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  1. Thanks Mooman. He died at age 18 of glioblastoma by the way, so the subject of whether a ketogenic diet might work as a supplemental treatment for brain cancer is near and dear to my heart. Cancer is scary and upon being diagnosed it is very understandable to want to take control of the situation through one thing that can be easily modify, namely diet. If there is one thing I learned from my son's experience, it sucks to feel helpless. If I were you I'd do two things. Talk to a nutritionist associated with the hospital where you are getting treatment, especially one with experience with cancer nutrition. Bring whatever evidence you have for the benefits of a KD and ask them what they think. And emphatically yes, if I were you I would increase both my calories and my protein until I stopped losing weight. In fact it seems to me you should target trying to get back at least to your original weight of 120, which would put your BMI at 17.7. One of the things we discuss a lot around here as a downside of serious CR is that you end up really thin. That may help to keep one from getting sick, but it makes one more vulnerable when one does get sick due to much lower metabolic reserves for fighting an illness. Thankfully, much of your weight loss so far is probably water, but 850kcal/day is not enough to support even your basal metabolic rate, to say nothing of providing adequate nutrition or supporting your daily activities. And you don't want to continue losing weight given what you are facing and given how thin you are to start with. Interesting saga and interesting case study. Thanks for sharing it. Reading her description of the events surrounding the journal rejection, it sounds like there were other issues involved rather than an outright refusal to consider a ketogenic diet for brain cancer treatment. In fact, the journal in question did publish a (different) case study showing positive outcome with a brain cancer patient on a ketogenic diet and that what she seems to be griping about (perhaps with very good reason). But if nothing else their publishing of the other case study would seem to undermine the theory that journals are refusing to publish such evidence. The author speculates her rejection was either a result of a conflict of interest on the part of one of the reviewers or "Our overwhelming experience is that journals massively sabotage researchers from Eastern-Europe and Russia." More generally, it may be that a ketogenic diet can be helpful, particularly for brain cancer where anecdotes and case studies appear to hint at positive outcomes. But reading the case study you point to, the patient lost 22 lbs on the diet, going from a BMI of 25.6 to 22.5 over the course of six months. Such a drop in weight from where you are now would be disastrous. And as you pointed out: So even if it does help for brain cancer, that doesn't say very much about whether low calorie ketogenic diet will help treat oral cancer in general, or yours in particular. I'd be very cautious and listen to the advice of trained medical professionals. If you think keto is the way to go, particularly after talking with them, then give it a try. But it would seem very unwise for you to lose weight while doing it. Best of luck with your upcoming scans. --Dean
  2. A Tale of Three Rodents - Part 3: Bats This is the third post in my three part series on long-lived rodents and BAT (brown adipose tissue) thermogenesis, in which I'll discuss bats. Note, in this post, lowercase 'bat' will always refer to the little flying creature, and uppercase 'BAT' will always refer to brown adipose tissue, if that weren't obvious. But before discussing bats' BAT, I'll share a statistic I came across about BAT that is simply amazing, and will be quite relevant for bats. Review article [1] says the following: BAT is characterised as possessing large amounts of the unique uncoupling protein (UCP) 1 which when activated enables the free-flow of protons across the inner mitochondrial membrane, resulting in the rapid dissipation of chemical energy as heat [ref]. Consequently, when maximally activated, BAT can generate up to 300 W[atts]/kg of tissue compared with 1 W[att]/kg from most other tissues [ref]. That 1 Watt/kg for other tissues seems on the low side - elite cyclists can generate a sustained 5-6 Watts/kg of body weight. Since their thighs are only a fraction (although a pretty large fraction☺) of elite cyclists' body weight, they are obviously