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  1. All, In a number of different threads lately we've touched on the issue of whether human CR as traditionally conceived (i.e. consuming fewer calories while meeting one's nutritional requirements) will provide significantly greater health & longevity benefits than a healthy diet without dramatic calorie reduction, but which includes enough exercise and calorie-restraint to avoid becoming overweight/obese. Several people, most notably & vocally, Michael and Saul, but also Khurram and Brian (who've sadly remain quiet lately) appear to hold the view that it's the absolute calories that count. Several others, including myself, Gordo, maybe James and maybe TomB, seem to think instead that human CR won't provide much (if any) additional health/longevity benefit beyond a healthy, obesity-avoiding diet & lifestyle. This thread is meant to be a venue where we can duke it out on this topic. ☺ In this post I'll try to kick things off by collecting together some of the evidence I've posted in the last few months, along with some new findings, which seems to me to undermine the hypothesis that CR will provide substantial benefits beyond those provided by a healthy, obesity-avoiding diet & lifestyle. The disappointing (by my interpretation) NIH-sponsored Monkey CR trials are an important part of this evidence, but as Saul points out, that was just one study. In addition I'll point to evidence from rodents, dogs and people to make the case against CR providing significant additional benefits. But before I dive in, I should note that what I'll be referring to is the practice of CR during one's years in the "sweet spot", not starting CR too young (before adulthood which might be beneficial in humans, but which is ill-advised and irrelevant for all of us), or continuing it too long into one's elder years. While the upper age cutoff may be controversial, I think there may be general consensus on this point - namely it's probably wise to back off serious CR at some point in one's 60's, 70's or 80's (depending on one's state of health) to avoid excessive frailty that may shorten rather than lengthen one's life. This topic of the optimal late-life BMI is discussed in detail in this thread, so let's not focus on it in this one. I will also not address my strengthening conviction that if CR is to provide benefits in any mammal species, it likely needs to be accompanied by a significant degree of cold exposure. In other words CR without exposure to a cold environment (not just the subjective feeling of chilliness that virtually all CR folks experience) appears not to work to extend lifespan in rodents, to say nothing of people. For anyone who wants to learn more about the evidence for this cold exposure hypothesis, which I consider pretty compelling, see the cold exposure thread, and this post in particular to start with. Evidence from Primates First, the NIH CR primate study. Michael did what I consider to be the most comprehensive and authoritative review of this very important, multi-decade study of CR in rhesus monkeys. I won't try to recapitulate all the analysis Michael did, but do my best to summarize. I'm hopeful Michael will correct any mistakes or oversights in my interpretation. I think Michael hit the nail on the head when he characterized the primate study (which was really two studies, at the U. of Wisconsin and at the NIA) as a "muddle". There were unfortunate shortcomings in both the study design and execution. The monkeys were of diverse and suspect pedigree which may have resulted in some of them dying earlier than they should have. The degree of CR in both the control monkeys and the CR monkeys was modest and in the later case may have dropped over the years to the point where it wasn't a very good test of CR (see [1]). And while I said I wasn't going to focus on it, the monkeys were housed at a thermoneutral temperature, potentially defeating CR benefits, per my theory about the importance of cold exposure on top of CR, as I discussed here. With those caveats in mind, it seems to me the best interpretation of the two monkey CR studies are the following: From the Wisconsin study [2], it appears that CR in monkeys can be effective - at least compared to controls who are allowed to become obese, and when both controls and CR monkeys are fed a highly refined, crappy diet similar in many respects to what an average American eats. But the real kick in the teeth for human CR came with the publication in 2012 of the NIA monkey study results [3], which I summarized here as follows: "The most parsimonious interpretation of the NIA monkey data (esp when coupled with the Wisconsin monkey data) is that once obesity is avoided, a healthy diet with (albeit only mild) calorie restriction is no better for primate longevity than the same diet without calorie restriction (or only enough CR to avoid obesity)." Here are the survival curves for male (M) and female (F) control (CON) and 30% calorie-restricted (CR) monkeys, both for all-cause (left) and age-related (right) morality: I don't know about you folks, but the corresponding CR and Control curves look pretty-darn indistinguishable to me. Hence the pessimism over the primate study results. Having read both studies, it appears to me the primary difference between the Wisconsin and NIA studies were that the NIA diet was much healthier and less refined, and the NIA control monkeys were very modestly calorie restricted to prevent obesity and its ill effects, which appeared to plague the Wisconsin controls to a much larger degree. Hence the interpretation that CR doesn't seem