Gordo Posted October 28, 2016 Report Share Posted October 28, 2016 (edited) Even I am skeptical of Dean's approach, my hunch is that what he is doing is sub-optimal for health and longevity (both in terms of total caloric intake, as well as high levels of repetitive endurance exercise) but I kind of hope none of us can talk him out of it because we'll only know if what he's doing works if he keeps doing it (since no one else will, haha). But regarding "since CR appears to "work" for such a wide range of creatures beyond us, why wouldn't it work for us, too?" I think this idea is largely debunked in this very thread. There is little evidence to support CR in and of itself as a longevity tool in mammals, especially bigger mammals. The primate studies do not support this idea. Even most mouse subtypes do not get longevity from CR (beyond obesity avoidance). As far as I know, CR has not been shown to work in any large animal whatsoever (compared to a healthy obesity avoiding diet and lifestyle), There are humans who have been practicing CR for decades, and so far it doesn't look all that promising based on anecdotes gleaned from these forums. The "godfather" of CR died at age 79. Many doing serious CR have developed osteoporosis. Some seem to have developed brain damage, others have had issues with infectious disease and glucose intolerance... Edited April 26, 2018 by Gordo Quote Link to comment Share on other sites More sharing options...
Sthira Posted October 28, 2016 Report Share Posted October 28, 2016 Even I am skeptical of Dean's approach, my hunch is that what he is doing is sub-optimal for health and longevity (both in terms of total caloric intake, as well as high levels of repetitive endurance exercise) but I kind of hope none of us can talk him out of it because we'll only know if what he's doing works if he keeps doing it (since no one else will, haha). Dean's a smart, conscious fellow, and flexible, too. I'm always impressed by people who totally, passionately dive in headlong into an idea, and just kinda balls out go for it. Then, what's most impressive, when the worm turns and "evidence" (such as it is) begins to point away from what was formerly seen as good, a person will drop the passion, release the activity, and let it go. Do something until it remains beneficial, then switch course as things change. I suspect this happened with loads of former CR practitioners, which feels tragic to me because so many on Al's list seemed so excited that CR was the best possible answer. The macaque studies of course threw us all out the door, and then our "leaders" vanished. So here we are in a falling down elegant mansion, wandering rooms of confusion. I jumped over to fasting. Is repeatedly fasting long term even healthy for my body? Dunno. I'm guessing yes maybe but I know I'm overdoing it. But I feel so much better fasting than I do eating (I know I'm strange) and I hope I'm developing no eating disorder, which is common in my field. I see serious eating disorders all around me, frankly, but they're different in texture from what I'm gambling with. I feel more like you, Dean, and others here -- orthorexic probably -- but conscious of the orthorexia (at least I am...) But regarding "since CR appears to "work" for such a wide range of creatures beyond us, why wouldn't it work for us, too?" I think this idea is largely debunked in this very thread. There is little evidence to support CR in and of itself as a longevity tool in mammals, especially bigger mammals. The primate studies do not support this idea. Even most mouse subtypes do not get longevity from CR (beyond obesity avoidance). As far as I know, CR has not been shown to work in any large animal whatsoever (compared to a healthy obesity avoiding diet and lifestyle), There are humans who have been practicing CR for decades, and so far it doesn't look all that promising based on anecdotes gleaned from these forums. The "godfather" of CR diet at age 79. Many doing serious CR have developed osteoporosis. Some seem to have developed brain damage, others have had issues with infectious disease and glucose intolerance... Yes, it's all disappointing and sad to me, and I think some grieving for others and the loss of what was considered a healthy practice is appropriate. CR might extend health, or it might not. But my notes from nearly a decade ago (wow) clearly say this is experimental, this has risks, this has benefits, this may mess up my body, maybe I shouldn't do this, warning, CR may be another false path. The thing is: we're all different. Fasting for me feels 75% healthier for my body than CR felt. Chronic calorie restriction never felt strong to me, and I was generally confused by reports of others who said CR made them feel good. Quote Link to comment Share on other sites More sharing options...
Michael R Posted April 22, 2018 Report Share Posted April 22, 2018 Going back a ways in the thread, as well as the calendar ... So, as usual, Dean, you've done a very good and useful job of identifying and summarizing the results of an interesting study, diving into the details and highlighting subjects of key interest to CR practitioners.However, you seem to be assuming/asserting that given the contrasting results of the Weindruch et al study(2) and the new one from Mitchell et al(1), the outcome of the Mitchell et al study must somehow be the result we should favor over the results of Weindruch et al. Why should that be the conclusion? At most, if all we had was two studies from two labs with similar methods and control groups, the situation would be frustratingly up in the air, and we would still have a very long record of other experiments in other strains of mice (and rats, and other species) showing that CR works well and in a dose-responsive manner.But of course, as you (Dean) rightly point out, "C57BL/6J mice [are] the canonical strain of mice for CR experiments" (or at least, they were for several of decades: more recently, the best labs have moved toward more genetically complex crosses, such as the NIA ITP's genetically heterogeneous UM-HET3 mice or Spindler's B6C3F1 hybrids). So you knew that this not only wasn't the first C57BL/6J CR rodeo, but was also not its second, third, or twelfth. I would have thought that the obvious thing would not be to throw up your hands and say "well, we just don't know now, do we?" — let alone (as you sure sounds like you're saying) to conclude that of all the studies that have been conducted, (1) uniquely has arrived at the "correct" result, which is that more severe CR is really quite detrimental. I would have thought that the obvious thing would instead have been to dig up a few previous results with this avowedly "canonical strain of mice for CR experiments" and see what those studies found (not to mention the wider track record of CR in other strains, and in rats), and decide on the basis of the balance of evidence.Additionally, as in many of your posts on this general topic, you've once again adopted of the affected outrage of a prosecuting attorney performing in front of a jury, instead of dispassionately presenting your report of the results of your examination of the evidence like a medical examiner.I'm going to leave aside the DBA2 result: this is, as you know, a quite buggered-up little animal, that responds poorly to CR and is not representative of the species or of CR's effects more generally, and focus on the C57BL/6J result which is correctly the focus of your analysis. New Rodent Evidence Against Serious CR (This is a minor point, but even if we take this study as definitive, it