generating a lot more than 5-6 Watts per kg of muscle fibers. But if you consider an elite cyclists body weight to be around 60kg, they are generating about 300 watts of total power (5W/kg * 60kg) that the pedals, using their entire body (e.g. cardiovascular system) to support it. It's quite astonishing how metabolically energetic BAT is. It doesn't take much to burn a lot of calories - comparable to rigorous exercise. OK - back to bats. First, my bad. Bats aren't even remotely related to rodents. Sorry about that. From this page on Myths and Facts about Bats: Bats are not flying mice; they are not even remotely related to rodents. Bats are such unique animals that scientists have placed them in a group all their own, called ‘Chiroptera’, which means hand-wing. Bats are grouped with primates and lemurs in a grand order called Archonta. Several traits set bats apart from other mammals. No, it's not their sonar, which they share with other mammals like dolphins. Instead, bats are the only mammals to have achieved (self-)powered flight. Plus, and most relevant for our purposes, they live a very long time for their size. The little brown bat (LBB - Myotis lucifugus) is really quite tiny (see image below) - weighing in at only 5-14g. That is about 1/2 the size of naked mole rats, and 40-100x smaller than grey squirrels. But the LBB can live up to 30 years - rivaling even the naked mole rat for longevity. The (slightly) bigger big brown bat (BBB - Eptesicus fuscus, discussed below) weighs 15-20g, and doesn't live quite as long (~20 years max). Cute - isn't he!? :-) LBBs eat 50% to 100% of their body weight in mosquitoes per night - which equates to about 5,000 and 10,000 mosquitoes! Their heart rate can vary from as low as 5-10 BPM during hibernation, to 200 BPM when at rest but not hibernating, to over 1000 BPM during flight. The LBB is an amazing creature! But enough of the fascinating bat facts - the question is do long-lived bats have BAT? Given how much energy they are burning simply at rest and in flight (with heart rates of 200 and 1000 BPM respectively), one might think they don't need to generate extra heat when not hibernating. And with a heart rate of on 5-10 BPM when hibernating, it would seem they can't be engaging in that much norepinephrine-induced BAT activity during that part of the year. But on the other hand, their small size and large surface area (including wings) means they radiate a lot of heat away, and they do hang out (literally) in cool, damp caves. So maybe they do require BAT to help them generate heat. So which is it? Lots of BAT, or not very much? As you might have guessed by now, it appears that bats have lots of BAT! I couldn't find data on LBBs specifically, but below is the table from [2], which measured the weight of various tissues & organs in Big Brown Bats (BBBs) both in summer, and during hibernation in winter: Let's compare these BAT numbers, both absolutely and in percentage terms, to rats. Below is a similar table from PMID 18593277 (discussed in this post), showing the amount of BAT in young (left column), old (middle column) and Old CRed (right column) rats. In absolute terms, the weight of BAT tissue in the BBBs and the rats is pretty similar, between 0.4g and 1g. So not all that remarkable. But then you realize that BBBs weighted ~25x less than the rats. The BAT in BBBs is between 2.8% (in summer) and 4.2% (in winter) of total body weight. That's huge! This compares with 0.1% to 0.15% of total body weight in rats. In other words, BBBs have ~30x more BAT than rats as a percentage of body weight. The authors of [2] suggest that the large amount of BAT the BBBs possess, especially in the winter, is critical for raising them from hibernation - basically the BAT enables them to jump-start their metabolism by burning calories stored in all that white adipose tissue to generate heat: There remains little doubt that differences in time required for arousal are primarily a consequence of seasonal differences in the mass of brown adipose tissue and therefore, in the amounts of heat produced by this tissue. Both shunting of blood to anterior body regions and initiation of the rewarming process depend largely on the ability of brown fat to assume a comparatively high metabolic rate at low temperatures (Rauch 1973)... Indeed, the success of [big brown bats] to elevate its body temperature in the cold depends primarily on brown fat as a source of heat. Both nutritional blood flow studies (Rauch 1973; this study) and data from direct