to provide much if any longevity benefit in primates relative to controls eating a healthy, obesity-avoiding diet. While acknowledging it's less than definitive, Michael seems to favor this interpretation of the Monkey CR studies as well, in this (extended) passage from is very thorough analysis of the monkey data, he acknowledges this as a pretty reasonable interpretation of the Wisconsin & NIA primate CR results, saying (my emphasis): A straightforward reading of the two nonhuman primate CR studies, then, is that in rhesus macaques, the relationship between energy intake, body weight, and lifespan is the commonsensical one, against which the rodent CR phenomenon stands as such a stark contrast: that overweight and excess adiposity are bad for one's health and prospects for long life, but that some normative "healthy" anthropometry is optimal, with diminishing returns at best as energy intake and body weight are progressively reduced beyond that juste milieu. Indeed, skeptics of the human translatability of CR have long argued that the weight loss that is associated with CR appears to only be salutary to health within a relatively narrow range. They argue instead that further limiting energy intake and adiposity will lead to progressively less marginal benefit, especially in light of the uniquely metabolically deranging effects of visceral adipose tissue, which is preferentially lost early in the process weight loss, whether achieved by diet or exercise.(ref) Such skeptics also point to the importance of maintaining lean mass — both muscle and bone — for preserving health during aging, and to the large number of epidemiological findings (eg. (ref,ref)) suggesting a J-shaped or U-shaped relationship between body mass index (BMI) and mortality, although the relevance of these findings to the Calorie restriction phenomenon is dubious.* In this interpretation, the slight restriction imposed on NIA control animals, leading to an energy intake and body weight that was intermediate between those of WNPRC's ad libitum and restricted groups, was sufficient to achieve or closely approach the point of diminishing health and longevity gains, and a further restriction from this point in the CR group therefore yielded no further extension of lifespan. This explanation of the discrepancy in the effects of CR as compared to internal control animals in the WNPRC (2) and NIA (3) studies has much to offer. It is conceptually straightforward; it is consistent the major findings of the two studies, and with an important body of research in humans; it fits with some models of the postulated evolutionary basis for the slow-aging phenotype of CR; and is not exclusive of some of the other explanations we have explored. And, as we shall see in the next section, it can also provide a consistent explanation for several differences in health and metabolic outcomes between the two studies, and accommodate a broader body of research on diet and metabolism in nonhuman primates. So Michael seems to concur that a good (perhaps the best) explanation of the disappointing CR primate results is that after calories are restricted enough to avoid obesity, there aren't many additional benefits to be had - "against which the rodent CR phenomenon stands as such a stark contrast." Evidence from CR in Rodents But is Michael even correct in his contrasting the failure of CR in primates with the success of CR in rodents? In particular, is the "CR phenomena" in rodents really as robust and linear with degree of calorie restriction as nearly everyone (including Michael) have always contented? We're all familiar by now which this famous graph from Weindruch's study [5], apparently showing consistent increase in longevity with degree of CR in mice, right up to 65% CR, which must be pretty close to the point of starvation: Looks very promising right? But it turns out there are quite a few rodent CR studies that show only marginal benefits of CR beyond obesity avoidance. For example, in this post, I discuss ]study [6] from last year, which found that in F344 rats "10% CR increased life span to almost the same extent as 40% CR." There was some extra benefit of severe CR in the last few rats to die (maximum lifespan), but that was offset by early mortality in the severe CR group. Overall the mean and median lifespans of the 10% CR and 40% CR rats were indistinguishable. And note these rats were CRed all their lives, from 6 weeks of age - which if anything should have maximized the benefits of severe CR and minimized the early mortality effect (which wasn't seen until middle age in the 40% CR group). Early onset CR is something none of us have the luxury of. The authors of [6] conclude: These data in combination with the data from Duffy et al.,[ref] which reported that feeding rats 10% and 25% DR was as effective as 40% DR in reducing the early mortality of male Sprague–Dawley rats, demonstrate that the lifespan of certain strains of rats and mice does not increase linearly up to 40% DR. Most of the extension of lifespan appears to be achieved by levels of DR much lower than 40% DR. And [6] isn't the only rodent study to show that mild CR is nearly as good as severe CR. In this post, I discuss [7], which studied lifelong CR in another commonly employed rat strain (Sprague Dawley rats). They found: The average lifespan of AL rats was 115 <sic> months [they mean weeks]. At 104 weeks on study (110 weeks of age), the survival rate for the AL and 10%, 25%, and 40% DR groups was 63.4, 87.5, 87.5, and 97.5%, respectively. The largest increase in survival (24.1%) occurred between AL and 10% DR, indicating that very