is not "Evidence Against Serious CR," but "Evidence Against Severe CR." People like me and previously you practice "serious CR," but as I've noted before, it's not credible that I or any free-living human practices Severe CR (40% from true ad libitum), which is what this study ostensibly provides evidence against). First let's look at the survival curves (A), which are broken down into four graphs, by strain and gender on the left of the figure. If you prefer to see the mean, median, 25% and 10% max longevity data, it is available in Table S1 in the supplemental material, which I've captured as in image but not embedded here for clarity & brevity.As you can see, the 50% survival times for both male and female D2 mice (lower survival curves) are identical. ...But it gets even worse for the weep-to-your-knees CR fanboys. Look that the longevity curves at the top from the C57BL/6J mice ... Here where we see 40% CR really sucked. In fact, in the female B6 mice, not only was their an early mortality effect of 40% CR ... [but] a (albeit modest) survival disadvantage relative to ad lib throughout most of their lives, with only the last few percent of CR40 mice able to hang on to barely match the longevity of the ad lib female B6 mice. How pitiful is that!? ...A similar, but not as dramatic pattern was seen in the male B6 mice. ......In short, across both sexes and two common strains mice, very modest, adult-onset, obesity-avoiding 20% CR (relative to a completely ad lib obesity-producing diet) did at least as well, and often a lot better, than serious 40% CR, in two strains of mice where the CR response is supposed to be most robust and reproducible!So much (once again) for the Weindruch CR study [2] of female C57BL/6J and the sexy survival graph gracing the CRS home page First: again, even if we had no other data than these two studies(1,2), why would this be "So much (once again) for the Weindruch CR study"? One could just as easily (and arbitrarily) say "But look at the Weindruch CR study [2] of female C57BL/6J and the sexy survival graph gracing the CRS home page. So much for Mitchell et al."But, of course, that would be foolish, barring some clear methodological reason to accept one study over the other (and you've not presented any, tho' you've certainly been at pains to show that the common methodological objections to many poorly-done LS studies don't apply to (2)). Instead, again, we sjpi;d dig up other studies on what was once (as you say) "the canonical strain of mice for CR experiments" and see what the balance of evidence is from the long scientific record.So, for example, here are the results for female B6 mice in (3) from the NIA's landmark Biomarkers of Aging study, using 40% CR initiated at 14–16 weeks of age (≈3.5 mo, intermediate between your (Dean's) two comparison studies): Mean and maximum (10% survivorship) LS were 753±22.6 and 1011 d for AL and 953±36.1 and 1220 d for CR —ie, a classic, robust response to 40% CR in females of this strain, similar to what Weindruch et al report (2) and in stark contrast to Mitchell et al.(1) Here is another study,(10) using 40% CR in a hybrid C57BL6x129SV strain of mice, males and females, starting CR at age 3 mo — again very young adult, intermediate between (1) and (2): (The "N AL" and "N CR" mice are the relevant ones for current purposes (normal AL and CR mice); the KO groups are mice of the same background strain with their growth hormone-releasing hormone (GHRH) knocked out). They don't give numbers on survivorship, but it's pretty clear that male and even more so females did very well indeed on this protocol.Let's try another: again, female C57BL/6 mice on 40% CR, this one from weaning (similar to Weindruch et al in (1)) (4): They don't actually have a table with detailed survival information, saying only "AL and DR animals have very similar rates of survival at 24 and 64 weeks of age, with DR having a slight increase in survival rate at 104 weeks of age. At about 100 weeks of age the survival probabilities of AL and DR mice begin to diverge, with DR animals showing subsequent higher rates of survival."(4) But the curve is clear, and they do give some quantitative information in a separate report on the same experiment (it refers back to this one) which makes it clear that this was not the result of short-lived controls, but were consistent all-around with decent husbandry: "By 64 weeks [448 d] the survival rate had declined to 93%, and remained essentially identical for AL and DR animals. At At 104 weeks [728 d] the survival rates had begun to diverge, with DR mice having an 85% survival rate and AL mice showing a 74% survival rate. At 144 weeks [1008 d] of age the AL survival rate was 4% and the DR rate was 53%."(5)So, no massive die-off at 40% CR here either: instead, yet again, a robust, classic CR effect on mean and maximum LS."But," you (Dean) correctly say, Weindruch [2] started his mice on CR abruptly, immediately after weaning. Study [1] started CR gradually in young adulthood, once the mice were fully growns. Sadly for serious CR believers, this is exactly the state each of us were in when we started CR... This objection certainly holds true for (4), while (3) and (10) are intermediate between weaning and the 6 mo onset in Mitchell (1). I can't think off of the top of my head of a suitable study of female mice initiated no earlier than 6 mo (there's a dearth of CR studies on females generally), but I can certainly dig up some for males, which we can more directly compare to the result for males in Mitchell et al — starting at the very beginning of such (properly-done) studies: Weindruch and Walford's landmark "yes, CR works in middle-aged mice" study, (6) with which you (Dean) are of course familiar. Here are the mean and maximum (10% survivorship) LS for male AL, 20%, and 40% CR mice starting at 6 months in (1) and, for comparison, W&W's data for male AL and 40% CR mice of the same strain starting when the animals were 12 to 13 months of age(6) (I'll call it "Walford"):Mitchell AL(1): 762 ... 897Walford AL(6): 758 ... 959Mitchell 20% CR(1): 958 (+25%) ... 1098 (+22%)Mitchell 40% CR(1): 881 ... 1023Walford 40% CR(6): 910 (+20%) ... 1162 (+21%)Here they are on the right: So, in absolute and relative terms, Walford and Weindruch's 40% CR mice enjoyed similar lifespans than Mitchell et al's 20% CR mice, despite having started on the program quite substantially later in life. Ditto for the B10C3F1 hybrid mice. Now, results in Mitchell et al's female mice didn't make any sense just prima facie, whereas just looking at the general shape of the curves in (1), and in ignorance of the previous body of evidence, one might reasonably have thought that that the result in the male mice was telling us something that was novel and important. After all, the survival curve for the 40% CR group looks roughly like what you'd expect from a classic CR effect — it's just that in this case, the 20% CR group did even better. So you might reasonably have wondered if, while many studies had found that 40% adult-onset CR can retard aging in mice, we'd been foolishly stuck on a level of severity that was actually (and counterintuitively) inferior to a more moderate 20% CR protocol. But that isn't supported by the actual LS data for these studies, where the 40% CR group in (6) lived longer than either 20% or 40% CR in (2), despite having been initiated substantially later in the lifespan. The same is true (even more so, tho' it's of course a different strain) for the B10C3F1 hybrids.And this is consistent with many previous studies as well, using C57BL/6 hybrid. For instance, C57BL/6 x C3H (B6C3F1) mice by Weindruch-sans-Walford(7); Spindler, both at 12 months((8), using B6C3F1 mice (C57BL/6NH x C3H/HeNH) and several other reports) and even when started in early seniority (19 months, another landmark paper much discussed hereabouts, with which you (Dean) are well-acquainted (9)): "CR [initiated at 19 mo] extended mean lifespan from 30.7 ± 0.7 (SE) to 35.4 ± 0.8 months [933.8 to 1076.8 d (+15%)] (P = 0.000017) and extended maximum lifespan from 37.6 to 43.6 months [1143.7 to 1326.2 d (+16%)] ((P = 0.000056."