thermometry (Smalley and Dryer 1963; Hayward et al. 1965; Rauch 1973; Studier 1974) suggest passive warming of organs of the posterior body, and that shivering thermogenesis by skeletal muscle is not essential for the arousal of this species (Hayward and Lyman 1967). But whatever the evolutionary reason, big brown bats (and almost certainly the little ones as well!), like grey squirrels and naked mole rats, have a LOT of BAT, and also like them, live a very long time relative to other small mammals. Obviously this correlation between amount of BAT and extreme longevity in all three of these species does not necessarily imply causation. But when combined with all the other evidence outlined in this thread (which just reached 100 posts!) for the health & longevity benefits of increased BAT, it seems extremely suggestive to me... --Dean ----------- [1] Scientifica Volume 2013 (2013), Article ID 305763, 14 pages http://dx.doi.org/10.1155/2013/305763 Brown Adipose Tissue Growth and Development Michael E. Symonds Early Life Nutrition Research Unit, Academic Division of Child Health, School of Clinical Sciences, University Hospital, The University of Nottingham, Nottingham NG7 2UH, UK Received 4 February 2013; Accepted 28 February 2013 Academic Editors: Y. Chagnon and G. Lopaschuk Free full text: http://www.hindawi.com/journals/scientifica/2013/305763/ Abstract Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by photoperiod. Increased understanding of the primary factors that regulate both the appearance and the disappearance of UCP1 in early life may therefore enable sustainable strategies in order to prevent excess white adipose tissue deposition through the life cycle. ------- [2] Écoscience Vol. 5, No. 1 (1998), pp. 8-17 Changes in body mass and fat reserves in prehibernating little brown bats (Myotis lucifugus) Thomas H. KUNZ, John A. WRAZEN and Christopher D. BURNETT Stable URL: http://www.jstor.org/stable/42900766 Full text: http://www.nrcresearchpress.com.sci-hub.io/doi/pdf/10.1139/z75-025 Abstract Changes in body mass, fat mass, lean dry mass, and energy content of little brown bats, Myotis lucifugus (LeConte), captured at a cave in southern Vermont, were quantified during the pre-hibernation period in late summer and autumn. Adults of both sexes showed maximum rates of increase in body mass from mid-August to mid-September, during which time the average gain was 2.3 g for males and 2.1 g for females. These gains represent 32.9% and 29.6% of the pre-hibernation body masses for adult males and females, respectively. Young-of-the-year of both sexes weighed about 1 to 2 g less than adults during most of the pre-hibernation period. In mid-September, adult females weighed significantly less than a cohort of adult females captured at a maternity roost on the same date. Adult bats reached their maximum pre-hibernating body mass in mid-September, whereas young bats reached their maximum pre-hibernating body mass one month later. From mid-July to mid-September, we found no significant differences in mean body mass between young males and females, but in mid-October when they entered hibernation, young females weighed significantly more than young males and almost as much as adult females. Young males and females arrived at the swarming-hibernation site in late summer with an average lean body mass and fat index approximately 20% lower than adults. By early October, young females achieved minimum adult levels of lean dry mass, but by the time they entered hibernation the lean mass of young males was still about 10% lower than adults. During the pre-hibernation period, lean dry mass and fat mass of all bats were significantly correlated with body mass. Regression equations derived from these data were used to estimate total energy content of bats. The acquisition of maximum fat reserves by M. lucifugus in the pre-hibernation period may be as important for successful reproduction as it is for sustaining hibernation. The fattest adult males may gain a reproductive advantage if they acquire enough energy reserves to sustain autumn mating and hibernation, and engage in multiple matings during the winter. The fattest females should gain a reproductive advantage by maximizing fat reserves before entering hibernation, and retaining sufficient energy reserves at the end of hibernation to facilitate ovulation. Relatively low survival and reduced fecundity in females at northern latitudes may reflect the relatively low fat reserves deposited by young females in their first autumn.