low levels of DR have a significant effect on survival. This further supports the idea articulated above, that most of the benefits of CR, at least for the average individual, can be had via modest, 10% CR to basically avoid obesity. Unfortunately all the rats in this study were sacrificed early to study their organs, rather than allowing them to live out their natural lives, so there isn't data on total lifespan, just survival to 104 weeks. One potentially troubling explanation for this discrepancy between successful mouse CR studies like Weindruch et al [5] and these less-successful rat studies is the highly in-bred nature of laboratory mice used in virtually all CR experiments. For example, Austed et al [8] studied early-onset 40% CR in male grand-offspring of wild-caught mice and found: Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups... In fact they observed higher mortality in CR wild-type mice throughout most of their life, with a few wild-type CR mice hanging on longer than any of the AL-fed mice at the end of life. Here is the AL vs. CR survival graphs for these wild-type mice: Importantly, the wild-type mice in [8] were literally fed as much food as they wanted, without any restriction. As a result, they were pretty overweight, topping out at around 32g in mid-life, which was nearly than twice the wild-type CR mice. But at 32g, this is still quite a bit less than the peak weight of really obese (and short lived) in-breed ad-lib fed mice, which often top out in the neighborhood of 40g in CR experiments. So we see that in a less genetically inbred, obesity-prone strain of mice, severe CR may in fact be detrimental for longevity except for a few very lucky individuals - a small advantage that may have disappeared altogether had the control mice been mildly restricted rather than given unlimited access to food. So in heavily inbred mice, the control mice get really obese and so CR which prevents obscene amounts of weight gain has benefits. But in naturally thinner wild-type mice, CR provided no average lifespan benefits relative to ad-lib fed controls. Sohal et al have taken these clues about the importance of obesity avoidance in rodent longevity to heart, and done a really interesting study [9] that shows in both inbred mice and rats, that CR benefits are directly proportional to degree of obesity it prevents. In other words, as can be seen from these graphs, strains of rodents that get really fat when fed ad lib benefit a lot from CR, while strains that naturally don't get so fat benefit much less: In short, Sohal et al argue that that what matters for lifespan benefits of CR is the amount of obesity burden avoided. In other words, in Sohal's model, obesity is like smoking. It not so much that CR (or not smoking) is actively good for your longevity. Instead, getting (and staying) obese is actively bad for you, just like picking up the habit of smoking is actively bad for you. And the more years you are obese, the worse it is for your longevity, just like the more "pack-years" you smoke, the worse it is for your longevity. The last sentence in Sohal's paper pretty much sums it up: In a nutshell, CR increases life span when it counteracts a significant energy imbalance. As a corollary, what Sohal is suggesting is that even in rodents, if there is no energy imbalance there will be little if any lifespan increase from CR. Put differently, avoiding obesity and maintaining an "energy balance" will get you most if not all of the benefits of CR. Speaking of varying benefits of CR across mouse strains, I know Michael is pretty critical of this Nelson study [10], which looked at 41 different inbred strains of mice subjected to CR, and found a tremendous range of benefits and harm depending on strain and sex, as illustrated by this figure. Bars below the 0 line represent CR shortening lifespan relative to ad lib controls in a particular strain: Regardless of Michael's criticism of the particular strains used in [10], which he mentioned at the recent Conference and which I discuss here, we shouldn't simply ignore these results. Instead, as good Bayesians, we should incorporate this negative result into our model representing the probability that CR will work in humans... And it's not that we lack any good explanations for the potential life-shortening effects of serious CR. On the contrary, we've got an entire thread devoted to how CR weakens the immune response and makes animals much more likely to die from an illness once they get sick - a point brought home by the presentation by Dr. Janko Nikolich-Žugich at the Conference and discussed in this thread. This is one of the major reasons why I think there is general agreement that people should back off serious CR when they reach elderly years, to allow their (hopefully) preserved immune system to "recharge" and get ready for the slings and arrows of illnesses and injury that inevitably (at least for now) accompany old age. Finally, like the successful Wisconsin primate study, (virtually?) all CR rodent studies feed both the CR and the control group pretty crappy, refined, unnatural diets of Purina rodent chow. It's no wonder eating less of a bad diet might give CR rodents a modest longevity advantage, just like was seen in the Wisconsin arm of the CR primate studies. Does anyone know of rodent studies where they fed the CR and AL animals a more healthy, natural diet? Lacking evidence from a healthy-diet rodent CR study, it seems to me that the discrepancy between the Wisconsin and NIA primate CR results (which appears likely to have hinged at least in part on diet quality) calls into question the