(9) Again, compare with:Mitchell AL(1): 762 ... 897Mitchell 20% CR, initiated at 6 months (1): 958 (+25%) ... 1098 (+22%)Mitchell 40% CR(1): 881 ... 1023Of course, what would be better would be single studies comparing two levels of CR in the same strain in adult-onset mice (ie, studies doing what Mitchell et al set out to do). here are the results of Weindruch and Walford op cit, with C67Bl/6 mice on 40% CR from age 12 mo (6), to the Weindruch lab's later study in the same strain of mouse of 26% CR starting at 12 mo:Mitchell AL(1): 762 ... 897Walford AL(6): 758 ... 959Pugh AL (12): 887 ... 1149Mitchell 20% CR @6 mo (1): 958 (+25%) ... 1098 (+22%)Mitchell 40% CR @6 mo (1): 881 ... 1023Pugh 26% CR @12 mo (12) 1009 (+13.4%) ... 1270 (+10.6%)Walford 40% CR @12 mo(6): 910 (+20%) ... 1162 (+21%)Pugh et al's mice actually lived longer all around in both AL and CR states than W&W earlier (6) or Mitchell et al (1) (good for the mice!), which from eyeballing their respective survival curves seems to be because of fewer deaths in the 12-20 month zone in AL and CR animals alike in (12) vs. (6) above: Maybe they'd gotten better at animal husbandry in the ensuing 17 years (remembering that W&W's original breakthru' came exactly down to factors like a more gradual onset of CR and a higher %protein in the diet). Certainly the percentage gain in LS was dose-dependent in the way you'd expect: roughly double the %CR, roughly double the relative gain in LS.There are also a ton of CR studies in rats — most (all?) of them in males — by Masoro (eg. (11)) and by Merry — in which CR was initiated at 6 or 12 mo, with robust effects. From their Table 1, median, mean, and "max LS" (eyeballed single longest-lived animal from the survival curves -- not the proper, 10th-decile survivorship operational definition, for which unfortunately they didn't provide numbers) were, in days (15):Lifelong AL (Group 1): 926 - 854 - 1100AL --> CR @ 6 mo (Group 7): 1078 - 1021 - 1240AL --> CR @12 mo (Group 5): 1031 - 1000 - 1230 I should add the caveat that developmentally, a 6 m.o. rat is significantly "younger" than a 6 m.o. mouse, so Masoro's(11) and Merry's (15) 6 m.o. rats are arguably "younger" than Mitchell's 6 m.o. mice. Presumably Merrry's 12 m.o. rats are also younger than 12 "mouse months," but clearly older than Mitchell's 6 m.o. mice.Now, I don't know what went wrong in (1). You (Dean) have rightly checked for obvious red flags and noted that the authors certainly seem to have done everything "by the book;" if there is a methodological flaw, it's either buried deep in the text of the report in a way that it passed under my nose, or it's somewhere in the implementation in the viviarium — or it's something totally out of left field, like a weird epigenetic oddity in these particular mice because of something happening to their parents at The Jackson Laboratories or they themselves before Mitchell et al even started changing their diets (remembering that got the parents from TJL, bred them in-house, and then changed their diets at 6 mo; they're all likely littermates or parallel cousins from the same lab at the same time period). Nor have I taken any extra steps to email the authors to ask about details (and I don't have any particular questions to ask them). But whatever explains this result, it's clearly an outlier, standing against a long track record of "C57BL/6J mice [being used as] the canonical strain of mice for CR experiments" — and of rodents generally. Indeed, with decades of published studies using this strain (and others), and with 40% CR as by far the most common protocol, it would be hard to imagine that it would have escaped anyone's noticed if the long track record of published studies were littered with fatalities, instead of successively contributing to the consensus that CR is the most robust (indeed, was for decades the only) protocol for retarding aging in laboratory rodents. Here is one partial explanation the authors' suggest for the failure of CR40 to beat CR20 [in Mitchell et al(1)] (my emphasis in this and all future quotes): Here, fasting levels of insulin, glucose, and IGF-1 were reduced with CR across all experimental groups ... In most cases 20% CR was sufficient to produce a dramatic decrease in these parameters with little to no further benefit by 40% CR. the table below from the supplemental material bears out what the authors say. ... In most of the biomarkers, 40% CR resulted in little additional change in the "good" direction relative to 20% CR. But in two important and controversial, closely-related (and inversely correlated) biomarkers (IGF-1 and IGFBF-1), CR40 had a consistently larger impact than CR20 - i.e. CR40 mice had much lower IGF-1, and much high IGFBF-1 compared with both AL and CR20 mice, as you can see from the first two columns of the table below:... it suggests that the changes in biomarkers the CR20 animals exhibited were sufficient to trigger the "CR Response", and the further changes brought about by CR40 were either negligible, or in the case of IGF-1 and IGFBF-1, where dramatic additional changes with CR40 did occur, they were unnecessary and apparently counterproductive when it came to boosting longevity. Now, again, just looking internally at this report, that's a very reasonable hypothesis to formulate — one to which I'm sympathetic, knowing both how dramatically I can drop my own IGF-1 down if I lower my animal protein intake down low enough, and that doing so is accompanied by clear deleterious physiological effects.Knowing, however, that this study is in fact inconsistent with a wide range of other data, the real question to ask is why the 40% CR males didn't live longer than the 20% ones despite their lower IGF-1 levels. (I'm not sure, by the way, why they focused on IGFBP-1: in humans, at least, IGFBP-1 exhibits a complex action on IGF-1 bioactivity, with IGFBP-3 exhibiting a more intelligible, classic binding protein activity along the lines of SHBP). I'm also unclear about why their reported IGF-1 levels are so high to begin with: C57Bl/6 mice are generally reported to have one of the lower levels of the hormone, and the levels they report for AL and 20% CR animals are much higher than for AL animals in other studies. Here are the data from the massive Mouse Phenome Project at The Jackson Laboratories, including data on 33 inbred strains of mice including and at 3 different ages (6, 12, and (here) 18 mo — ie, younger than the 23-24 m.o. mice in Mitchell) (published as (16): If you look back at their data for the 6- and 12-m.o. animals, you can see that in both genders (and, surprisingly, at all ages), IGF-1 levels in AL C57BL/6J mice cluster pretty tightly around 250 ng/mL (the 18 mo females are somewhat anomalously higher, at 310 ng/mL, but still lower than the AL or 20% CR animals in Mitchell et al) — and note that this is on the low side for inbred mouse strains.I see that, unfortunately, Mitchell et al used "an in-house ELISA assay" for testing IGF-1 and IGFBP-1 levels,(1) which is always a