  3. Dean Pomerleau

    Genetics of Obesity

    Rodney, You bring up two good points about the propensity to be thin as it relates to the practice of CR. First, its well known that too abrupt onset or too severe calorie restriction can be detrimental to health and longevity in rodents, and presumably in other mammals (including humans). Having more metabolic reserves (in the form of fat), and a tendency not to lose whatever reserves one has, may help one avoid the negative effects of the stress/shocks associated with CR. The late-life "obesity paradox", where elderly people who are overweight and even obese have better odds of surviving than very thin people can be attributed at least in part to having more metabolic reserves, allowing one to weather the wasting that often accompanies illness or injury during old age. Your second observation is that excessive thinness may be an indicator of latent disease (e.g. a early sign of cancer) that could reduce one's life expectancy. Indeed, when studies of the association between weight and mortality are done well, they ignore the first 5-10 years after the baseline measurements are made, to weed out thinness and increased mortality resulting from metabolic wasting due to latent disease. In such studies, the so called "obesity paradox" is usually attenuated - i.e. thinness is not (greatly) associated with excess mortality. Study [1] is an interesting recent example. It measured men's weight at two widely separated time points (mean age at study onset was 47, and a second measurement was made 26 years later, when subjects were, on average, 73). Following the second measurement, mortality rates were tracked over the subsequent 12 years. They found that having constant normal weight, or gaining weight between the two measurement points 26 years apart were associated with about equal, and relatively low mortality. But either being overweight/obese at the time of both measurements, or (especially) losing weight between the two measurements, was associated with either 30% or 80% excess mortality, respectively. The excess mortality for weight loss wasn't significantly attenuated even when diagnosed diseases at the time of the second measurement were controlled for, but the weight loss could have been a sign of latent, undiagnosed disease that would kill they guy over the subsequent 12 years. Another explanation sometimes given for the obesity paradox is that when (nearly) everyone is eating a crappy diet, eating more of it can sometimes be beneficial, allowing one to avoid nutritional deficits. Protein is one nutrient sometimes cited as having pro-longevity value when consumed in extra amounts in the elderly (e.g. [2]), because of the difficulty elderly people have in assimilating it. If there are any takeaway messages from these, they would seem to me to be: If possible, start CR in early or middle adulthood, when the body is more resilient. Ease into CR, to avoid a big shock, especially if starting relatively later in adulthood. Back off on the severity of one's CR practice (and perhaps add extra protein) when one's gets to be in the elderly range (65-70+), to avoid nutrient deficiencies and maintain some metabolic reserves so one can weather the 'slings and arrows' that will eventually come. --Dean ----------------- [1] Am J Epidemiol. 2013 Nov 1;178(9):1452-60. doi: 10.1093/aje/kwt157. Epub 2013 Sep 5. The "obesity paradox," frailty, disability, and mortality in older men: a prospective, longitudinal cohort study. Strandberg TE, Stenholm S, Strandberg AY, Salomaa VV, Pitkälä KH, Tilvis RS. An inverse relationship between overweight and mortality (the "obesity paradox") is well documented, but there are scarce data on how body weight during the life course affects this relationship. In the Helsinki Businessmen Study, we examined the effect of weight trajectories on incident disability, frailty, and mortality by stratifying 1,114 men (mean age of 47 years in 1974) into the following 4 groups based on body mass index (weight (kg)/height (m)(2)) values measured twice, in 1974 and 2000: 1) constantly normal weight (n = 340, reference group); 2) constantly overweight (n = 495); 3) weight gain (n = 136); and 4) weight loss (n = 143). Twelve-year mortality rates (from 2000 to 2012) and frailty and mobility-related disability in late life were determined. Compared with constantly normal weight, weight loss was associated with disability (odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.1, 4.9) and frailty (OR = 3.7, 95% CI: 1.3, 10.5) in late life. Constant overweight was associated with increased disability (OR = 1.9, 95% CI: 1.1, 3.2). Men with constantly normal weight had the fewest comorbidities in late life (P < 0.001). Higher 12-year mortality rates were observed both with weight loss (hazard ratio = 1.8, 95% CI: 1.3, 2.3) and with constant overweight (hazard ratio = 1.3, 95% CI: 1.03, 1.7). Those with constantly normal weight or weight gain had similar outcomes. We observed no obesity paradox in late life when earlier weight trajectories were taken into account. PMID: 24008903 ----------- [2] Cell Metab. 2014 Mar 4;19(3):407-17. doi: 10.1016/j.cmet.2014.02.006. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Levine ME(1), Suarez JA(2), Brandhorst S(2), Balasubramanian P(2), Cheng CW(2), Madia F(3), Fontana L(4), Mirisola MG(5), Guevara-Aguirre J(6), Wan J(2), Passarino G(7), Kennedy BK(8), Wei M(2), Cohen P(2), Crimmins EM(1), Longo VD(9). Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality. Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages. Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity. Copyright © 2014 Elsevier Inc. All rights reserved. PMCID: PMC3988204 PMID: 24606898