relevance of any of the positive results of CR in rodents. In fact, it seems to me the only really credible rodent evidence would be a study of nearly wild-type mice (i.e. not heavily inbred), like the mice Austad used in [8], feeding them a healthy, natural diet either in modestly CRed amounts (i.e. 10% CR) vs. serious CR (40%). If the serious CR mice in such a study lived substantially longer, I'd interpret that as significant evidence in favor of CR efficacy. Short of that, I'd say none of the rodent data tells us very much. Given what we do know, the available evidence (e.g. lack of mean/median lifespan benefits with wild-type mice fed a crappy diet completely ad lib [8]), suggests to me that the seriously CRed mice wouldn't have any advantage in the ideal experiment I describe. Evidence from CR in Dogs Before discussing evidence from humans, there is one more mammal species where CR has been experimentally investigated - namely dogs. Here is the post where I discuss [4], a study of 25% CR in Labrador retrievers. Since I discussed it in detail in that post, I won't go into weeds about it here, but my summary of that study is: The control dogs in this study were fed too much, given their caged lifestyle, so they grew fat. The CR dogs were fed an amount commensurate with (or a bit higher) than is recommended by canine nutrition experts, remained slim (in the lower part of the recommended weight range for Labradors) and lived 17% longer than controls, enjoying nearly as much CR longevity benefit as can be hoped for in [relatively long-lived] mammals. In other words, it looks like in dogs, as well as monkeys and rodents, that simply avoiding obesity is where most if not all of the benefits of CR are to be had. Evidence from Humans So what about the species that really counts - humans? What can we learn from studies of people about the relative advantage of serious CR vs. simply avoiding obesity while eating a healthy diet? Fresh in my mind is a discussion I had with Michael about [11], the recent, widely-discussed study (critiqued by me here - which includes my "fragile test tube" analogy) that appears to show that over the last 30-40 years, the healthiest BMI has shifted dramatically higher among healthy never-smokers, from an optimal BMI around 18 in folks in a cohort started in 1976-78 to a BMI around 26 in folks in a cohort started in 2003-2013. 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. The reason I was a bit surprised by Michael's explanation for the cause of the increase in the healthiest BMI is that it would seem to undermine to some degree the motivation for practicing CR. By analogy, once vaccines, antibiotics and other medicines for combating infectious diseases were invented, one no longer needed to avoid infections like the plague (both literally and figuratively ☺). Similarly, since we can now prevent and/or manage the negative consequences of obesity better, it isn't as critical to stay rail-thin in order to live a long time. But you should be thinking "but Dean, study [11] was in the general population - people who are lucky to live 75-80 years, with the last few years spent managing and suffering from diseases of excess. I don't want to live like that. I want to live a healthy life for as long as possible, free from any of the debilitating consequences of obesity. Surely serious CR is the best bet we have for accomplishing that - right? Isn't that what the Okinawans have shown us?" In short, no. As I discussed in my post comparing Okinawans to Adventists, the Adventists, particularly male Adventists, live substantially longer than Okinawans eating their traditional diet, and the longest-lived Adventists had a "medium" BMI (22.5-25). In fact, according to [12], having a medium BMI added approximately 1.5-2.5 years to an Adventists' lifespan relative to a lower or higher BMI. So in the the longest-lived population in the world, the clean-living, healthy-eating Adventists from Loma Linda California where (like us) they enjoy the benefits of modern healthcare, and where the men live to a ripe old average age of 87, the best weight to be is not rail thin, and therefore not seriously calorie restricted. In short, based on the available evidence from primates, rodents, dogs and people, it appears to me that serious CR is unlikely to significantly benefit human longevity relative to a healthy diet eaten in moderation and coupled with an active lifestyle sufficient to avoid obesity and keep a person in the BMI "sweet spot" of ~20-24, or perhaps even 22-25. --Dean ---------- [1] Neurobiol Aging. 2005 Jul;26(7):1117-27. Epub 2004 Dec 10. Age-related decline in caloric intake and motivation for food in rhesus monkeys. Mattison JA(1), Black A, Huck J, Moscrip T, Handy A, Tilmont E, Roth GS, Lane MA, Ingram DK. Author information: (1)Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. Full text: http://gen.lib.rus.e...3&downloadname= Human studies have documented age-related declines in caloric intake that are pronounced at advanced ages. We examined caloric intake from a longitudinal study of aging in 60 male and 60 female rhesus monkeys (Macaca mulatta) collected for up to 10 years. Monkeys were provided a standardized, nutritionally fortified diet during two daily meals, and intake was measured quarterly. About half of the monkeys were on a regimen of caloric restriction (CR) representing about a 30% reduction in caloric intake compared to controls (CON) of comparable age and body weight. CR was applied to determine if this nutritional intervention retards the rate of aging in monkeys similar to observations in other mammalian studies. Following