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Mechanism

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  1. McCoy! Great to hear from you. Hope you and family are all well- and into Covid round 2+ ( if there ever was a lull). yes, that’s a lot of EVOO- if nothing else places into context concerns re: FMD. Indeed, the initial reports may have been I. Part from using refined oil and without vitamins ( summary of those details here, worth the read for anyone not familiar): https://www.oliveoiltimes.com/world/uc-davis-researcher-advises-opt-out-of-olive-oil/51579 Regarding dosing in PREDIMED, “Participants in the group assigned to a Mediterranean diet with extra-virgin olive oil received 1 liter of the oil per week per household, with the recommendation to consume at least 4 tablespoons per day of extra-virgin olive oil per person” though real consumption was less (https://www.nejm.org/doi/full/10.1056/NEJMoa1800389). I owe my initial introduction to EVOO to Michael. Though I think it is possible to have a healthy diet without EVOO, if choosing an oil, EVOO is the best bet. MR’s choice? “I insist on verifiably superior EVOO qualities: high (≥76%) oleic acid content (for oxidative stability, and see above on DHA-accelerated aging hypothesis: olives from different cultivars and regions can vary from 55-83% oleic acid); low peroxide value (<9, and preferably <6 meq/kg), and high (≥350 mg/kg) total phenolics, assayed using caffeic acid equivalents. ” His own take on the literature and I do not disagree is: “The epidemiology strongly suggests 2-3 T/d. I get an average of 5-6 tsp (ie, 2 T or just a bit shy of it); I also get a lot of additional MUFA from nuts (also on 'the list'), Peruvian olives, and occasional avocado, tho' of course EVOO is not just a MUFA source.” By contrast, Valter Longo - hedging his bets a bit the other way [ I won’t mention the flawed / lower quality low-far vegan school of thought data as not to invoke the ire of MR... though I would not dismiss it out of hand either] as a compromise, as detailed in his Longevity Diet book), has advised in the ballpark of 3T/d. There is no perfect data out there but as a whole foods purist (I still prefer nuts!) I have been thoroughly persuaded harm, if any, is minor in the context of a healthy diet/lifestyle and that evidence and statistics favor moderate EVOO as a net positive in the vast majority of diets via in large part from polyphenols, MUFA, and substitution effect for low quality / high GL carbohydrates & “true” nasty refined elements. Mechanism
  2. I was a skeptic at first too Ron (a great health and scientific literacy quality I might add), but looking deeper into the matter, I ultimately came to the conclusion that while yet unproven, there are likely additional benefits ( not by oleic acid alone)! For a sense of perspective, if faced with a choice I would prioritize keeping EVOO (vs refined lower quality OO) much higher than the need for cold exposure . This, even and perhaps especially for those with substantial metabolic dysfunction & metobesity for whom there remains the greatest plausibility for material CE health outcome benefits. The work since this 06’ classic paper (1) has done much more to support than to undermine the evidence: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01963.x (1) Pacheco YM, López S, Bermúdez B, Abia R, Muriana FJ. Extra-virgin vs. refined olive oil on postprandial hemostatic markers in healthy subjects. J Thromb Haemost. 2006 Jun;4(6):1421-2. doi: 10.1111/j.1538-7836.2006.01963.x. PMID: 16706995.
  3. Glad you are doing well Saul. Stay healthy and stay safe!
  4. Thanks for the update Saul. I am very happy to hear you are doing well both health wise and also with a wonderful sense of purpose you have always had - teaching math at the University of Rochester. And with an excellent attendance rate too I recall. Many ease up CRON a bit with age because of the evidence keeping a little extra reserve may prove helpful in the event of an injury or metabolic insult, with some evidence to this effect. Obviously it depends on personal circumstances. I am curious, what made you decide to get “more strict on CRON?” I presume you still follow your biomarkers along with your doctors including the “CR-sympathetic” nephrologist you referred to in the past. You have always been understandably proud of your outstanding lipid panel ratios. Wishing you well, Mechanism PS- I will declare Covid in “a new era” when Kriplalu re-opens. No word yet, AFAIK.
  5. McCoy recently posted re: this fantastic interview- much more detail then the comparatively superficial TED Talk: https://peterattiamd.com/jamesokeefe/
  6. That’s great about the temperature. Hang in there.
  7. Sorry to hear about Mom. I’m glad it had been mild for you, and at least Dad is over it most quickly so will be better able to look out for her too. I don’t think anybody has the answers but I’m sure it will be studied. A shorter course need not mean fewer antibodies. Be well and best to Mom, Mechanism
  8. Hope your family, and you with the exposure, do well Matt. You have statistics in your favor for a milder course.
  9. Dean, are you interested in being interviewed by Peter Attia and debating the cold exposure literature ( meant with encouraging humor; in all seriousness I think that would make a very interesting show) ? For those who are paying/supporting members ( sorry, only first few minutes accessible if not), from here https://peterattiamd.com/ama16/ Listen from 19:57--> 34:05 . Better yet, listen to the whole thing. Great analysis of Sauna therapy data, which he was more enthusiastic about: In essence for Cold Exposure (CE), most data on Delayed Onset Muscle Soreness (DOMS), minimal data in persons for depression and immunity (there actually are some positive studies for immunity, but they did not cite them), and noted for Life Extension (LE) with CE, some data on drosophila and fish, but they reported there was none they saw for mice. They may not have been aware of Dean's oft-cited ""rats with cold feet" study": Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory" J. O. Holloszy and E. K. Smith Journal of Applied Physiology 1986 61:5, 1656-1660 https://doi.org/10.1152/jappl.1986.61.5.1656 This above study has its limitations, and true enough despite the wide variety of promising results described in this thread - including metabolic studies and suggestive inter-species and geographic life extension work - murine life extension studies with good controls remain limited. The evidence for metabolic benefits and some synergies with longevity pathways is relatively stronger than the hypothesis that "CE is a requirement for CR to produce life extension," per se. If CR works at all in humans (in which case I anticipate a modest effect in lifespan but a more robust effect in healthspan), my feeling about it right now is that limiting BCAA/Cys/Met to RDA levels or below is more likely to be a conditional variable for the CR to be effective. Not so much CE by comparison. Some of CR is mediated by pathways overlapping with GH/IIS/mTOR and related pathways, and from the study I cited in my previous post [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253058/] it appears at least some of these pathways (though they did not study CR per se) may work fine regardless of temperature (and perhaps a little better in females at the higher temperature). Finally, Dr. Attia made a point re: causality: whereas CE triggers thermogenesis, the amount of BAT and beige fat appears to be far more under the influence of metabolic health such as remaining slim - without necessarily any special attention to getting in more cold exposure. Not here to debate but rather to be helpful as this is a topic of interest. Agree or disagree, just reporting his comments. Hope all is well in CR-land....
  10. Mechanism

