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  1. Hi Ron, See the follow up Leiden Longevity Study publication, Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study (1). There they found that "lower IGF-1/IGFBP3 molar ratios conferred a survival benefit at the age of ninety years or older [and] Secondly, lower IGF-1/IGFBP3 molar ratios were associated with better functional status at the age of ninety years or older." To reconcile these findings with the earlier work you cited they speculate: This is within the context of an overall literature whereby a " large number of studies have reported an association between reduced IIS activity and longevity in various model organisms as well as in human studies showing life extending effects of reduced IGF-1 signaling." For more on this literature see ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective (2). The references in this brief piece cite some of the classic studies to unpack further. With regard to targets, I agree with Michael that provided nutritional adequacy and no other pertinent contraindications or individual and medical condition exceptions, that simulating IGF-1/IGFBP3 ratios more closely approximating the "low protein" group than the "low calorie" and "standard American diet" groups is likely generally better: See the first page of this thread where Sibiriak helpfully provided the link-out to the earlier thread. Consistent with the bar chart that Michael reproduced from the Aging Cell paper is data from (1). A ratio of ~ 0.09-0.15 may be optimal. References (1). van der Spoel E, Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, de Craen AJ, Westendorp RG, van Heemst D. Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study. Aging (Albany NY). 2015 Nov;7(11):956-63. doi: 10.18632/aging.100841. PubMed PMID: 26568155; PubMed Central PMCID: PMC4694065. (2) Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective. Front Endocrinol (Lausanne). 2019 Feb 1;10:27. doi: 10.3389/fendo.2019.00027. PubMed PMID: 30774624; PubMed Central PMCID: PMC6367275.
  2. 💥 Dang autocorrect! Gets me every time....
  3. The thermonuclear housing debate - current standing in 4 Links Forgive me Dean for any redundancy, but a recent commentary strung together very nicely the current standing of the research landscape. I think including them here, in sequence, as a shortcut for those new to the issue to quickly get up to speed on the controversy and state of the science may be helpful. And fortunately the debate is narrowing with increased consensus that indeed ( as #4 concludes): “mice should be housed slightly below thermoneutrality to best mimic humans thermal conditions.” 1) Here is Speakman’s original 2013 paper and argument that thermonuclear housing is adequate ( discussed previously along with critiques and reposted here to recapitulate the story line ). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757658/?report=reader#__ffn_sectitle 2) 2018 experimental data - with a very elegant design - from Jan Nedergaard investigating Speakman’s hypothesis and calling into question his conclusion https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784327/?report=reader#__ffn_sectitle 3) Speakman’s 2019 follow up experiment and response to Nedergaard — despite the tone, please observe on a close read that the conclusions have more commonalities than differences with the Nedergaard study. Indeed they revise upward their estimate optimal temperature from the original first publication. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599456/?report=reader#__ffn_sectitle 4) Hot off the press now: Nedergaard’s response. For CRONIES looking for a quick bottom line, if you read nothing else, start here and work your way back to the other links provided to fill in details and examine the raw data for yourself Here the authors summarize their own work cited above from 2018 evaluating Speakman’s hypothesis, and cite the 2019 by Keijer / Speakman work emphasizing that both publications found that for mice the daily metabolic rate at 30 °C is about 1.7-1.8 times higher than their BMR — approximately the same ratio as found in free dwelling persons. This makes the case for their conclusion that: “thermoneutrality is the optimal housing temperature for mouse metabolic studies directed to being translatable into humans.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667698/#__ffn_sectitle Of course much more work remains to establish the extent of impact, for what medical conditions, interventions, and populations, so there is a lot more detail to fill in here I have found much of the utility of this thread pertains not only to this but moreover, on a practice level, to incrementally address and better characterize who benefits, by how much, and for what magnitude ( dose/duration/frequency) of different CE exposures along a multitude of potential health-related dependent variables of interest.
  4. Great summary Dean, I thought you would appreciate it too. And Sibiriak - I love your irreverent humor. True enough while I favor “natural” approaches over drugs whenever possible at multiple levels and for many reasons ( though they are usually not mutually exclusive) - when technology advances to intervene with greater efficacy and safety, I would not hesitate either - even the “D” word. The challenge is that evolution has had a head start of hundreds of millions of years coupled with massive parallel statistical reshuffling for both safety and efficacy - for most lifestyle conditions and most of the time nature is still much smarter than us!
  5. Very interesting: Though I practice some “convenience CE” I more formally maintain low dietary BCAA and (M+C). So this new publication piqued my interest. It is testimony to the mounting documented crosstalk between CE and geroprotective nutrient sensing metabolic pathways. https://www.nature.com/articles/s41586-019-1503-x
  6. Mechanism