reproductive maturity at 6 years of age, there was a consistent age-related decline in caloric intake in these monkeys. Although males had higher intake than females, and CON had higher intake compared to CR, the sex and diet differences converged at older ages (>20 years); thus, older CR monkeys were no longer consuming 30% less than the CON. When adjusted for body weight, an age-related decline in caloric intake was still evident; however, females had higher intake compared to males while CR monkeys still consumed less food, and again differences converged at older ages. Motivation for food was assessed in 65 of the monkeys following at least 8 years in their respective diet groups. Using an apparatus attached to the home cage, following an overnight fast, monkeys were trained to reach out of their cage to retrieve a biscuit of their diet by pushing open a clear plastic door on the apparatus. The door was then locked, and thus the biscuit was irretrievable. The time spent trying to retrieve the biscuit was recorded as a measure of motivation for food. We observed an age-related decline in this measure, but found no consistent differences in retrieval time between CR and CON groups of comparable age and time on diet. The results demonstrate an age-related decline in food intake and motivation for food in rhesus monkeys paralleling findings in humans; however, we found no evidence that monkeys on a long-term CR regimen were more motivated for food compared to CON. Examining the relationship of selected blood proteins to food intake following 7-11 years on the study, we found a negative correlation between globulin and intake among males and females after accounting for differences in age. In addition, a positive correlation was observed between leptin and intake in males. PMID: 15748792 --------- [2] Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4. PubMed PMID: 19590001; PubMed Central PMCID: PMC2812811. ----------- [3] Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R.Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012 Sep 13;489(7415):318-21. doi: 10.1038/nature11432. [Epub ahead of print] PubMed PMID: 22932268. ----------- [4] J Am Vet Med Assoc. 2005 Jan 15;226(2):225-31. Influence of lifetime food restriction on causes, time, and predictors of death in dogs. Lawler DF(1), Evans RH, Larson BT, Spitznagel EL, Ellersieck MR, Kealy RD. Author information: (1)Néstle Purina PetCare Research, 835 S 8th St, St Louis, MO 63164, USA. Free full text: https://www.avma.org...a_226_2_225.pdf OBJECTIVE: To describe effects of lifetime food restriction on causes of death and the association between body-mass characteristics and time of death in dogs. DESIGN: Paired-feeding study. ANIMALS: 48 dogs from 7 litters. PROCEDURES: Dogs were paired, and 1 dog in each pair was fed 25% less food than its pair mate from 8 weeks of age until death. Numerous morphometric and physiologic measures were obtained at various intervals throughout life. Associations of feeding group to time and causes of death were evaluated, along with important associated factors such as body composition components and insulin-glucose responses. RESULTS: Median life span was significantly longer for the group that was fed 25% less food, whereas causes of death were generally similar between the 2 feeding groups. High body-fat mass and declining lean mass significantly predicted death 1 year prior to death, and lean body composition was associated with metabolic responses that appeared to be integrally involved in health and longevity. CONCLUSIONS AND CLINICAL RELEVANCE: Results were similar to results of diet restriction studies in rodents and primates, reflecting delayed death from species- and strain-specific intrinsic causes. Clinicians should be aware that unplanned body mass changes during mid- and later life of dogs may indicate the need for thorough clinical evaluation. PMID: 15706972 ------------- [5] Weindruch R, et al. (1986). "The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake." Journal of Nutrition, April, 116(4), pages 641-54. ------------ [1] Aging (Milano). 2001 Aug;13(4):263-72. The effects of different levels of dietary restriction on aging and survival in the Sprague-Dawley rat: implications for chronic studies. Duffy PH(1), Seng JE, Lewis SM, Mayhugh MA, Aidoo A, Hattan DG, Casciano DA, Feuers RJ. Author information: (1)Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA. pduffy@nctr.fda.gov Comment in Aging (Milano). 2001 Aug;13(4):261-2. Aging Clin Exp Res. 2002 Apr;14(2):152-4. A study was undertaken to determine the effects of incremental levels of dietary restriction (DR) in rats. Survival, growth, reproductive, and dietary intake (DI) variables were monitored in a chronic study in which male Sprague Dawley (SD) rats (NCTR colony) were fed their ration ad libitum (AL), or DR. The main objectives were to determine if low levels of DR could be used to increase the survival rate of SD rats in the chronic bioassay, and to identify the survival characteristics of a long-lived SD rat strain (NCTR colony). The average life span of AL rats was 115 months. At 104 weeks on study (110 weeks of age), the survival rate for the AL and 10%, 25%, and 40% DR groups was 63.4, 87.5, 87.5, and 97.5%, respectively. The largest increase in survival (24.1%) occurred between AL and 10% DR, indicating that very low levels of DR have a significant effect on survival. Whole-body, liver, prostate, and epididymis weights and body length were decreased by DR, whereas brain weight, testicular weight, and skull length were not altered by DR. Rats from the NCTR colony were