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  1. Saul, I don't think we disagree. I am not arguing against CR. It is the use of the phrase “radical human life extension” that usually conjures living 150 years+ , which is not realistic as uni-therapy. Restricting calories can be good or bad, depending on the extent, the manner, and person. Anyone is and should be free to pursue their own destiny, ideally applied soundly and with appropriate counsel and knowledge of risks and benefits. Michael Rae, for example, executes CR brilliantly.
  2. Mechanism

    Metformin and appetite

    Many scientific legitimate debates may linger indefinitely because sufficient evidence has not arisen to resolve the matter one way or another. Worse yet, some questions can never have the definitive study because they are impractical, unethical, too costly or lengthy, or even by design. Fortunately not all matters are opaque. When empirical evidence is available at an outcomes level - provided sufficient strength, clarity and consistency and convincing in nature - debating mechanisms may not be required except for other purposes such as to answer other questions, make actionable inferences. I am not commenting on these publications per se, but consider them high yield as far as the matter of MTOR1 inhibition, mechanistically. Still in the gray is Metformin in man with regard to sarcopenia one way or the other. Peter Attia MD for example no longer takes Metformin for multiple reasons, as hr discusses in his The Drive podcast recent joint interview of Joan Mannick and Nir Barzilai. The diminution of gains in muscle hypertrophy ( which Nir argues does not matter since there was no significant difference in strength), the modest lower VO2max in another study (which is a strong predictor - along with strength>hypertrophy re: the former consideration - of mortality ), the question of whether benefits>risks in metabolically healthy and physically active individuals near their ideal weight, etc. were among his other considerations - tipped off by the observation of increased lactate levels working out on Metformin ( and the clinical impact of a minor shift in anerobic threshold is also ambiguous and may or may not matter). Reasonable differences of opinion can prevail here; notably animal models have been very favorable for Metformin ( and generally at higher dose-equivalents than used in man though this also begs the question of how much benefit in man at the lower levels we can tolerate) this and some other measures of frailty better in mice too. Noteworthy is the ITP’s more rigorous attempt to recapitulate life extension failed as a null finding but even if this could be generalized to man ( it can’t), there may be other benefits - and risks - and tradeoffs depending on the individual , their circumstances and their values. Provided no major hitches, the outcomes from TAME should be more definitive. Back to the matter of mechanisms vs. outcomes.....as patients we care more about the latter but moreover **throw out the theory** if there is good definitive evidence ( see above) one way or another measuring the outcome(s) that you care about. In persons, studies like TAME will tell us a lot more, though no doubt with room for debate such as pertinence to healthy populations very different than the older, less optimized study population. It would however provide much more of a more reliable framework. The decision to make inferences from some of the considerations above and decide pro or con in the meantime is a very personal one; it only should be intimately familiar with the major studies so that informed choices can be made with the respective prescriber. Besides that work, these two references I will provide with no comment or opinion. I share them only for pertinence to some of the peripheral issues distinct from the Core Metformin discussion ( because quality RCT outcomes evidence trumps mechanism around the narrow issue of what outcome we would expect, right?..... there are exceptions even here because mechanisms matter not only for observational studies that can confuse cause and effect but likewise even in quality RCTs if they explain why you may or may not respond the same as study participants or if the intervention arm undergoes more than one potentially causative intervention ) debated above. Carefully studying the state of the science edifies healthy, reasonable and productive discourse. If you find this interesting, enjoy, CR-gang ( and if it tickles your fancy debate anew with this knowledge)! Deliberately set up so you need to click on the mysterious links to get the title.... and hopefully be swayed to read on, in full, so you can make up your own mind, and keep reading new evidence, and broadly... 1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015237/ 2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738401/
  3. Mechanism

