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  1. I just want to reiterate, that there is another "legal way" of testing rapamycin - primates. While the dog-trial did not yet start, there is an ongoing lifespan trial in a species of short-lived primates, done by an established aging-research team: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415526/ Their results will be available before the dog-trial is going to be finished. I'm not an expert, but I think that their data from primates might be almost as relevant for humans as data from dogs - though maybe somewhat less, because they don't have a brand-name research star on their team and don't constantly talk about it on podcasts. Also if I recall correctly, CRON introduced in aged mice does not extend lifespan. On the other hand rapamycin administered starting at old age (in mice) did.
  2. I know that people are in love with their dogs and Kaeberlein is a well known guy. But please do not forget the ongoing rapamycin-longevity study in marmoset monkeys, which aims to determine life-extension and health outcomes of rapamycin in short lived primates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415526/ They started the primates at 8 years of age and are already running the intervention for 2,5 years. Marmosets have a typical life expectation of 12 years - so the results in primates will be available before the dog-project is over. The team at the Institute for Longevity and Aging Studies at UT San Antonio is also invovled in running experiments for the Interventions Testing Program of NIA; so they have some experience. So please - yes, dogs are interesting. But the rapamycin lifespan-study in primates (finishing soon) are more relevant for humans - don't you agree?
  3. The question is: does Rapamycin work in humans for life-extension or disease-mortality similar to what studies in mice suggest. Sure: if Peter Attia takes 6 mg of Rapamycin once a week it does not have much side effects. But does it have any intend effect at that dose either? I did some rough calculations based on a paper of Kaeberlein some time ago - as it turns out the mice are getting an enormous dose of Rapamycin by 3 different metric. Far more than Peter Attia is reportedly taking: https://www.longecity.org/forum/topic/89073-new-rapamycin-study-up-to-60-increase-in-mouse-lifespan-anyone-experimenting-with-this/page-25#entry876052 So given the lack of evidence in humans or other long-lived animals, there seems to be little basis on taking something like 5 mg to 10 mg of Rapamycin once every 7 days. Little side-effects. But probably also little effects.
  4. Guest

    Fasting for CR Benefits?

    Just to add in favor of CR: there have been some mice studies, where the researchers tested different levels of CR under similar conditions (mouse strain, laboratory conditions, feed etc.). Generally a more stringent level of CR lead to better lifespan-effects. This indicates, that calories probably play some role - it would be interesting to look up, if the feeding-schedule in those were identical.
  5. Guest

    Fasting for CR Benefits?

    The literature on all this is rather elusive: - it seems this is the first CR study that had a true adlib-feeding pattern for the CR mice; otherwise all CR studies in mice also used fasting (from 12 to 23 hours), which makes it so challenging to disentangle - as you are pointing out, there are other metabolic influences in the background which again complicates things So what are the actionable consequences - assuming for the point of argument that the findings are correct? 1. If the CR-effect in mice is indeed predominantly a fasting effect, it appears there is not much to translate. The equivalent fasting periods in humans - at least a couple of days every week, if not even 6 days a week - are very impractical to implement. 2. If its a temperature effect - is this really something that applies to humans? Also again considering the body temperature changes of mice. Mice are species that can and do undergo torpor and after 7-8 hours of fasting demonstrate a notable decline in basal body temperature. That is clearly not seen in humans after short fast of 1 or 2 days.
  6. Guest

    Fasting for CR Benefits?