found to be ideal for chronic studies because they are much longer-lived than other SD stocks. Although the 104-week survival rate for these SD, non-obese AL rats exceeds the FDA's "Redbook" survival guideline (> 50%) for chronic bioassays, the use of DR is advocated because it reduces individual variability in body weight. PMID: 11695495 --------- [9] Free Radic Biol Med. 2014 Aug;73:366-82. doi: 10.1016/j.freeradbiomed.2014.05.015. Epub 2014 Jun 2. Caloric restriction and the aging process: a critique. Sohal RS(1), Forster MJ(2). Free full text: http://www.ncbi.nlm....les/PMC4111977/ The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. PMCID: PMC4111977 PMID: 24941891 --------- [10] 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: from life 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 San Antonio, San Antonio, TX 78229, USA. Comment in Aging Cell. 2010 Jun;9(3):448-9; discussion 450-2. Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. 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 shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal. PMCID: PMC3476836 PMID: 19878144 ------- [11] JAMA. 2016 May 10;315(18):1989-1996. doi: 10.1001/jama.2016.4666. Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013. Afzal S(1), Tybjærg-Hansen A(1), Jensen GB(2), Nordestgaard BG(1). Full text: http://sci-hub.cc/10.../jama.2016.4666 Importance: Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed. Objective: To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades. Design, Setting, and Participants: Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13 704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97 362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first. Exposures: For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared. Main Outcomes and Measures: Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality. Results: The number of deaths during follow-up was 10 624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95% CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95% CI, 9-30]), and 5580 in the 2003-2013 cohort (6%; MR, 4/1000 person-years [95% CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI value that was associated with the lowest all-cause mortality was 23.7 (95% CI, 23.4-24.3) in the 1976-1978 cohort, 24.6 (95% CI, 24.0-26.3) in the 1991-1994 cohort, and 27.0 (95% CI, 26.5-27.6) in the 2003-2013 cohort. The corresponding BMI estimates for cardiovascular mortality were 23.2 (95% CI, 22.6-23.7), 24.0 (95% CI, 23.4-25.0), and 26.4 (95% CI, 24.1-27.4), respectively, and for other mortality, 24.1 (95% CI, 23.5-25.9), 26.8 (95% CI, 26.1-27.9), and 27.8 (95% CI, 27.1-29.6), respectively. The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95% CI, 1.23-1.39; MR, 46/1000 person-years [95% CI, 32-66] vs 28/1000 person-years [95% CI, 18-45]) in the 1976-1978 cohort, 1.13 (95% CI, 1.04-1.22; MR, 28/1000 person-years [95% CI, 17-47] vs 15/1000 person-years [95% CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95% CI, 0.92-1.07; MR, 5/1000 person-years [95% CI, 2-12] vs 4/1000 person-years [95% CI, 1-11]) in the 2003-2013 cohort. Conclusions and Relevance: Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications. PMID: 27163987 --------- [12] Arch Intern Med. 2001 Jul 9;161(13):1645-52. Ten years of life: Is it a matter of choice? Fraser GE(1), Shavlik DJ. BACKGROUND: Relative risk estimates suggest that effective implementation of behaviors commonly advocated in preventive medicine should increase life expectancy, although there is little direct evidence. OBJECTIVE: To test the hypothesis that choices regarding diet, exercise, and smoking influence life expectancy. METHODS: A total of 34 192 California Seventh-Day Adventists (75% of those eligible) were enrolled in a cohort and followed up from 1976 to 1988. A mailed questionnaire provided dietary and other exposure information at study baseline. Mortality for all subjects was ascertained by matching to state death tapes and the National Death Index. RESULTS: California Adventists have higher life expectancies at the age of 30 years than other white Californians by 7.28 years (95% confidence interval, 6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88 years) in women, giving them perhaps the highest life expectancy of any formally described population. Commonly observed combinations of diet, exercise, body mass index, past smoking habits, and hormone replacement therapy (in women) can account for differences of up to 10 years of life expectancy among Adventists. A comparison of life expectancy when these factors take high-risk compared with low-risk values shows independent effects that vary between 1.06 and 2.74 years for different variables. The effect of each variable is assessed with all others at either medium- or high-risk levels. CONCLUSIONS: Choices regarding diet, exercise, cigarette smoking, body weight, and hormone replacement therapy, in combination, appear to change life expectancy by many years. The longevity experience of Adventists probably demonstrates the beneficial effects of more optimal behaviors. PMID: 11434797
  2. All, I was wondering if CR has ever been studied in large creatures? It seems that the effects of CR seem to scale down as the size of species goes up. For example, I believe we can double or triple the lifespan of flies and worms, and modestly extend maximum lifespan in larger species like dogs. The evidence for humans is of course murky and the jury is still out on whether maximum lifespan will be effected, or just health span. I'm wondering though if CR has ever been studied in a species physically larger than humans. Perhaps horses? Deer? Cows? Buffalo?