    Metformin and appetite

    Mike, I quoted you to a loved one for both insight and inspiration. The ripple effect is extraordinary. Thank you for sharing your story.
  4. I agree with Gordo. On the subject of fasting & TRF, many great reviews. Start with this one: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388543/ Both authors are pioneers in their fields.
  5. Right. The most sensible guide to supplements I have read - from a philosophical standpoint - was from none other than MR. I don't necessarily follow or endorse his protocol per se - but rather the philosophy behind it, which closely parallels my own. In his thread on the subject ( https://www.longecity.org/forum/stacks/stack/122-michaels-tiered-supplement/ ) he quoted Oakman, and I will credit Michael for crediting him: "This is put very well in Oakman's "pothole theory" of supplementation" ----> from Oakman "If you don't have a 'hole' in your metabolism, meaning a diminished ability to produce something due to age or malfunction, or lacking it altogether, supplementation isn't unlikely to help. Plus, you only need enough to fill the 'hole,' not more (i.e., a "bump" is as bad as a "hole")." Mechanism again: Precision, personalized medicine recognizes everybody is different, so in my book there is no one supplement regimen fit for all. But whether you take lots of supplements or just vitamin D or vitamin B-12, remember Oakman's wisdom.*** *** [ Mechanism footnote]: Every great rule has exceptions; there is something to the difference between sufficiency and optimal levels... it is a matter of semantics as well as practice how high a dose is needed to fill the hole.... it may be more than the RDA depending on the person, condition, circumstances, etc. Though the ultimate role for geroprotectors are still being worked out, it would be prudent to optimize the dietary foundation of good nutrition through a moderated calorie, minimally processed and refined diverse whole foods based diet first, only then turning to supplements if and as required and desired beyond those limits.
  6. This paper (1) is downright fascinating, linking two topics of interest here through a mitochondrial BCAA transporter: 1) BCAA ( which connects with nutrient-sensing pathways, metabolism, sarcopenia among other themes) and 2) brown fat metabolism and health The authors (1) identified a mechanistic link between BCAA's favorable role in energy metabolisms in some contexts, yet contribution to metabolic syndrome and related conditions in others, and it appears that brown fat activity appears to mediate the relationship in a context-dependent manner. In a nushell, BCAA catabolism in BAT promotes BCAA utilization and clearance via thermogenesis, and paraphrasing them from below, this mechanism has the potential to mitigate diet-induced obesity and glucose intolerance. Remarkably in the follow-up work from their rodent models they found that valine and leucine "was significantly reduced, preferentially in high BAT subjects following cold exposure, whereas no statistical change was seen in low BAT subjects." The cold exposure was not extreme, and was set at deliberately below the shivering thermogenesis temperature threshold, with cold exposure (19°C) for 2 hours - that's just over 66 Farenheit(!). We still need to study and measure the clinical impact of these reductions in BCAA, but taking it from lab to the subjects and then measuring and confirming a significant drop in BCAA ( a surrogate for metabolic health among sequela) is very much to their credit, and a boon to the potential implications of this work. The abstract pretty much sums it up: "Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health." The discussion was short, but to the point: Our study suggests the following model (Fig.4j besides glucose and fatty acids, cold stimuli potently increase mitochondrial BCAA uptake and oxidation in BAT, leading to enhanced BCAA clearance in the circulation. This process requires SLC25A44, a previously uncharacterized mitochondrial BCAA transporter in brown adipocytes. In turn, defective BCAA catabolism in BAT leads to impaired BCAA clearance and thermogenesis, leading to the development of diet-induced obesity and glucose intolerance. This model provides important implications in the regulation of systemic BCAA metabolism under an obese or diabetic state in which impaired BAT activity and increased circulating BCAA levels are observed in humans and rodents. It has been suggested that the accumulation of incompletely oxidized intermediates derived from BCAA oxidation, such as 3-hydroxyisobutyrate (3-HIB), cause insulin resistance9,23,24. Conversely, lowering circulating BCAA levels by inhibiting the kinase BDK or overexpression of the phosphatase PPM1K in the liver improves glucose tolerance independently from body weight loss in rats25. Furthermore, reduced mitochondrial BCAA oxidation and subsequent accumulation of intracellular BCAA concentration leads to constitutive activation of mTOR signaling, resulting in persistent IRS-1 phosphorylation by mTORC1 and inhibition of insulin signaling6,23,26. The present study suggests a distinct yet non-mutually exclusive mechanism in which impaired BAT activity under an obese or diabetic state reduces systemic BCAA clearance, while active BAT acts as a significant metabolic-filter for circulating BCAA and protects against obesity and insulin resistance. It is conceivable that enhanced mitochondrial BCAA catabolism via SLC25A44 may serve as a promising strategy to improve systemic BCAA clearance and glucose homeostasis. Lots more of interest in the paper methodology details ( you are all now reading the papers, right? 😉) (1) Yoneshiro, T., Wang, Q., Tajima, K., Matsushita, M., Maki, H., Igarashi, K., Dai, Z., White, P. J., McGarrah, R. W., Ilkayeva, O. R., Deleye, Y., Oguri, Y., Kuroda, M., Ikeda, K., Li, H., Ueno, A., Ohishi, M., Ishikawa, T., Kim, K., Chen, Y., … Kajimura, S. (2019). BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature, 572(7771), 614–619. https://doi.org/10.1038/s41586-019-1503-x