somewhat fraught thing to do, as it means by definition that no one external to them has validated it against standard assays or confirmed from ring-testing that different operators can use it and get consistent, reliable results. By contrast, the studies underlying the Mouse Phenome Project were done using "a radioimmunoassay as previously described" in the literature, in a report from a decade previous that was originally used in a study by another group to characterize the relationships between skeletal growth and strength with gene variations and factors including IGF-1,(14) in a report has been cited at least 65 times.This might mean that the high IGF-1 levels reported in (1) reflect something about the assay method rather than the underlying biological state of the animals — that is, it could be yielding relative values that are internally consistent but scale to lower reported values using other assays, which would do the job for present purposes — or it could be somehow nonspecific, and catching else other than the intended target, so that their reported IGF-1 levels actually reflect IGF-1 + [analate X] in a way that skews the data one way or the other.However, I don't want to overemphasize this, first because we have no way to determine which is correct, and also because eg. (13) found a similarly-high IGF-1 level in their B6 mice — and although (in an amusing coincidence) they got their animals from The Jackson Laboratory, they used a standard commercial kit method for testing IGF-1. In any case, the lifespan data from many other studies makes all this mechanistic hypothesizing moot on the core point. BrianMDelaney hasn't posted to these forums since early March, and was a no-show at the recent CR Conference, without telling anyone he wasn't going to be there, which among other things, wasn't cool. And it's not like he's dropped off the face of the earth. ...As we've speculated about elsewhere, I suspect Michael's nearly complete disengaged with this community and especially Brian's long silence are at least in part a result of their seeing the writing on the wall - namely that serious CR is unlikely to be beneficial in humans, and as a result have lost faith & interest in the topic, and in Brian's case, perhaps the practice as well. Dean, your habit during the period of your original posting of constantly second-guessing people's motives was very disappointing. You know full well that Brian has other reasons for not being much engaged in the Forum. And as I've indicated previously, my own reasons are quite pedestrian and unrelated to some collapse of my confidence in the translatability of CR: it's time commitments, and Groundhog Dayism (tho' happily the Forums are far less plagued by this than the List used to be), and the sheer effort required to put together posts I consider adequate to address complex issues — such as the ones you tend to raise — and with an actual research basis that tends to entail an extensive dig to address. I have a ridiculous number of half-drafted posts to the Forums; each time I start a new one, another gets more remote from returning to the surface of the vast sea.------------[1] Cell Metab. 2016 Jun 14;23(6):1093-112. doi: 10.1016/j.cmet.2016.05.027.Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.Mitchell SJ, Madrigal-Matute J(2), Scheibye-Knudsen M(3), Fang E(4), Aon M(5), González-Reyes JA(6), Cortassa S(5), Kaushik S(2), Gonzalez-Freire M, Patel B(2), Wahl D, Ali A, Calvo-Rubio M(6), Burón MI(6), Guiterrez V, Ward TM, Palacios HH, Cai H(7), Frederick DW(8), Hine C(9), Broeskamp F(10), Habering L(10), Dawson J, Beasley TM, Wan J(12), Ikeno Y(13), Hubbard G(13), Becker KG(14), Zhang Y(14), Bohr VA(4), Longo DL(14), Navas P(15), Ferrucci L, Sinclair DA, Cohen P(12), Egan JM(7), Mitchell JR(9), Baur JA(8), Allison DB, Anson RM, Villalba JM(6), Madeo F(10), Cuervo AM(2), Pearson KJ(17), Ingram DK(18), Bernier M, de Cabo R(19).Free full text:http://www.sciencedirect.com/science/article/pii/S1550413116302492PMID: 27304509----------[2] J Nutr. 1986 Apr;116(4):641-54.The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake.Weindruch R, Walford RL, Fligiel S, Guthrie D.Full text: http://sci-hub.cc/http://jn.nutrition.org/content/116/4/641.longPMID: 39588103: Turturro A, Duffy P, Hass B, Kodell R, Hart R. Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. J Gerontol A Biol Sci Med Sci. 2002 Nov;57(11):B379-89. PubMed PMID: 12403793.4: Srivastava VK, Tilley RD, Miller S, Hart R, Busbee D. Effects of aging and dietary restriction on DNA polymerase expression in mice. Exp Gerontol. 1991;26(1):97-112. PubMed PMID: 2055287.5: Srivastava VK, Tilley RD, Hart RW, Busbee DL. Effect of dietary restriction on the fidelity of DNA polymerases in aging mice. Exp Gerontol. 1991;26(5):453-66. PubMed PMID: 1756777.6: Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982 Mar 12;215(4538):1415-8. PubMed PMID: 7063854.7: Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med. 2004 Apr 15;36(8):1043-57. PubMed PMID: 15059645.8: Spindler SR, Mote PL, Flegal JM, Teter B. Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386. PubMed PMID: 23432089.9: Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25. PubMed PMID: 15044709; PubMed Central PMCID: PMC397416.10: Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife. 2013 Oct 29;2:e01098. doi: 10.7554/eLife.01098. PubMed PMID: 24175087; PubMed Central PMCID: PMC3810783.11: Yu BP, Masoro EJ, McMahan CA. Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol. 1985 Nov;40(6):657-70. PubMed PMID: 4056321.12: Pugh TD, Oberley TD, Weindruch R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res. 1999 Apr 1;59(7):1642-8. PubMed PMID: 10197641.13: Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6216-20. Epub 2003 Apr 30. PubMed PMID: 12724520; PubMed Central PMCID: PMC156352.14: Rosen CJ, Churchill GA, Donahue LR, Shultz KL, Burgess JK, Powell DR, Ackert C, Beamer WG. Mapping quantitative trait loci for serum insulin-like growth factor-1 levels in mice. Bone. 2000 Oct;27(4):521-8. Erratum in: Bone 2000 Dec;27(6):877. PubMed PMID: 11033447. 15: Merry BJ, Kirk AJ, Goyns MH. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. 2008 Jun;129(6):341-8. Epub 2008 Apr 22. PubMed PMID: 18486188. 16: Yuan R, Tsaih SW, Petkova SB, Marin de Evsikova C, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell. 2009 Jun;8(3):277-87. Epub 2009 Apr 9. PubMed 19627267FullText Quote Link to comment Share on other sites More sharing options...
mccoy Posted April 23, 2018 Report Share Posted April 23, 2018 (edited) Michael, this sure has been discussed before but maybe a brief update or a good link on the translability of the studies on mice to humans would be helpful. This of course would be the premise of all studies on mice and would retort any possible underlying skepticism denying the effectiveness of CR merely on the basis of mice-to-humans extrapolation. I personally, as surely many others, give it for granted by now that in lab mice CR absolutely prolongs lifespan. But, what is it that we can transpond with some degree of reliability to human beings in real life and which are the relevant studies. I have only a very pale idea of the extrapolation concept. Right now, I would tend, as other members of this forum do, again, to believe that there is conclusive evidence of longer lifespan in CRed mice in lab conditions, but does that really apply to humans, considering there have been no controlled trials of a lifetime duration? Edited April 23, 2018 by mccoy Quote Link to comment Share on other sites More sharing options...