  3. All, Al's latest post about new CR paper contained a really interesting new study in rhesus monkeys [1], with potentially troubling implications for men practicing serious CR with (resulting) low testosterone. It was a study of middle-aged (~12 yo) male rhesus monkeys, making it more relevant to us than any of the rodent studies. Half the monkeys were orchidectomized ☹ to put the kibosh on their testosterone level, and the other half were subjected to mock surgery. After two months of recovery on a standard chow diet (15F / 27P / 59C) supplemented with fresh fruits & vegetables, both groups were made pudgy by shifting them for six months to a western style diet (WSD) that has a similar macronutrient profile to the diet many of us eat day-to-day (33F / 17P / 51C). Then, for 4 additional months, they calorie-restricted both groups by putting them back on the standard chow + F&V diet, but giving them only 70% of their individual baseline (pre-surgery) calorie intake (i.e. 30% CR). They intended to model in their rhesus monkeys the life history of men who undergo androgen deprivation therapy (ADT) for treatment of prostate cancer, so see if calorie-restriction could prevent the metabolic syndrome such treatment often induces in men. But while not perfect, the parallels with us CR folks are unmistakable - i.e. chronic CR resulting in the combination of reduced muscle mass and low testosterone. What they found appears to me to be pretty troubling, as I alluded to in the title and introduction. First, two months after the surgery, while still eating the standard, low-fat chow + F&V diet ad libidum, the orchidectomized (O) monkeys (OMs), but not the intact (I) monkeys (IMs) showed a decrease in lean mass. Not too surprising - lean mass drops with low testosterone. During the six-months of western-style diet (WSD), both groups gained fat. No surprise. But unlike the I monkeys, the O monkeys also lost additional lean mass and bone mass during the WSD period. Once again we see the negative effects of low-T on body composition. In short, the OMs became pretty classic examples of hypogonadal middle-aged men - pudgy, with little muscle mass and low testosterone. Now comes the interesting part - what happened as a result of 30% CR? Obviously both groups lost significant (and comparable) amount of fat mass. Both groups also lost lean mass. As a result, after the CR period both groups had returned to their relatively-lean baseline (pre-surgery) weight. But relatively to baseline, both groups had a higher percent body fat that they started with, and the O monkeys in particular had a lot less lean mass. The O monkeys also exhibited reduced bone mineral density as a result of CR, and effect not seen in the I monkeys. In short, low testosterone dropped the O monkey's lean mass and bone mass, and CR did nothing to counteract this effect - if anything it exacerbates it. But is that necessarily such a big deal? Maybe having low testosterone and reduced muscle mass after CR isn't a problem. In fact, without all that metabolically active muscle tissue, a CR practitioner could presumably eat fewer calories, and hence get more of the healthspan and lifespan benefits of CR, since "CR works by reducing Calorie intake -- period" a famous CR proponent once said. But so as to avoid getting myself into hot water yet again, I'll note that even he recognizes the importance of maintaining lean mass and bone mass via exercise while practicing CR... Obviously late-life sarcopenia and frailty is one concern some of us have about sacrificing too much muscle and bone mass to the CR gods. Unfortunately this short-term study didn't investigate the impact of these effects. But what they did find was even more germane to one of the negative side-effect that has been front and center in our discussions lately (discussed in depth here and here), namely impaired glucose tolerance (IGT). Not surprisingly, glucose tolerance (as measured by an OGTT) got worse in both I and O monkeys after eating the western diet for six months. But then, after 30% CR for four months, the I monkeys' glucose tolerance improved to the point where it was close to baseline again. In contrast, the poor, skinny, low-testosterone O monkeys, lacking much muscle mass, continued to show impaired glucose tolerance. The authors summarized their result as: CR improved these metabolic parameters [i.e. hyperinsulinemia and insulin resistance - DP] only in intact animals, whereas orchidectomized animals remained glucose-intolerant, despite a significant loss in fat mass. Put another way, CR coupled with low testosterone results in a precipitous drop in muscle mass, which led to impaired glucose tolerance. Note - the impaired metabolic health of the CR + Low-T monkeys was not a result of either differences in food intake or physical activity between the two groups - "... there was no significant group differences in these parameters under any of the dietary regimens studied." But they did observe an interesting effect of physical activity. At the end of the western diet period (i.e. pre-CR), across the entire population of monkeys, as well as within each group, monkeys that engaged in more physical activity had a lower percent fat mass (and by implication, a higher percent lean muscle mass), and exhibited better glucose metabolism, as illustrated in these two graphs showing % body fat (left) and OGTT glucose area under the curve (right), as a function of how active each of the monkeys was, as measured by a collar-worn accelerometer (Open circles = O monkeys, solid circles = I