swedish register data for up to 35 years. We examined biomarkers of metabolism, inflammation, liver, renal, anemia, and nutritional status using descriptive statistics, logistic regression, and cluster analysis. In total, 1224 participants (84.6% females) lived to their 100th birthday. Higher levels of total cholesterol and iron and lower levels of glucose, creatinine, uric acid, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, and total iron-binding capacity were associated with reaching 100 years. Centenarians overall displayed rather homogenous biomarker profiles. Already from age 65 and onwards, centenarians displayed more favorable biomarker values in commonly available biomarkers than individuals dying before age 100. The differences in biomarker values between centenarians and non-centenarians more than one decade prior death suggest that genetic and/or possibly modifiable lifestyle factors reflected in these biomarker levels may play an important role for exceptional longevity.

Full PDF of paper is available at the above link

Higher levels of total cholesterol and iron and lower levels of glucose, creatinine, uric acid, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, and total iron-binding capacity were associated with reaching 100 years.

Implies Cholesterol is good, and Glucose control is important, which I think means insulin sensitivity is a key factor in living to 100

One really good aspect of this study vs the normal "blue zone" observational studies, is there is hard data, accurate biographic data (i.e. no poor record keeping, or incentives to lie about age).

A very interesting overview of concussion protocols, the multiple windows of concussive damage, the brain physiology both at the time of impact and during recovery.

Dr. Mason covers some papers that overview dietary interventions post concussion to look at recovery rates.

Dr. Sanjeev Balakrishnan holds a Master of Medicine in Family Medicine from the National University of Singapore and is currently a GP working in Perth, Western Australia. Dr. Balakrishnan has more than two decades of experience and is very passionate about the management of obesity, type 2 diabetes and metabolic syndrome through healthy eating. He is an advocate for the low carbohydrate-high healthy fat diet and is the creator of Low Carb WA. He is a fully credentialed Family Physician in Singapore and is a Fellow of the Royal Australian College of General Practitioners.

A review of different mental health models over time, and the possible impact of nutrition, as well as discussions of areas of exciting possible research.