Dean Pomerleau Posted April 23, 2018 Author Report Share Posted April 23, 2018 Thanks Michael, Nice post. I think we agree about quite a few things about the article I discussed (Mitchell [1]): It seemed to go against conventional wisdom, namely that more severe CR (CR40) usually beats less severe CR (CR20) at least in this strain of mouse. Mitchell [1] didn't appear to do anything obviously wrong in their methodology / animal husbandry that would explain their results. The longevity of the AL groups in Mitchell [1] compares favorably with AL groups in other studies, supporting the idea they weren't messing up care of the animals. Several of the studies you cited to support CR40 benefits either started CR immediately after weaning, and most of the rest that started post-weaning didn't start quite as late as the 6 month point that Michell [1] started at. None of the studies you cited also had a moderate CR comparison group, i.e. your posted studies showed that CR40 extends lifespan, rather than comparing several degrees of CR within the same strain for their relative effectiveness. You said: Indeed, with decades of published studies using this strain (and others), and with 40% CR as by far the most common protocol, it would be hard to imagine that it would have escaped anyone's noticed if the long track record of published studies were littered with fatalities, instead of successively contributing to the consensus that CR is the most robust (indeed, was for decades the only) protocol for retarding aging in laboratory rodents. I'm not saying CR40 doesn't work. I'm just saying it might not be as robust a result as we've been assuming, and in some instances CR20 may work comparably well, and perhaps even better. None of your posted studies actually showed CR40 resulted in increased longevity relative to a moderate CR group within the same experiment, and cross-study results are notoriously hard to interpret, since so many things can impact results. But one cross-study observation I would like to point out is between my study Mitchell [1] and the study you cite as Sun [10]. Both were in a similar (although not identical) strains of mice (C57BL/6J vs. C57BL6x129SV). Mitchell [1] started its mice on CR at 6 months (approx. human equiv of 30 years old) while Sun [10] started CR at 3 months (~human teenager). I've rearranged the graphs you posted from [10], erased the growth-hormone knockout groups from the graphs, and posted them below the corresponding graphs from Mitchell [1]. The Mitchell [1] graphs are in the top row and the Sun [10] graphs are in the bottom row: Looking at the lifespan graphs on the left side, the AL-fed females (first column) in both groups has a max lifespan of about 140 weeks, and the both groups of males (second column) also had maximum lifespans of about 140 weeks. So a pretty good baseline match between the two studies. We also see the lifespan benefits of CR40 (red curves in all graphs) is somewhat more robust in males than females. In particular, early deaths in the female CR40 group took its toll in both studies. In the males, CR40 showed a robust and comparable life extension benefit in both studies. It's just that CR20 males in Mitchell (blue line in second column in top row) did even better than the CR40 male mice. But what I find most interesting is the weight trajectories in the two studies, shown in the right two columns. In both sexes, the CR40 mice in Sun [10] (lower two graphs on the right) started out at CR onset weighing less than their counterparts in Mitchell [1] (top two graphs on the right), which isn't surprising, since they were half the age of the mice in Mitchell (3mo vs. 6mo) at CR onset. Even more interesting the Sun [10] CR40 mice continued to gradually gain weight throughout most of their life, until the very end of life when it started to drop. In contrast, the CR40 mice in Mitchell had a pretty precipitous drop in weight right after CR onset and if anything drifted somewhat downward in their weight throughout their lives. In fact, the CR40 mice in Mitchell started out heavier (since they were older at CR onset) but eventually dropped below the weight of the CR40 mice in Sun [10]. Further, the weight trajectory and maximum adult weight of the CR20 mice in Mitchell [1] look a lot more like the CR40 mice in Sun [10]. If I had to guess what is going on, I would say that the stress of CR40 was well-tolerated when the onset was in adolescence (i.e. Sun [10]), moderating the mice's growth and keeping them lean throughout their adult life. But started CR40 in young adulthood (i.e. Mitchell [1]) once the mice had reached maturity, was more severe than was optimal for the mice, causing them to lose weight initially and be less robust and long-lived relative to their less severely CR'ed counterparts (the CR20 mice). It was really interesting to me to see those CR40 weight trajectories in Sun [10]. The fact that these animals continued to gain weight after CR40 was initiated, just more slowly than the AL group, really shows me how different human CR is, at least a commonly practiced. That is, at least for most of us, we started CR well past when we were fully grown, and lost a substantial amount of weight after going on CR. In this sense we humans are much more like the Mitchell CR40 mice in terms of our weight trajectory than the Sun CR40 mice. If this is true, the moral would seem to be that if you start CR early, you can tolerate and benefit from more severe CR. If you start later, and in particular if CR results in a dramatic weight loss, you might not be doing yourself a big favor. Better to find a target calorie level that keeps you lean and your weight stable than to cut calories to the bone and become very skinny, especially if you start CR in middle age like most of us. P.S. I agree that my tone in earlier posts has sometimes been more caustic than it should have been. I apologize for that. --Dean --------- [1] Cell Metab. 2016 Jun 14;23(6):1093-112. doi: 10.1016/j.cmet.2016.05.027.Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.Mitchell SJ, Madrigal-Matute J(2), Scheibye-Knudsen M(3), Fang E(4), Aon M(5), González-Reyes JA(6), Cortassa S(5), Kaushik S(2), Gonzalez-Freire M, Patel B(2), Wahl D, Ali A, Calvo-Rubio M(6), Burón MI(6), Guiterrez V, Ward TM, Palacios HH, Cai H(7), Frederick DW(8), Hine C(9), Broeskamp F(10), Habering L(10), Dawson J, Beasley TM, Wan J(12), Ikeno Y(13), Hubbard G(13), Becker KG(14), Zhang Y(14), Bohr VA(4), Longo DL(14), Navas P(15), Ferrucci L, Sinclair DA, Cohen P(12), Egan JM(7), Mitchell JR(9), Baur JA(8), Allison DB, Anson RM, Villalba JM(6), Madeo F(10), Cuervo AM(2), Pearson KJ(17), Ingram DK(18), Bernier M, de Cabo R(19).Free full text:http://www.sciencedi...550413116302492PMID: 27304509 --------- 10: Sun LY, Spong A, Swindell WR, Fang Y, Hill C, Huber JA, Boehm JD, Westbrook R, Salvatori R, Bartke A. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife. 2013 Oct 29;2:e01098. doi: 10.7554/eLife.01098. PubMed PMID: 24175087; PubMed Central PMCID: PMC3810783. Quote Link to comment Share on other sites More sharing options...
Mechanism Posted April 23, 2018 Report Share Posted April 23, 2018 (edited) Edited Edited July 19, 2020 by Mechanism Quote Link to comment Share on other sites More sharing options...
Gordo Posted April 26, 2018 Report Share Posted April 26, 2018 Its fun to debate the science, but do you ever feel like you are just rearranging the chairs on the deck of the titanic? I also see repeated statements that indicate a belief that the majority of mouse subtypes benefit from CR (or at least have > longevity under CR). Are you sure that isn't a myth? I remember seeing some study or document breaking down the effects of CR by mouse subtype, and I'm sure there was a link to it somewhere in the forums, but I can't find it right now. Anyone know what I'm talking about? I know there is also a currently ongoing study of this very thing, I believe it received funding a year or two ago? I remember emailing the lead researcher about it (I was interested in knowing if he was using thermoneutral conditions and/or variable temps)... Then there is the whole discussion/debate around CR vs. CE. Mice which have been engineered to have a reduced core body temperature have increased lifespan independent of calorie restriction: https://www.ncbi.nlm.nih.gov/pubmed/17082459 To the point of "how much does any of this translate to humans out in the real world"? We now have decades of at least small numbers of humans practicing CR - shouldn't we have some compelling anecdotes at least by now? Instead we have a handful of people that may be aging better than average (not really hard to do if you are actually trying), but nothing to get terribly excited about, others seem to have quite a lot of health problems that could very well be linked to CR (certainly osteoporosis at least). Are there any CR Society members that have even made it to 100? Quote Link to comment Share on other sites More sharing options...