    @ Dean That is a valid point. Unfortunately it's no addressed in the review paper. The corresponding study for the 12 hour weight loss can be found here: https://link.springer.com/article/10.1186/1471-2164-8-361 They are not analyzing the effect of intestinal content in assessing the body mass changes (though water is provided round the clock). however, they measure the change of mass of intestines after cleaning them of content (see methods section at the end). The result is displayed in this graph: Edit: the graph doesn't seem to load; it's Figure 2-A in the paper So the intestines - after emptying their content - lost somewhat more percent of mass than the entire body in percent after 12 hours (relative to non-fasted mice and their empty intestines mass). I can only speculate, if this corresponds to the entire body mass loss (as no information is given on adjustment for the latter). To complete the picture, here are some of the changes in the review paper for 12 hours fasts - noting, that for a range of parameters no data for 12 hours is included/available in the paper: - leptin is at a low-stable level from 12 hours onwards - unclear data in insulin level; but one study finds that after 12 hours there is low-stable level compared to 2-6 hours (but on didn't) - contradictory results for gastric content; mice at 12 hours had similar gastric content as non-fasted mice - but at 4 and 8 hours their gastric content declined - no change in cytochrome P-450 level at 12 hours (but at 24) - mean time of initiation of first topor bouts: 13,3 hours ; initial drop of body temperature at 7-8 hours - first changes in hepatoxic markers at 12 hours (and increasing from there on), but not at 6 hours
  7. Guest

    Fasting for CR Benefits?

    Adding to the question, whether the CR-effect in mice can be partly explained by fasting: This review - though a little outdated (2013) - summarizes a broad range of studies investigating mice metabolic responses to fasting from 4 hours to 48 hours: https://journals.sagepub.com/doi/full/10.1177/0023677213501659 The issue isn't clear cut - certain metabolic markers are clearly changed after 12 hours of fasting. Others are not significantly different from 6 hours of fasting (fasting in MICE). In the Discussion section at the end of the paper the authors note, that the longest voluntary interval observed between meals was 5 hours and they note previously, that 4 hours constitute an "overnight"-fast in mice. Another data-point is the bodyweight response - 12 hours of fasting in mice results in a 12% loss: In comparison - in humans a much longer fast is needed to produce similar results; e.g. in this study of monitored therapeutic starvation in obese individuals a 35 days to 41 days fasting lead to a 10,6% to 20,5% weight loss: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC535723/pdf/jcinvest00209-0174.pdf So in terms of body weight loss a 12 hours fast in mice is similar to at least several weeks fasting in humans (and even more than one month in some individuals). Therefore I find it hard to just dismiss, that fasting can explain some of the effect of CR-mice even in those receiving a "spread-out"-CR over 12 hours. Any thoughts or additional data points?
  8. Guest

    Fasting for CR Benefits?

    Hello; I'm a longtime lurker finally deciding to register. I'm a tenured non-research college lecturer in business (with a physics background), also known as "Guest" on the longecity forum and did CRON from 2010-2014 before for a variety of reasons switching to a low-meat "normal" diet - still maintaining a BMI of 20-21. This paper is pivoting the IMO still unclear question, of the CR-effect in mice is largely due to fasting. For that it is worthwhile remembering, that fasting in mice is very different than in humans. A mouse undergoing 24 or 48 hours of fasting is demonstrating a very substantial loss in body-weight and increase in autophagy - not paralleled in humans on that schedule. For example a 72 hour fast in humans lead to a rise of 30% in a common autophagy marker (LC3B-II) in human test subjects: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102031 In mice autophagy is upregulated much more pronounced; i.e. in this study the same marker is increased by 250%-840% in mice undergoing a 48 hour fast: https://www.jmcc-online.com/article/S0022-2828(13)00277-0/fulltext There have been prior studies trying to implement a "spread out" CR in mice - but to my knowledge these still left a 12-hour timeframe of "fasting". Of course 12 hours would hardly qualify as "fasting" in human subjects - but given the enormous response of mice in terms of bodyweight and autophagy for 24-hour and 48-hour fasts it is theoretically possible that even 12 hours would lead to substantial response (thus still partly explaining the success of CR in those mice). What I'd therefore like to enquire: 1. Are there CR-studies in mice using a feeding scheme comparable to ad-lib feeding (so no defined 12 hour or longer break)? 2. Are there studies of body-weight loss and autophagy markers in mice undergoing a 12 hour fast (my quick google-search didn't yield any results)? This could indicate, that even in "12-hour feeding" CR-mice a part of the lifespan effect is due to fasting.
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