    Cronometer results for the FMD

    WRT common causes in fasting, if the cramping is uncomplicated and reproducible and not due to dehydration ( can check urine color if not supplementing and more diluted than straw colored) , electrolyte imbalance is high in the differential diagnosis. Hypomagnesemia ( low Mg++) would be #1 though hyponatremia (low Na+) and hypokalemia ( low K+) are typically mentioned in the same breath. All of these are more common with multi-week or month prolonged fasting as opposed to shorter and/or partial (e.g. FMD) fasts - hence important to exclude other potential etiology as per my original post. Electrolytes can be an issue, depending on the diet composition, with the ketogenic diet and/or metabolic ketosis too: Here's the short version: https://blog.virtahealth.com/muscle-cramps-ketogenic-diet/
  7. Sibiriak, Nice links and insightful comments, as always. Indeed the supplement industry - perhaps in exaggerated fashion relative to some other sectors - is a microcosm of life: in answer to “why things are they way they are,” at least part of the explanation is often, “follow the money.” The initial promise of NR was not without reason. Indeed MR takes NR ( coincidence? I think not! “Michael Riboside” has a nice ring to it, and “Nicotinamide Rae” may trump that). He does so with ample caution and qualification though - see https://www.longecity.org/forum/stacks/stack/122-michaels-tiered-supplement/ . For my part I have followed the NR story over the past few years and every time I edged closer to seriously considering supplementation, without delay it was followed by another study raising sufficient concern over risk outweighing hypothetical and questionable efficacy - particularly in healthy non-geriatric CR’d individuals. I have held off. As with all things lifestyle, when the preponderance of data changes, I will change with the data.
  8. Mechanism

    Remember the precautionary principal

    I’m happy to hear that Ron. i also enjoy STEM talks very much. The host has a bit of pro high protein, pro-keto orientation, but generally they try to remain as objective as possible, and moreover consistently have good questions for their guest in this well-curated podcast.
  9. Mechanism

    Blood Pressure

    Thanks Tom, enjoy the selection 😊
  10. Mechanism

    Blood Pressure

    Hi Tom, that’s wonderful - hiking and walking and biking are my thing ( Ms Mechanism also loves hiking - we will be in the San Diego and San Francisco area next week so any tips out there are welcome - will probably see some redwoods and tour wine country ) - easier on the joints but also enjoy jogging periodically. I spend most of the day on my feet and ( home) cycle OMAD postprandially on non-fasting days myself. As for podcasts I listen to dozens ( like you walking/hiking and also biking) so hard so many choices but after Attia which is the best, a couple of my favorite are Found My Fitness through these come out more seldom than I wished and “STEM Talk”. HumanOS is like Attia’s “Drive” is another high quality one. Others are hit or miss but can have great guests on occasion, like Joe Rogan occasionally has good guests as does HVMN, sometimes Ben Greenfield, Revolution Health, Mastering Nutrition, Kevin Rose, Doctor’s Farmacy, Tim Ferris, Quantified Body, TED talks, etc . There is a tremendous amount of misinformation and low yield too basic info which unfortunately makes up the majority even among my 2nd tier choices so I am quite selective which episode I listen to depending on the guests. Another fun one that I pulled the plug for before is Live Long and Master Aging - more like a storycorp of longevity enjoyable human interest piece. As I have progressed up the rungs of geroscience health education I have gravitated more towards talks from conference proceedings and lectures to supplement my reading primary journals such as Cell, Nature, The Lancet, NEJM, JAMA and the Archives, Cell Metabolism, Science Translational Medicine, Biogerontology, Aging Cell, Nutrients ( for fun), etc. The lectures sometimes have additional researcher insight and/or unpublished observations or data that complement going through and analyzing their published findings. I get wind of conferences and lectures available online via search of YouTube vs. sometimes threads from Longecity, Reddit’s in longevity, food science, and fasting, and Longecity, lifespan.io, Fight Aging! ( one of my favorite for quality commentary) and other publications, Etc and tweets and/or Facebook entries from organizations and researchers. For example Luigi Fontana, Valter Longo ( when he has a more scientifically oriented interviewer so that it can stray more from his Longevity Diet and FMD taking points for the less acquainted), Matt Kaeberlein, Satchin Panda, and many others as well updates from the Buck, AFAR, SENS, the Glenn Foundation, etc. it depends on your interest and how deep your interests go. I will soon likely take another hiatus from the board to allow time to dive deeper and invest further in my geroscience core competencies and information acquisition. I have posted a little more recently in part to “give back” as I benefitted tremendously from so many here and have had the benefit of building on that on my over my last hiatus away from the forums. I have a ways to go but the biggest step function improvement has been committing to digging into the methods section and making my own critique of the original results in the paper’s tables and otrher representation of their data prior to pursusal of the author’s own interpretation of their results ( which I often disagree with), review of the of the primary publications and dialogue between researchers in editorials, commentaries, discussions and at conferences and symposium. These were mostly skill set from my PhD years but I had to commit to them with discipline like I have been for keeping up with the medical knowledge in my own clinical field. Happy to make other recommendations but those are a few of the big ones and how it fits I with the rest of my learning. Eventually I will be going systematically through at least one textbook, but focusing on rounding out my lifestyle and preventative medicine ( clinical as opposed to basic science) learning objectives first. Oh, one more pearl, this is going to take you a little time to go through ( which should be good)- not as high yield in terms of actionable guidance but I personally found fascinating ( listened to it 3 times): https://podcasts.apple.com/us/podcast/bio-4125-biology-of-aging-with-doc-c/id302734065 ( a few error in there but mostly good from this undergraduate lecture series). Needless to say Coursera, EdX and other Moocs occasionally have a health or aging related course and I have taken a number of these free. Best, Mechanism PS- sorry for the typos- 90% of my posts including this one are thumb typed ( often while peddling my home bike or on an elliptical or off-road level hike) and have autocorrect which sometimes messes things up; happy to clarify where needed.
  11. Mechanism