    No wonder SCIENCE is scorned!

    I found this a helpful overview. The authors are not without conflicts of interest, but the data, in my estimation, is pretty solid: A Pesco-Mediterranean Diet With Intermittent Fasting James H. O’Keefe, Noel Torres-Acosta, Evan L. O’Keefe, Ibrahim M. Saeed, Carl J. Lavie, Sarah E. Smith, Emilio Ros J Am Coll Cardiol. 2020 Sep, 76 (12) 1484-1493. https://www.onlinejacc.org/content/76/12/1484 Hope this stirs more interest than controversy!
  11. Fang Y, McFadden S, Darcy J, Hascup ER, Hascup KN, Bartke A. Lifespan of long-lived growth hormone receptor knockout mice was not normalized by housing at 30°C since weaning. Aging Cell. 2020 May;19(5):e13123. doi: 10.1111/acel.13123. Epub 2020 Feb 28. PMID: 32110850; PMCID: PMC7253058. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253058/ Abstract follows: Abstract Growth hormone receptor knockout (GHRKO) mice are remarkably long-lived and have improved glucose homeostasis along with altered energy metabolism which manifests through decreased respiratory quotient (RQ) and increased oxygen consumption (VO2 ). Short-term exposure of these animals to increased environmental temperature (eT) at 30°C can normalize their VO2 and RQ. We hypothesized that increased heat loss in the diminutive GHRKO mice housed at 23°C and the consequent metabolic adjustments to meet the increased energy demand for thermogenesis may promote extension of longevity, and preventing these adjustments by chronic exposure to increased eT will reduce or eliminate their longevity advantage. To test these hypotheses, GHRKO mice were housed at increased eT (30°C) since weaning. Here, we report that contrasting with the effects of short-term exposure of adult GHRKO mice to 30°C, transferring juvenile GHRKO mice to chronic housing at 30°C did not normalize the examined parameters of energy metabolism and glucose homeostasis. Moreover, despite decreased expression levels of thermogenic genes in brown adipose tissue (BAT) and elevated core body temperature, the lifespan of male GHRKO mice was not reduced, while the lifespan of female GHRKO mice was increased, along with improved glucose homeostasis. The results indicate that GHRKO mice have intrinsic features that help maintain their delayed, healthy aging, and extended longevity at both 23°C and 30°C. Keywords: GHRKO; growth hormone receptor; lifespan; metabolism; temperature; thermogenesis.
  12. 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.
  13. 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/
  14. 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.
  15. 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.
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