  4. Dean Pomerleau

    Optimal Late-Life BMI for Longevity

    Mike Lustgarten has penned an interesting blog post in which he looks at data from several sources, including these two meta-analyses [1][2]. Study [1] found the optimal BMI for adults in general (median age 58), was pretty flat and optimal between BMI of 19-25. Here is the graph: But [2] found in older adults (65+) the optimal BMI was much higher: As we've discussed here, this late-life "obesity paradox" might be a result of latent disease making people thin and more likely to die. Or it could simply be that heavier people have more metabolic reserves, which is important to enable the elderly to weather the "slings and arrows" of aging / decrepitude (e.g. falls & fractures, hospitalization, sarcopenia, loss of appetite, etc.) But the most interesting graphic from Mike's post is this one, in which Mike looked through a bunch of references (see his blog post for the list of references) and apparently did his own meta-analysis of the average BMI of centenarians (thanks Mike!): As you can see, most centenarians have a BMI between 19 and 24. He concludes: Centenarians have a BMI between 19.3-24.4 kg/m2. Shouldn’t that be the BMI reference range for those interested in living past 100? On the CR Society Facebook Group discussion of Mike's blog post, I question his rationale for this statement, saying: To play devil's advocate, it seems like the only way to answer [the question of the optimal BMI for living past 100] is to see if [the centenarians] have maintained that BMI from a much younger age, or have only gotten that thin as a results of sarcopenia and other unintended weight loss. Or maybe they've gained weight relative to their younger selves. There just isn't enough information to know what is optimal based on late-life BMI in the extremely old. I further suggest something we've discussed before (in the thread mentioned above): The optimal strategy may be to remain thin until one's elderly years to gain the benefits of CR, then put on weight to serve as a metabolic reserves when adverse events are likely to require them in old age. --Dean ------- [1] Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, Moore SC, Tobias GS, Anton-Culver H, Freeman LB, Beeson WL, Clipp SL, English DR, Folsom AR, Freedman DM, Giles G, Hakansson N, Henderson KD, Hoffman-Bolton J, Hoppin JA, Koenig KL, Lee IM, Linet MS, Park Y, Pocobelli G, Schatzkin A, Sesso HD, Weiderpass E, Willcox BJ, Wolk A, Zeleniuch-Jacquotte A, Willett WC, Thun MJ. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010 Dec 2;363(23):2211-9. doi: 10.1056/NEJMoa1000367. Erratum in: N Engl J Med. 2011 Sep 1;365(9):869. ---- [2] Winter JE, MacInnis RJ, Wattanapenpaiboon N, Nowson CA. BMI and all-cause mortality in older adults: a meta-analysis. Am J Clin Nutr. 2014 Apr;99(4):875-90.
  5. Dean Pomerleau

    Body-mass index and all-cause mortality

    Michael wrote: Apparently not only haven't you read the report, you haven't read about the report either. The discussion by your reliable blogger (on June 29th) was long before this brand-new meta-analysis [1] that Todd pointed to was published in the Lancet this week. In fact, like your reliable blogger, I discussed that other study (PMID 27146380) that he covered (and you mistakenly think is the new one) in this post on May 8th, including the same J-shaped mortality curve you (and he) posted above (although w/o the https so you may not have seen it... corrected now). So you may have read about that older study (from May) in my post as well, since it is a thread you started and apparently monitor, although perhaps not too carefully... ☺ But your confusion is not surprising, given the fact that the titles of the two papers are similar, and since they are both huge systematic reviews of virtually all studies done to date about the association between BMI and mortality. In fact, they almost entirely overlap in the the 230+ studies they analyzed. But it is definitely two different analyses, with the newer study Todd points to [1] including a few more studies in its data. In fact [1] isn't even in Pubmed yet. One other striking difference is the number of authors. The older review (PMID 27146380) had eight authors. This new one has too many authors to even bother counting, to say nothing of list in the abstract. In fact, the full author list is over two pages long, and included not in the free full text but in the appendix. Interestingly, just two days ago Paul McGlothin teased this new BMI study [1] in his weekly CR Way newsletter as more reason to avoid getting too thin, saying: A new paper is out reinforcing other findings that maintaining a higher BMI - 20 to 25 - did better for longevity. This reinforces what we've observed among CR Way travelers who have lived to greatly advanced age. Maintaining a higher BMI does not interfere with activating longevity signaling. Meanwhile, it may be protective of body structures, making disasters like osteoporosis-related fracture less likely. This is obviously in line with my hobby horse of late - namely that serious CR probably won't beat a healthy, obesity-avoiding diet (by "serious" I mean CR that results in a BMI of ~18.5 or less). This is borne out by the uptick in the mortality