Dean Pomerleau Posted April 26, 2018 Author Report Share Posted April 26, 2018 Gordo, Let me play a bit of devil's advocate, just for the fun of it :-). You wrote: Its fun to debate the science, but do you ever feel like you are just rearranging the chairs on the deck of the titanic? To give credit where credit is due, Michael is perhaps the one among us who isn't just rearranging deck chairs with idle debate, since he is directly involved in SENS's efforts to do something about aging. Putting our disagreements regarding the finer points about CR efficacy & translatability aside, Michael deserves huge kudos for his efforts at SENS, and the more we distract him the less he can contribute to actually solving the problem of aging! Anyone know what I'm talking about? Yes, here is a link to the discussion of one controversial study (Nelson [1]) showing the effectiveness of CR varies dramatically with mouse strain, which Michael has suggested we should ignore since he says a good fraction of the mutant strains in [1] are seriously messed up. Mice which have been engineered to have a reduced core body temperature have increased lifespan independent of calorie restriction: https://www.ncbi.nlm...pubmed/17082459 Yes, but even more interestingly, evidence suggests that mice engineered to have more brown fat and a higher than normal body temperature as a result, have increased mean and maximal lifespan independent of calorie restriction. See this recent post in the cold exposure thread. houldn't we have some compelling anecdotes [of extended lifespan in human CR practitioners - DP] at least by now? ... Are there any CR Society members that have even made it to 100? I don't know of any CR Society members who've been doing CR for long enough to approach centenarian status. While Walford's original "The 120 Year Diet" book was first published in 1987, the CR Society didn't really get off the ground until the mid 90s. That means there's only been a little over 20 years during which someone could be expected to be intentionally practicing CR for life extension. For someone who started 20 years ago to make it to 100, they'd have to have been approaching 80 when they started (obviously). But anyone starting CR at 80 is unlikely to see much life extension benefit since benefits are proportional to the fraction of one's life spent under CR, and because late life CR is apt to hurt survival as much as help, as we've discussed on other threads. But having said that, there is one anecdote I've heard about someone recently reaching centenarian status subsequent to long term CR - Paul McGlothin's friend Ralph. I can't independently verify what Paul claims about Ralph and his CR practice since I've only heard of him through Paul, but here is what Paul says about Ralph in this Humanity+ article: Closer to home, the longest-lived member of the CR Society, Ralph Cornell, followed that same philosophy. He said his most important exercise was the Thumb Exercise: He pushed himself away from the table with his thumbs when he started to get full. And he lived 104 healthy years. So there is one anecdote of impressive human longevity for a CR practitioner (edit - see below for more details on Ralph). --Dean --------------------- 1] Aging Cell. 2010 Feb;9(1):92-5. doi: 10.1111/j.1474-9726.2009.00533.x. Epub 2009 Oct 30.Genetic variation in the murine lifespan response to dietary restriction: fromlife extension to life shortening.Liao CY(1), Rikke BA, Johnson TE, Diaz V, Nelson JF.Author information:(1)Department of Physiology, University of Texas Health Science Center at SanAntonio, San Antonio, TX 78229, USA.Comment inAging Cell. 2010 Jun;9(3):448-9; discussion 450-2.Chronic dietary restriction (DR) is considered among the most robustlife-extending interventions, but several reports indicate that DR does notalways extend and may even shorten lifespan in some genotypes. An unbiasedgenetic screen of the lifespan response to DR has been lacking. Here, we measuredthe effect of one commonly used level of DR (40% reduction in food intake) onmean lifespan of virgin males and females in 41 recombinant inbred strains ofmice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL)feeding and 6- to 10-fold under DR, in males and females respectively. Notably,DR shortened lifespan in more strains than those in which it lengthened life.Food intake and female fertility varied markedly among strains under AL feeding,but neither predicted DR survival: therefore, strains in which DR shortenedlifespan did not have low food intake or poor reproductive potential. Finally,strain-specific lifespans under DR and AL feeding were not correlated, indicatingthat the genetic determinants of lifespan under these two conditions differ.These results demonstrate that the lifespan response to a single level of DRexhibits wide variation amenable to genetic analysis. They also show that DR canshorten lifespan in inbred mice. Although strains with shortened lifespan under40% DR may not respond negatively under less stringent DR, the results raise thepossibility that life extension by DR may not be universal.PMCID: PMC3476836PMID: 19878144 Quote Link to comment Share on other sites More sharing options...
Dean Pomerleau Posted April 26, 2018 Author Report Share Posted April 26, 2018 I did a little more digging and found more about Ralph on this very interesting, if outdated, web page about the science of CR. Here is what it says: In 1956, at the age of 53, Ralph Cornell (left), of Massilon, Ohio, began skipping lunch. From then on, he became voluntarily calorie restricted. On March 13, 2006, Mr. Cornell celebrated his 103rd birthday. He continued to drive every day to and from his real estate business until he was 101. At that time, he fell on his front porch and broke his hip (osteoporosis?) He then retired from his real estate operations. Ralph has now outlived all his siblings, including his sister, Edna, who died recently at 93. (Many members of Ralph's family have lived into their 90's.) In addition to his broken hip, Ralph has also suffered from a serious heart attack. Still, he couldn't have known until fairly recently what's now known about the nutritional requirements unique to CR. Also, his heart disease might have been preventable given early attention. Note that Ralph is reading. If you're 25, you may think, "So what?", but if you're 80 or 90, you'll realize that at 103, most people can't read. Ralph is the Neil Armstrong of calorie restriction. While we can't draw too much from what happens to one man, or two or three, it's encouraging that what is happening is consistent with what we might expect CR to accomplish in humans. Ralph has been a close friend of Paul McGlothin and Meredith Averill for many years. June 7, 2008 Update: Ralph Cornell celebrated his 104th birthday on March 13, 2007, but I don't see any indications that he was still alive for his 105th birthday in 2008. Still he had quite a life, and was still enjoying it at 104 (when he attended a football game). (He certainly doesn't look like the typical centenarian in this picture.) He had a very serious heart attack a few years ago. It's my impression that he avoided doctors, and of course, some of the recent ideas regarding nutrition for the calorie-restricted wouldn't have been available to him until recently. CR begun at the age of 53 probably added 10 years to his life span and allowed him to drive to and from his office until he was 101. Here is the picture of Ralph referenced above: He does look pretty good for 103! --Dean Quote Link to comment Share on other sites More sharing options...
AlPater Posted April 27, 2018 Report Share Posted April 27, 2018 (edited) Re Ralph, there is this obituary: http://www.legacy.com/obituaries/cantonrep/obituary.aspx?page=lifestory&pid=86809055 although the only mention of CR in his Guest Book http://www.legacy.com/obituaries/name/ralph-cornell-obituary?pid=86809055&view=guestbook was by Paul. Also there is the https://en.wikipedia.org/wiki/Luigi_Cornaro story. Edited April 28, 2018 by AlPater Quote Link to comment Share on other sites More sharing options...