monkeys): Unfortunately, they don't report correlation between physical activity and glucose metabolism after the CR period. But given the across-the-board drop in lean mass as a result of CR that they observed, it seems likely to me that the observed relationship would still-hold, and perhaps be exaggerated, post-CR. So how do the authors interpret their results? Here are some of the key passages from the discussion section: The present study demonstrates that skeletal muscle loss in testosterone-deficient [non-human primates] correlated with the development of [insulin resistance] and glucose intolerance during the [western style diet] and CR periods. Surprisingly, there was no significant effect of testosterone deficiency on diet-induced change in fat mass, including fat gain during the WSD period and fat loss during the CR period, suggesting that insulin resistance in [low-testosterone androgen deprivation therapy] patients is related to the loss of skeletal muscle, which is the primary anatomical site responsible for glucose disposal. In other words, according to the authors: low-T (with or without CR) → reduced muscle mass → impaired glucose tolerance. Thus, testosterone may play a protective role in male physiology, while its deficiency may increase the susceptibility of males to metabolic syndrome. While this study was really meant to model men who are hypogonadal as a results of android deprivation treatment for prostate cancer, it seems to me to have potentially important implications for CR folks1, many of whom exhibit low-T, low muscle mass, and impaired glucose tolerance. The silver lining may be the observation about physical activity. By staying active (particularly after meals), and eating enough to maintaining muscle mass and avoid getting too skinny, we may be able to mask (if not altogether prevent) the negative effects of impaired glucose tolerance associated with serious CR that many of us have observed. --Dean ------- 1And Todd A in particular. ------------ [1] Int J Obes (Lond). 2016 Aug 18. doi: 10.1038/ijo.2016.148. [Epub ahead of print] Perpetuating effects of androgen deficiency on insulin-resistance. Cameron JL, Jain R, Rais M, White AE, Beer TM, Kievit P, Winters-Stone K, Messaoudi I, Varlamov O. Full text: http://sci-hub.cc/10.1038/ijo.2016.148 Abstract Background/Objectives: Androgen deprivation therapy (ADT) is commonly used for treatment of prostate cancer, but is associated with side effects such as sarcopenia and insulin resistance. The role of lifestyle factors such as diet and exercise on insulin sensitivity and body composition in testosterone-deficient males is poorly understood. The aim of the present study was to examine the relationships between androgen status, diet, and insulin sensitivity. Subjects/Methods: Middle-aged (11-12-yo) intact and orchidectomized male rhesus macaques were maintained for two months on a standard chow diet, and then exposed for six months to a Western-style, high-fat/calorie-dense diet (WSD) followed by four months of caloric restriction (CR). Body composition, insulin sensitivity, physical activity, serum cytokine levels, and adipose biopsies were evaluated before and after each dietary intervention. Results: Both intact and orchidectomized animals gained similar proportions of body fat, developed visceral and subcutaneous adipocyte hypertrophy, and became insulin resistant in response to the WSD. CR reduced body fat in both groups, but reversed insulin resistance only in intact animals. Orchidectomized animals displayed progressive sarcopenia, which persisted after the switch to CR. Androgen deficiency was associated with increased levels of interleukin- 6 and macrophage-derived chemokine (CCL22), both of which were elevated during CR. Physical activity levels showed a negative correlation with body fat and insulin sensitivity. Conclusion: Androgen deficiency exacerbated the negative metabolic side effects of the WSD, such that CR alone was not sufficient to improve altered insulin sensitivity, suggesting that ADT patients will require additional interventions to reverse insulin resistance and sarcopenia. Key words: androgen deprivation therapy, hypogonadal, Western-style diet, obesity, sarcopenia. Abbreviations: ADT, androgen-deprivation therapy, CR, caloric restriction; NHP, nonhuman primate; SM, skeletal muscle; SC, subcutaneous; VIS, visceral; WAT, white adipose tissue; WSD, Western-style diet. PMID: 27534842
  4. Arg.... Forum ate my post. Take 2. ---------- Dean, I have the same results as you, also on the 5th SNP, rs3751812! By the way, there's a much easier way to check status on any SNP than logging into 23andMe. Use SNPTips with FireFox. Yes, we learn a lot about the thin phenotype, but I think the real question is the effect on the possibility of benefitting from CR. CR might be easier for you and me, one might guess. I'd say almost the opposite: being thin is easier, but that's not the goal. Someone with the opposite genetic tendency might go from a BMI of 30 to a BMI of 22 or 21 on CR, benefit tremendously, not look scrawny -- maybe not have really low testosterone, etc. -- whereas we, on CR, go from a BMI of 22 or 23 to 18 or less, and maybe don't get as many CR benefits, and get a lot of the downsides. Maybe. Leanness per se confers some health benefits, according to some studies. But being in "survival mode", as you rightly have called it, might be the real goal. And we might not be able to be in extreme survival mode without being dangerously fat-less. Here's where a citizen science project might be very useful! Zeta
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