    Remember the precautionary principal

    Great comments McCoy. Besides the risk/reward ( and anticipated probability) considerations I also find like you that philosophy influences my health and lifestyle choices. These can change over time too. I aspire to maintain scientific objectivity being open to new data, and this, in turn, encourages new insights and paradigms in health. For example, the ancestral paradigm with a whole foods / minimally processed emphasis is a conceptually sound heuristic towards mitigating risk and other benefits. My initial feeling growing up in the 80s was vegetable oils are by their nature processed and eschewed them. This seemed to be supported by the limited lower quality evidence at the time. However as the data evolved, so has my position and hence philosophy to be congruent with it. So although most of my fat intake comes from nuts and avocados ( olives making up only a small % due to the sodium), I do partake in EVOO. Particularly if enables a particular dietary goal - for example for diversification or if I desire to keep my net carbohydrates modest while gaining substantial weight on a given day and do not wish to exceed my personal upper limit on nut consumption. I have had a similar evolution in “unnatural” supplementation staring initially with vitamin B12, then D3, etc. My own evolution of philosophy makes me sympathetic to individual differences in our preferences, values, risk aversion, subjective assessment of the likelihood and magnitude of benefit as well as personal circumstances in governing health choices. I feel that the governing principal for a wise choice is one that is based on awareness of the best current “state of the science” evidence with self-awareness. Mindful choices also should be congruent with our long term values projecting forward into implications of our choice on our future self and the broader stakeholders including our loved ones. I like your example of CE. There is increasing support for the position that fat remodeling and related cell biology ( for example in the peroxisomes and mitochondria) mediates a significant portion of the influence of CR in model organisms, for example through PGC1alpha. Indeed, Rosalyn Anderson speculates that part of the mechanism by which 40% CR failed in some mouse strains may be due to inadequate remodeled fat to mediate the metabolic and signaling switch seen in CR. Recall follow-up work demonstrated less aggressive CR worked for most of these such that now ~95% of models have demonstrated CR benefit. So is this the CE effect on that minimal residual fat needed to mediate CR or another mechanism? Adipose tissue remodeling and metabolic pathways indeed seem to be playing an important role - but whether CE per se is is not yet well-established. There are a multitude of questions such as “is browning necessary and if so how much?” and even if it is necessary whether CR by itself can mediate this effect adequately and if so under what conditions and limitations ( WAT goes up and BAT goes down with obesity and the reverse with lower weight), etc. Despite the greater uncertainty of the contingent dependence of, extent of benefit, etc, lest of all the balance of potential good for a given individual, I have for several years now hedged bets with “convenience CE.” I do this not because I am convinced it is a material benefit for my fairly optimized lifestyle, but because at these modest levels I perceive this natural approach to be low risk even while the upside is not well defined for someone following my relatively evidence-based lifestyle. This represents low hanging fruit that are unlikely to materially harm, yet have the potential for upside. The harder question and greater risk is the temptation to “go all out” and reach for something that may indeed confer significant benefit but with far less certainty than focusing energy on optimizing better established and safer practices. Particularly so when - in contrast with my modest CE example - the extent and magnitude of the risk are correspondingly less defined.
  12. The other day I was at a research conference conversing with a good number of intelligent, motivated, health optimizers who were going to great lengths to improve their health through sometimes quite elaborate self-experimentation with novel experimental therapies. these conversations and hearing their stories motivated me to offer one perspective.here taking a specific example, for consideration. In a forum of optimizers it is easy to forget the enemy of a good plan is the dream of a perfect plan. Incremental or lower probability gain is often reached for with disproportionate risk. Take for example transfusion of “young blood” modeled after parabiosis. This podcast is priceless but a few nuggets to emphasize here: https://www.ihmc.us/stemtalk/episode-91/ summary is mine : 1) parabiosis in contrast with transfusion therapy has not only blood factors but also the organ reserve and function of the younger organism and psychosocial and physical stimulation of close proximity to a companion ( via suturing the skin together) 2) current data suggest more benefit from diluting old blood harmful factors than enhancing protective factors ( though probably involves both) 3 Risk of infection, 4) risk of anaphylaxis 5) risk of rare but serious GVHD 6) any method to filter the blood to reduce the risk of infection may also remove any potential benefits 7) perhaps most insidious the unknown - even with thousands using similar technology for other purposes, inadequate data to exclude subtle and delayed hypothetical predisposition to potentially life changing autoimmune conditions such as multiple sclerosis. Though they obviously stand to gain financially from it I like the Conboy’s proposed solution better ( I will leave you in suspense to listen , otherwise you will miss a lot of other great content such as increasing evidence for oxytocin’s connection with protection from sarcopenia, osteoporosis, etc. We should certainly be proactive and be willing to take on appropriate risk for our tolerance and values and all be granted the autonomy and respect to make our own choices. It is good in making such assessments to consider that a strong motivation to mitigate risk can sometime bring on substantially more risk, cost, or possibility of serious harm than what is likely to be gained by stretch for “perfect” If after considering all the risks as well as benefits the choice is made to go forward, should something happen regret is minimized knowing the decision was made with open eyes.
  13. Mechanism