Gordo Posted April 30, 2018 Report Share Posted April 30, 2018 All good points above. Also I totally appreciate the fact that Michael may be the only one of us that is actually out there working in the field we all put so much value and emphasis on. Somewhat related to the topic of this thread, new study out of Harvard, popular press link made it to today's front page of the DrudgeReport: https://www.theguardian.com/science/2018/apr/30/the-five-habits-that-can-add-more-than-a-decade-to-your-life The five habits that can add more than a decade to your lifePeople who stick to five healthy habits in adulthood can add more than a decade to their lives, according to a major study into the impact behaviour has on lifespan. Researchers at Harvard University used lifestyle questionnaires and medical records from 123,000 volunteers to understand how much longer people lived if they followed a healthy diet, controlled their weight, took regular exercise, drank in moderation and did not smoke. When the scientists calculated average life expectancy, they noticed a dramatic effect from the healthy habits. Compared with people who adopted none of them, men and women who adhered to all five saw their life expectancy at 50 rise from 26 to 38 years and 29 to 43 years respectively, or an extra 12 years for men and 14 for women. “When we embarked on this study, I thought, of course, that people who adopted these habits would live longer. But the surprising thing was how huge the effect was,” said Meir Stampfer, a co-author on the study and professor of epidemiology and nutrition at the Harvard TH Chan School of Public Health. The researchers performed the analysis in the hope of understanding why the US, which spends more on healthcare as a proportion of GDP than any other nation, ranks 31st in the world for life expectancy at birth. According to the World Health Organization, life expectancy at birth in 2015 was 76.9 and 81.6 years old for US men and women respectively. The equivalent figures for Britain are very similar at 79.4 and 83 years old. The study, published in the journal Circulation, suggests poor lifestyle is a major factor that cuts American lives short. Only 8% of the general population followed all five healthy habits. The research focused on the US population, but Stampfer said the findings applied to the UK and much of the western world. The five healthy habits were defined as not smoking; having a body mass index between 18.5 and 25; taking at least 30 minutes of moderate exercise a day, having no more than one 150ml glass of wine a day for women, or two for men; and having a diet rich in items such as fruit, vegetables and whole grains and low in red meat, saturated fats and sugar. Men and women who had such healthy lives were 82% less likely to die of heart disease and 65% less likely to die of cancer compared with those with the least healthy lifestyles, over the roughly 30 years of the study. Given that the habits of a healthy lifestyle are well known, the mystery is why we are so bad at adopting them, said Stampfer. Part of the problem is that many people struggle to give up smoking, and the continuous peddling of unhealthy food, as well as poor urban planning, which can make it hard for people to exercise, also feed in, he said. “I do think people need to step up and take some personal responsibility, but as a society we need to make it easier for people to do that,” he said. “People can get stuck in a rut and think it’s too late to change their ways, but what we find is that when people do change their ways, we see remarkable benefits.” Quote Link to comment Share on other sites More sharing options...
kpfleger Posted May 1, 2018 Report Share Posted May 1, 2018 It's great to see another good epidemiological study on lifestyle and long-term health, and great for it to get press as yet another reminder to people, most of whom are doing many of the wrong things, but I found the talk in some places of the new study's results being surprising to be very poor scholarship. These new results are very consistent with previous results, many of which were nicely collected and described for a lay-audience in Jeff Novick's classic Triage Your Health post. This is just yet another reminder. As for Michael being the only one to be actually working to solve the problem, I commend Michael for doing so much but for the rest of us don't think you can't help. Everyone can donate what to SENS. I do. There are other things people can do to help if you have extra time or money or good contacts or other things to bring to the table. Quote Link to comment Share on other sites More sharing options...
Gordo Posted May 1, 2018 Report Share Posted May 1, 2018 (edited) I saw this today and it reminded me of this thread, because Dean was talking about Ralph who died at age 104, and this guy just turned 104, he also looks pretty good in his picture, and both of them were reading books at 104, but apparently this guy has been wanting to die for the last 20 years, hah: A scientist just turned 104. His birthday wish is to die. "For the past two decades, Goodall has been a member of Exit International, a nonprofit organization based in Australia that advocates for the legalization of euthanasia." UPDATE: He got his wish today: https://www.msn.com/en-us/news/world/david-goodall-104-year-old-scientist-dies-in-assisted-suicide/ar-AAx3SmS?OCID=ansmsnnews11 Edited May 10, 2018 by Gordo Quote Link to comment Share on other sites More sharing options...
mccoy Posted May 1, 2018 Report Share Posted May 1, 2018 The Australian Broadcasting Corp. reported at the time that after nearly two decades on the campus, Goodall was told to leave amid concerns about his well-being. The incident gained international media attention, with Goodall, then 102, calling it ageism in the workplace. Ageism in the workplace at 102, nice ! Quote Link to comment Share on other sites More sharing options...
TomBAvoider Posted May 1, 2018 Report Share Posted May 1, 2018 He's in apparently declining health, but it's not clear if it's the health issues that are the cause of his wishing to die. This points to the importance of healthspan as well as lifespan. I saw this today and it reminded me of this thread, because Dean was talking about Ralph who died at age 104, and this guy just turned 104, he also looks pretty good in his picture, and both of them were reading books at 104, but apparently this guy has been wanting to die for the last 20 years, hah: A scientist just turned 104. His birthday wish is to die."For the past two decades, Goodall has been a member of Exit International, a nonprofit organization based in Australia that advocates for the legalization of euthanasia." Quote Link to comment Share on other sites More sharing options...
Gordo Posted May 2, 2018 Report Share Posted May 2, 2018 (edited) Just wanted to point out that the recent Harvard study mentioned above found that the ideal BMI is between 18.5-22.9. They also found that >=6 hrs moderate or vigorous activity per week is ideal, along with a bit of daily alcohol. Edited May 2, 2018 by Gordo Quote Link to comment Share on other sites More sharing options...
edmundsj Posted November 11, 2020 Report Share Posted November 11, 2020 On 5/30/2016 at 3:19 PM, Dean Pomerleau said: I was surprised at what Michael said was the most likely explanation - which I hope he'll forgive and correct me if I get it not quite right.What I understood Michael to be saying was that the reason the lowest mortality BMI has increased so much in the last 30-40 years is that, as the authors of [11] suggest, medical advances (e.g. statins, metformin, stents, etc.) have dramatically reduced the deleterious effects of being obese and overweight.In short, being very thin doesn't pay as much as it used to in terms of longevity dividends. Very thin folks are still saddled with the burden of increased fragility (e.g. likelihood of dying if/when they get sick), while more robust chubby folks aren't penalized as much as they used to be for being overweight/obese as a result of the hundreds of billions of dollars that have been spent over the last few decades to develop treatments to prevent and manage the deleterious effects of obesity and obesity-related diseases like CVD and diabetes. Incoming fist to the face (re: duking it out). All in good fun. Fiat Lux! No. Wrong. First of all, chubby folks are still badly penalized by increased risk for chronic disease (diabetes, CVD), which modern medicine is barely a band-aid for. We've gotten great at curing bacterial disease, keeping a lid on some viral diseases, and we're ok-ish at treating very few forms of cancer. Testicular, thyroid, and child leukemia come to mind. We're also pretty good at orthopedic surgery. Other than that, modern medicine is absolute garbage at providing treatment and cures for chronic diseases. We can't even get rid of plaque buildup in arteries. Second, when inferring longevity from BMI, you have to be very careful because of one major problem: reverse causation. People with exceptionally low BMI's are much more likely to have that BMI because of some type of wasting disease, or just advancing age, or have achieved that BMI in response to a disease. For this reason, when trying to infer the independent effect of BMI on health you need to be careful to exclude prior chronic disease, and then incorporate the effect of BMI on the development of that disease. This was done in a review by Fontana [1] (attached) in 2014, who found monotonically decreasing risk of developing chronic disease with decreasing BMI down to a BMI of <21 using a pooled analysis of individual data from ~2M people. The Danish study you refer to was a total of ~10K people and only corrected for smoking. Weak power, weaker methodology. [1] Fontana, Luigi, and Frank B. Hu. "Optimal body weight for health and longevity: bridging basic, clinical, and population research." Aging cell 13, no. 3 (2014): 391-400. Fontana_2014_Optimal-body-weight-caloric-restriction.pdf Quote Link to comment Share on other sites More sharing options...