graph Michael posted above (and I posted in May here) in folks with a BMI below 20, even restricting to studies with 20+ years of follow-up and limiting analysis to healthy, never-smokers. In short, it appears to pay to be on the thin side, but not too thin. But that conclusion was based on analysis of PMID 27146380 and other past studies of the association of BMI and mortality. What does Todd's new study [1] say on the topic? Let's find out, shall we? First a little background from the intro, on the study and it's huge set of authors: The Global BMI Mortality Collaboration was established to provide a standardised comparison of associations of BMI with mortality across different populations. It includes individual-participant data for 10·6 million adults in 239 prospective cohort studies in 32 countries, mainly located in Asia, Australia and New Zealand, Europe, or North America, about 4 million of whom were never-smokers without reported chronic diseases (mainly cardiovascular disease, cancer, or chronic respiratory disease) at recruitment and who were still being followed up 5 years afterwards. Obviously this was a big meta-analysis, both in terms of number of authors, countries, studies and subjects included. And right off the bat you can see that this study had a relatively short minimum follow-up period of 5+ years, and so may be open to criticism regarding latent disease potentially skewing the results against the health benefits of being very thin. But more on that below. Next, they winnowed down their initial study population of 10M people to ~4M never-smokers - so that's good. No confounders associated with thinness due to past or present smoking habits. Interestingly, per Tom's speculation optimal BMI shifting with age, they found that as one ages, the optimal BMI for longevity increases, as illustrated in this figure, showing mortality vs. BMI curves for 35-49 year olds (left), 50-69 year olds (middle) and 70-89 year olds (right). From the full text: The [mortality] nadir depended on age, and was BMI=22 kg/m² for baseline age 35–49 years, BMI=23 kg/m² for baseline age 50–69 years, and BMI=24 kg/m² for baseline age 70–89 years. This increase in optimal BMI with age is consistent with the strategy of packing on some pounds as one gets older to have more metabolic reserves to recover from the inevitable slings and arrows associated with advancing age, as discussed in depth on the optimal Late-Life BMI for Longevity thread. The authors recognized that bad analysis in some prior studies unfairly penalized low BMI: Compared with the strict primary analyses described above, crude analyses that ignored smoking and any effects of prior disease at baseline, and did not exclude the first 5 years of follow-up, yielded different (presumably substantially biased) results, with exaggerated HRs for underweight, inverted HRs for overweight, and less than half of the excess risk for grade 1 obesity suggested by the strict primary analyses (tables 1, 2, appendix p 43). So the so-called "Obesity Paradox" does go away when you do the analysis right. But you'll notice that in all of the three age groups there was still a penalty for having a BMI below 20, even using their improved methodology. This held true across all countries (Figure 1, data now shown) and for both men and women. On the issue of gender, they found something interesting. For men, it was substantially worse to be too fat, or too thin, relative to women, as you can see from this graph showing BMI vs. mortality separately for each gender. Eyeballing the graph, it looks like for men, having a BMI in the 18.5-20 range increases mortality risk by over 50% relative to a BMI of 22.5 - 25. In fact, the mortality risk of the 18.5-20 BMI men was almost as high as men with a BMI in the 30-35 range! Being a healthy never-smoker with a BMI less than 18.5 almost doubled a man's mortality risk. Ouch! Digging into the weeds of the Appendix, here is an interesting graph showing how various adjustments impacted the association between BMI and mortality: Look at the two pairs of points I've circled in green. They show the different between not excluding the first five years (red points) and excluding the first five years (black points) of follow-up from the analysis. As you can see, excluding the first five years makes the penalty for being thin smaller - presumably because of latent health conditions (like undiagnosed cancer) that caused people both to be thin at study onset, and to die within the first five years. But as you can see, the reduction in the thinness penalty was pretty modest from excluding the first five years, and additional reductions in the thinness penalty for longer initial exclusions would almost certainly be even more modest - i.e. longer initial exclusions would likely reduce the thinness penalty only a little bit more. This is borne out by the continued J-shape of the mortality curve in PMID 27146380 when data was limited to studies of healthy never-smokers with at least 20 years of follow-up. In short, it appears to pay to be on the thin side, but not too thin, especially if you are a man. And even that summary comes with some caveats and nuances (favoring being fatter) that should be considered, as Michael and I discussed at the recent conference, and I elaborated on recently here. In short - "too thin" for optimal longevity may be a moving target - i.e. optimal BMI may actually be increasing over time. First, the longevity penalty for being