  7. Luigi Ferrucci is NIA's scientific director. Much of his work has focused on the relationship between inflammation and frailty. He wrote a very nice review of the subject in 2017: "Aging, Inflammation and the Environment" (1). It does a great job going into the underlying basic science. A more clinical focus ( and easier read for the casual reader less comfortable going into mechanisms and more interested in applications) was a collaboration published in Nature Medicine (2). You will recognize many of the authors here such as Nir Barzilai ( of his TAME study [re: metformin] and the "Age Later" book), Judith Campisi for her pioneering work on senescence, Eric Verdin from the Buck, etc. It was very well written and has sections focusing for example on physical activity, environmental toxins, nutrition, the microbiome, etc. I would be remiss not to mention one other review, specifically focusing on CR and Senoinflammation (3) - recall that much of inflammation is SASP byproduct from senescent cell ( along with primarily non-specific immunological activation with some hotspots such as in association with visceral fat, endogenous and exogenous sources of AGE / glycosylation, etc.). Lots of focus on the anti-senoinflammatory effect of CR, as well as a few CR-mimetics. Lots of others, but these are my current favorites. I mentioned the problem of reverse-causality in the previous post ( association is not causation, and aging can cause inflammation rather than just vice versa; certainly some degree of both is happening and these relationships are still being elucidated) and another issue was brought up above is regarding the use of antioxidants - which are mostly not helpful supplementing except to replete a deficiency or address specific stress situations and have been found to be counter-productive for most "natural" models of aging; indeed the oxidative theory of aging has been undermined over the years by various evidences but that is a whole other story). There was a beautiful recent publication in Harvard Magazine ( excerpt from a book, and regretfully not without a quick citation though I'm sure it is not hard to pick up the individual studies, some of which we have read and discussed here previously - the vitamin C, E, and A studies are absolute classics, I am sure we are all familiar with them), which looked at this from the perspective of exercise. I will quote this eloquent short passage here (source: https://www.harvardmagazine.com/2020/09/features-active-grandparenting "The problem is that dozens of studies have found that taking antioxidant pills is no substitute for physical activity to fight senescence. Three or four studies reported a modest benefit, but the rest found that antioxidants provided no benefit or even increased the risk of dying. To add insult to injury, additional studies suggest antioxidants may sometimes do more harm than good when combined with exercise. This head-turning conclusion followed from a groundbreaking 2009 experiment by Michael Ristow, a researcher in Zurich who studies aging and metabolism. His team asked 40 healthy young males with varied fitness levels to undergo four weeks of supervised exercise. Half the participants were given large doses of vitamins C and E, the other half received a placebo. Muscle biopsies taken before and after their exercise bouts showed that, as expected, physical activity induced plenty of oxidative stress, but those who took antioxidants incurred more oxidative damage because their bodies produced much lower levels of their own antioxidants. The antioxidant pills apparently suppressed the body’s normal anti-stress response, probably because oxidative damage from exercise itself is needed to trigger the body’s health-promoting antioxidative defense mechanisms." (1) Bektas, A., Schurman, S. H., Sen, R., & Ferrucci, L. (2018). Aging, inflammation and the environment. Experimental gerontology, 105, 10–18. https://doi.org/10.1016/j.exger.2017.12.015 (2) Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., Ferrucci, L., Gilroy, D. W., Fasano, A., Miller, G. W., Miller, A. H., Mantovani, A., Weyand, C. M., Barzilai, N., Goronzy, J. J., Rando, T. A., Effros, R. B., Lucia, A., Kleinstreuer, N., & Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. Nature medicine, 25(12), 1822–1832. https://doi.org/10.1038/s41591-019-0675-0 (3) Kim, D. H., Bang, E., Jung, H. J., Noh, S. G., Yu, B. P., Choi, Y. J., & Chung, H. Y. (2020). Anti-aging Effects of Calorie Restriction (CR) and CR Mimetics based on the Senoinflammation Concept. Nutrients, 12(2), 422. https://doi.org/10.3390/nu12020422
  8. That's a great study Mike. I was going to say yes, consistent with a study that Rhonda Patrick of Foundmyfitness.com has cited several times. Then I clicked on the link handily provided, and found it is the same 2015 study. Just as true now as then - with evidence for both causality and reverse-causality, and almost certainly both operating. Thank you Mike!
  9. Welcome aducknamedjoe, It looks like you are one of its authors ( you list your website in your profile as https://www.longevityadvice.com/ ). I read it prior to your post , very recently when it came out and you posted it to social media. I read the bios of the creators too. It is great to see enthusiasm towards life-extension and healthy living culminated in a project that is also a calling ( from what it sounds like, I assume you are J.P.?). I hope it helps generate awareness across the community and moreover enjoy the process. I am sure you are going to learn a lot - not only more on LE, but also running a business! t is a big playground and lots of people to reach. Perhaps you can synergize with lifespan.io somehow? In any case, good luck with your new enterprise!
  10. Mechanism