Ron Put Posted November 12, 2020 Report Share Posted November 12, 2020 On 11/11/2020 at 1:46 PM, edmundsj said: chubby folks are still badly penalized by increased risk for chronic disease (diabetes, CVD), which modern medicine is barely a band-aid for. My thoughts, exactly. Genetics and available medical services certainly play a role, but all things equal, fat folks are still more likely to have more health issues than slim ones. I do agree with Dean that a balance between calories and exercise is important, as a physical activity such as walking appears to be correlated with healthspan and longevity, based on the population studies I've seen, and it makes sense to me. Dean is on the more extreme end as far as walking distances but based on his stats, it works damned well for him. Quote Link to comment Share on other sites More sharing options...
mccoy Posted November 14, 2020 Report Share Posted November 14, 2020 ONLY FOR DUDES: Interesting graphs from the Fontana study. What I read though, is that extreme leanness does not appear to provide an edge in all risks. Upt to BMI = 22 kg m-2, risk is the same for all. Up to BMI= 24, risk is about the same for all except for T2D. If I were to express an objective judgment based on those data I would say that it is useless or maybe detrimental to go below BMI 22, for the same reasons cited by Dean Pomerleau: increased risk of injury or delayed or stunned recovery in case of hospitalization (serious injuries, IC like in SARS-COV2 infections). Barring people who have higher blood sugar, it may even be a better option not to go below BMI=24. Last but not least, I don't know if the studies have been corrected for adiposity. If the BMI is a proxy for adiposity, then it may be pretty misleading as we know. CR is more complex since it means very low adiposity and very low muscle mass. Quote Link to comment Share on other sites More sharing options...
Ron Put Posted December 3, 2020 Report Share Posted December 3, 2020 On 11/14/2020 at 9:43 AM, mccoy said: If I were to express an objective judgment based on those data I would say that it is useless or maybe detrimental to go below BMI 22, for the same reasons cited by Dean Pomerleau: increased risk of injury or delayed or stunned recovery in case of hospitalization (serious injuries, IC like in SARS-COV2 infections). Not necessarily, especially if you are Japanese. The problem with BMI studies which include subjects with comorbidities is that there is no good way to tell if leanness is intentional or the result of a progressing/advanced illness. Here is a study in centenarians:Implications of obesity in exceptional longevity "Centenarians show exceptional longevity (~20+ years more than the average Westerner) and most have postponed, and some even escaped major diseases despite their advanced age. The latter represents the paradigm of extended healthy life expectancy that any individual would dream of reaching. We assessed BMI in three independent centenarians’ cohorts of both sexes that we have studied extensively (7): n=81 from Northern Italy (Lombardy, Piedmont); n=84 from Spain (central area); and n=467 from Japan [participants in the Tokyo Centenarians and semi-supercentenarians (SS) study] (7). The Italian centenarians were free of major age-related diseases (cancer, CVD, dementia). BMI assessment was done during 2009–2013 (Spain), 2011–2014 (Italy), 2000–2004 (Japanese centenarians) and 2002–2016 (Japanese SS) (7). We compared BMI mean values and categories across cohorts with one-group ANOVA and χ2 tests, respectively. We obtained approval from the local ethics committees [European University of Madrid (Spain), 2E Science (Italy), and Keio University (Japan)]. The study followed the tenets of the Declaration of Helsinki for Human Research. Results are shown in Table 1. Aside from some geographic-specific differences (Japanese centenarians had the lowest BMI and a high prevalence of underweight–which is concurrent with the typical profile of this country compared with most Western societies), a main result is that the percentage of obese centenarians was well below the estimated current values for adults [age-standardized obesity of 10.8% (95% CI: 9.7–12.0) in men and 14.9% (95% CI: 13.6–16.1) in women] (1). Notably, we found no obese male centenarians in any of the cohorts. Italy has one of the world’s highest percentages of obese people [ranked number 9 (men) and 14 (women) in 2014] (1). And yet there were no obese disease-free centenarians in the Italian cohort. ... According to our results, obese people do not show healthy life expectancy." Quote Link to comment Share on other sites More sharing options...
mccoy Posted December 3, 2020 Report Share Posted December 3, 2020 (edited) 4 hours ago, Ron Put said: According to our results, obese people do not show healthy life expectancy." interesting table, Japanese has its own characteristics, but I don't know if they gave details about the low BMI (small muscle mass? Small adiposity? Porous bones?) . Also, there is one value in the table which is probably wrong, minimum BMI in the Japanese cohort = 11.9, that would mean a quasi-skeleton, it may be but if so it should have been discarded from the study. Most western centenarians are not underweight. Edited December 3, 2020 by mccoy Quote Link to comment Share on other sites More sharing options...
Jim Pearce Posted 9 hours ago Report Share Posted 9 hours ago (edited) Wow, I finally finished it all. I want to comment on the arthritis thing. I'm not in as good a shape as I was last year. Last year the 6 mile hike in the hills I took today would have taken less than 90 minutes. Today it took 97 minutes. My left knee is ate up with arthritis so bad my left leg is visibly deformed by it. People tell me watching me walk, especially from behind, is kind of a sight to see because of my deformed leg. So there's that. I have eaten a whole foods plant based lifestyle and practiced moderate CR for a few years now. Either one or the other or both together must be making me able to walk like I definitely can. I do recall, some time in the last couple years seeing an article online somewhere touting that many people were choosing a whole foods plant based lifestyle over knee surgery. I've wondered if I could find it again, but I've never tried. The other thing I'm curious about is the monkey trials. Ok, no significant difference in lifespan in the NIA study where they were fed healthy food and weren't allowed to gorge themselves like western humans. In the other study where they were all fed crap but the CR monkeys just got less of it, I'd like to know if those crap eating CR monkeys lived as long as the healthy eating monkeys in the other study. And the benefits w/regard to suffering less cancers, heart disease, and diabetes..did the CR monkeys being fed a less healthy diet benefit enough from CR on those fronts to compare equally with the ones who ate healthier food? After reading all this, I doubt CR "lengthens" our life. But it might appear to in the end. People are chowing down on pizzas, double cheeseburgers, ice cream, cookies, donuts...and many of them are living into their 80's anyway these days! They are the crap eating control monkeys. We are the CR monkeys. And...we don't even know what our true potential lifespan really is! Jean Calmente smoked and ate 2 pounds of chocolate a week. I read that. Who knows what other bad habits she might have had. So she was an anomaly with incredibly good luck, whether genetic or some other unknowable factors. Someone like us will live longer than she did. What I believe is the control monkeys in the NIH study, confined to cages and getting to eat all they wanted of crappy bad food probably aged faster than they should have. Maybe the CR monkeys in that trial didn't age slower. Maybe they just aged normally. What if all the crap eating people around us aging "normally" are aging faster than they should too? Which one would you rather be? Edited 9 hours ago by Jim Pearce Quote Link to comment Share on other sites More sharing options...
Jim Pearce Posted 9 hours ago Report Share Posted 9 hours ago Wow! I thought I had read it all! I didn't realize there were 3 more pages! Back to reading.. Quote Link to comment Share on other sites More sharing options...
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