    Blood Pressure

    That’s great Tom. I’m also pleased with your LDL improvement. I think you would enjoy listening from about 55 minutes to about 1 hr 5 minutes into this podcast - interviewing Dr Peter Attia - starting with the discussion of PCSK9 inhibitors and then moving on to statins and the rationale for risk mitigation in some individuals even when other biomarkers look good, if for no other reason based on what we do know about atherosclerosis mechanistically and the precautionary principle. i couldn’t have said it better myself and in the future will refer proponents of the indefensible position that statins are universally harmful to this snippet. Statins are indeed overprescribed and associated with some real risks yet are simultaneously one of the most potent risk mitigators for appropriate candidates and save thousands of lives annually Enjoy: https://shows.pippa.io/the-doctors-farmacy/enhancing-your-healthspan-to-live-well-for-100-years-with-dr
  14. Mechanism

    Blood Pressure

    Hi Tom, this isn’t medical advice , but I thought the overview here was helpful. https://www.heart.org/en/health-topics/high-blood-pressure/the-facts-about-high-blood-pressure/low-blood-pressure-when-blood-pressure-is-too-low Indeed, as it begins “Most doctors will only consider chronically low blood pressure as dangerous if it causes noticeable signs and symptoms” and I understand your low BP is without symptoms, long-standing, and consistent. A lot common knowledge in that article but with a few nuggets in there. for potential etiology secondary to anemia, which is not well known. assume you see your GP at least annually and no major medical conditions and that s/he checks your BP every time to monitor for inappropriate change. Just s couple of thoughts presuming your provider is monitoring and not concerned: 1) as was suggested above as you know BP is a well-established biomarker of CR, and if you are practicing it to any significant extent ( my BP has always been lowish, but it went down further following CR). 2) Some of higher BP with age may be adaptive. You mentioned concern re getting adequate CNS perfusion and I agree exercise is a great idea, and I think there there is an additional theoretical consideration here. Over time all of our vessels become less compliant, consequently greater BP for a given cardiac contractility*pulse (=cardiac output). However the rate of this change varies by individuals, and If your vessels are in better shape due to your impeccable CRON lifestyle not only will a healthy vasculature result on lower BP, but similarly your healthy CNS vessels will need less pressure for adequate perfusion. BTW, while not dismissing the concern for low BP for some individuals esp. with specific pathology & appreciate the value of epidemiology, even when comorbidities and other sources of potential bias are exhaustively identified, measured adjusted for in these observational studies the residual confounding is a huge problem: nutritional or renal pathology hypoalbuinemia, reduced ejection fraction/ CHF, etc. Hence the magnitude and frequency of low BP related poor health outcomes is likely overestimated in the general population. hope that helps. You do a lot to take care of your health. I think it will, and may it, pay off.
  15. Mechanism

    A CR Garden

    Great photos Dean! I have never tried it. These days my diet has been lower net-carbohydrate, but I will be looking for them in our co-op and plan on making ( what sounds like) a delicious exception.
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