    New book on aging

    Even the seemingly highest quality studies can have a multitude of problems, known, and unknown. For this reason it seems fair to look at the preponderance of evidence, weighing more heavily the highest quality evidence - a sort of fuzzy mental meta-analysis if you will. Unfortunately with the cost, length, and other barriers, prospective life-long monkey trials like these two in CR are unlikely to occur ( except much more modestly in shorter lived more distant primates like lemurs, has produced some publications, with note underway). Lest of all in people. So what are we left with? Longo’s so called pillars of evidence including biomarkers, other animal models, natural history studies, etc.... and making the best of the data we do have. Matt’s citation of the summary from the NIH corresponds to an extensive 2017 effort and collaboration between the two centers “to more fully assess possible explanations for the discrepant findings between the two studies” [through] “comprehensive assessment of longitudinal data from both sites highlighting differences that may have contributed to the dissimilar outcomes.” Though the authors were in my estimation appropriately cautious and qualified in their analysis concluded “Data from both study locations suggest that the CR paradigm is effective in delaying the effects of ageing in nonhuman primates but that the age of onset is an important factor in determining the extent to which beneficial effects of CR might be induced” and that “Taken together, data from both UW and NIA studies support the concept that lower food intake in adult or advanced age is associated with improved survival in nonhuman primates” Even presuming agreement here (dissent and healthy skepticism and counter-interpretation of the evidence are proud and valuable scientific traditions) , to what extent restricted calories yielded benefit through prevention of obesity, metabolic syndrome and related factors versus by true “CR” restricting calories beyond that point remains an open question. So this still does not answer Dean’s question ( or proposal). There is lots of room for interpretation. The skeptic will argue that the controls are sedentary and overfed ( and a quick glance at their diet compared to NIA is certainly reminiscent of the standard American diet - pretty terrible) while the optimist may concede this point but still argue that the controls were a bit too restricted in their feeding protocol and point toward the superior glucoregulatory control and some biomarkers and reduced cancer incidence in CR group at both centers. It is easy to go back and forth in debate indefinitely from there. For example that the lower cancer and better glucose disposal if helpful must statistically speaking be hindered by other poor outcomes at the NIA site given a failure to show appreciable net life-extension.... and then a number of potential counter-counter arguments from there, such as that these deaths are perhaps avoidable or artifacts of the study protocol..... Potential objections are in practice subjectively weighed in mind and discourse, depending on how one perceived those other pillars of evidence. Such as Matt’s citation above investigating transcrional profiles among CR persons documenting “The PI3K and AKT transcripts were significantly down-regulated 1.7 and 2 folds” , upregulation of AMPK, downstream transcripts of FOXO3A, the sirtuins, PGC-1α, etc. as we see in other model organisms under CR. In your Bayesian mental model of “truth” how much ( if any ) does that push your overall appraisal in one direction or another? The point is, the pillars of evidence are at a minimum subjective - certainly in the absence of a strong enough stacking of data one way or another relative to the null hypothesis on CR. People are different than model animals. Surrogates are still just surrogates. There is biological plausibility, and a portfolio of data, and with no prospect for a true CR RCT in man. Given the inexact science, where does that leave us? 1) Look at all the pillars 2) Read the studies yourself, and understand them. It doesn’t matter how many times the 2017 study has been cited if you don’t scrutinize it yourself - and the evidence and publications consistent and inconsistent with it. 3) Respect science and the limitations of the boundaries of knowledge. The larger the departure from a strong evidence base and common practice, the more caution that is warranted. This does not mean being a “sheep” and following the herd off the cliff of the standard American lifestyle. Every choice not taken is a choice as well, and both have consequences, for worse or better. It does mean educating yourself, performing due diligence, and consulting colleagues and professionals as appropriate for your situation. Proactive pursuit of a healthy lifestyle is not easy, but it is well worth the effort. Best, Mechanism PS-, if you have not read it yet, this reference is a real beauty. I hope this helps a little. Stay safe and be well!! (1) Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063. Published 2017 Jan 17. doi:10.1038/ncomms14063 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247583/
  11. Mechanism

    TMAO & Cardiovascular Disease

    Thank you Sibiriak for sharing. Prospective randomized designs do not eliminate the potential for confounding but help. You may be interested in this randomized crossover RCT (1) just published in the American Journal of Clinical Nutrition. I am not sure what to make of the order effect ( nor necessarily the authors ), but with the solid methodology this strong effect size is compelling: ”Mean ± SEM TMAO concentrations were significantly lower overall for Plant (2.7 ± 0.3) than for Animal (4.7 ± 0.9) (P = 0.012)” Open questions as I see it are the relative dietary quality of the two interventions, and ongoing research needed to assess the clinical impact of the differences in TMAO level. Regardless of the apparent quality of the study, consistent replicability of the findings is also imperative. (1) Anthony Crimarco, Sparkle Springfield, Christina Petlura, Taylor Streaty, Kristen Cunanan, Justin Lee, Priya Fielding-Singh, Matthew M Carter, Madeline A Topf, Hannah C Wastyk, Erica D Sonnenburg, Justin L Sonnenburg, Christopher D Gardner, A randomized crossover trial on the effect of plant-based compared with animal-based meat on trimethylamine-N-oxide and cardiovascular disease risk factors in generally healthy adults: Study With Appetizing Plantfood—Meat Eating Alternative Trial (SWAP-MEAT), The American Journal of Clinical Nutrition, , nqaa203, https://doi.org/10.1093/ajcn/nqaa203 (https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqaa203/5890315?redirectedFrom=fulltext )
  12. As noted in the first post , in this case “inducing hyperglycaemia in the weeks before exercise training is associated with blunted gains in exercise capacity and aerobic remodelling, suggesting that hyperglycaemia may impart a resistance to aerobic training adaptations.“ As per Tom’s recounted responses to exercise and perennial and recent discourse into “individualized responses,” ( and the post above), the authors speculated that this may account for these differences in at least some individuals. OTOH, to Dean’s point in other threads, indeed there was still some improvement even with blunted aerobic capacity, and other benefits such as improved insulin sensitivity. Ar least this mechanism is partially modifiable via CR; there are others no doubt not so much or not at all.... so like so many things a mixed picture. (1) MacDonald TL, Pattamaprapanont P, Pathak P, et al. Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise [published online ahead of print, 2020 Jul 20]. Nat Metab. 2020;10.1038/s42255-020-0240-7. doi:10.1038/s42255-020-0240-7 Direct Link: https://www.nature.com/articles/s42255-020-0240-7
  13. Sorry Sibiriak, McCoy -- I read some of my old posts and found that across the board most of the historical posts were at a minimum amateur, poorly cited, and low in quality, or else worse incomplete, inaccurate, or outdated. I was concerned that maintaining it could lead to misappropriation of information and potentially harm. As my knowledge base has expanded substantially I now hold myself to a new standard.... I felt it better for the board to repopulate with more newer, more timely, and accurate information than to maintain information that potentially may lead others astray. Information can change, but qualifications, citations, etc. can at least be supported and appropriately qualified, as I now feel is an appropriate standard for a semi-permanent medium. Preferences for discourse can change too - recall Dean used to have an active link to his biomarkers which was subsequently removed. I respect this personal choice, and can understand. Ultimately though, given the voluminous nature, it was more realistic to systematically remove than curate individually - this was the only way to ensure it was systematic and provide confidence I would not be negligent in my intention. Thank you for understanding - I regard the posts by MR and Dean to be the closest to a gold standard here, with lots of excellent contributions worthy of evergreen status by others throughout the community. Not all is lost. I am happy to provide helpful info - please PM me if I can help with anything. Best, Mechanism.
  14. Mechanism

    April's CR Diary

    I just read the most recent 2020+ entries. You are a natural writer. I was very sorry to hear about Mom ( and doggy). I wonder whether now might be a good time to re-read “"Rant: Moderate CR" from which the title of this post was taken... Sept. 2002”? I have never read it so I don’t know whether it would help or hurt but you speak fondly of it. ( on that note if you still have it can you PM it to me? I am a CR member so I should be able to find in the archives in principal, but the interface is buggy and I can’t access it. best wishes and keep writing. ps- I take the side of moderation > true CR for the masses since it is lower risk and yields most of the benefit and would have higher compliance. Those that would benefit from further CR without undo risk and permit screening to see whether they are good candidates for stronger forms. It depends on the individual - physical and mental health as well as genetics and age, comorbidities, etc. but anything you can do to spread the word on safe moderation of calories would make a world of difference to the patient ( and as per your conversation with Brian and your own subsequent MPH) and public health. Another thought for you. If you are looking for inspiration, consider attending national conferences. For example the breakout social intermissions at NYC’s ending age-related disease conferences ( online this year). Not CR-focused per se, but health optimization certainly.
  15. Mechanism

    April's CR Diary

    Great to see the blog revived April, thank you for updating us. The underlying mechanisms for CR are better understood than ever. Keep it up 👍