overweight, obese, or even high-normal BMI may have actually gone down over the last several decades, as a result of improved medical treatments, particularly for CVD (e.g. stents and statins). So studies with a very long follow-up that show "it pays to be very thin" may be behind the times. What such long follow-up studies are actually saying is "it used to pay to be very thin". Decades ago it was good to be very thin because that was the only way you could minimize risk of dying from CVD. But these days, being thin provides less of a benefit, or more accurately, being fat provides less of a penalty, when it comes to longevity. And because being very thin carries with it some additional risks (due to fewer metabolic reserves to fight illness or recover from accidents) relative to carrying more meat on your bones, the trend has been towards a shift upwards in the best BMI for longevity over the last several decades. Further, despite what Michael's "credible blogger" says, it seems to me just crazy to think that a latent condition (e.g. cancer) at the start of a study was making people thin, and contributing to their demise 15-20 years later, so the only way to see the benefits of being thin is to wait 20+ years of follow-up. The modest effect of excluding the first 5 years discussed above bears witness to the silliness of this "long follow-up required to really exclude latent conditions" nonsense. The much more likely explanation for the attenuation of the thinness penalty in studies with very long follow-ups (besides a rising optimal BMI over the decades due to medical improvements) is the one I described here, using an analogy with robust beakers (fat people) and fragile test tubes (skinny people) and their survival prognosis in a laboratory. I really liked that analogy, and I think it sheds light on what's going on with optimal BMI. In a nutshell, in the short term, it sucks being thin because thin people are more fragile and therefore more likely to die if they get sick or injured. But in the long run, it pays to be thin since you're accumulating less obesity-related damage (i.e. clogged arteries, diabetes, etc) which eventually catches up with fat people and makes them more prone to dying than thin people in their later years. As a result, it is natural for studies with a very long follow-up to show an advantage for being thin relative to being fat, since with a very long follow-up the penalty for being fat has a chance to catch up with the fatties. For those of you more visually inclined, here is a schematic graph of my explanation for why short-term follow-up studies look bad for thin folks and long-term follow-ups look good for them (note it is only meant to be a schematic - the slopes, shapes and positions of the curves are not meant to be accurate): Just now I thought of another reason that could explain why it looks better to be thin in longer follow-up BMI-vs-mortality studies. In nearly all prospective studies like these, BMI is measured once at the beginning of the study and perhaps a second time in the early years of follow-up, if they are lucky. Over time, the BMI of the initially-thin people will gravitate upwards, as most people pack on the pounds as they age. So if there really is a consistent & persistent penalty for being thin, it's effect on the data will be attenuated with longer follow-up since the initially thin people won't be as thin (or therefore, as death-prone) as the study progresses and as they slide upwards into the higher, less death-prone BMI categories. In other words, they were thin at the beginning of the study, but not by the end many years later, so being thin at the beginning doesn't look as detrimental. Overall, it does not appear to me that there is any data supporting the idea that being a healthy, very thin never-smoker is any better than being a healthy, normal-weight never smoker. If anything the evidence points in the opposite direction - in line with my "serious CR won't beat..." hypothesis. But I will acknowledge that the diets of most people (thin and chubby alike) are on average pretty bad in all these studies of average people, so it is a bit hard to generalize to healthy-eating thin folks like us. --Dean --------- [1] Lancet, 10.1016/S0140-6736(16)30175-1 Body-mass index and all-cause mortality: individualparticipant-data meta-analysis of 239 prospective studies in four continents The Global BMI Mortality Collaboration* Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in diff erent populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the fi rst 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m². Findings All-cause mortality was minimal at 20·0–25·0 kg/m² (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m²; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m²), and increased signifi cantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m²; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m²; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m²). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m²) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m²) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m²) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m², mortality increased approximately log-linearly with BMI; the HR per 5 kg/m² units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m² units higher BMI (for BMI over 25 kg/m²) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. PMID: 27423262 DOI: 10.1016/S0140-6736(16)30175-1
  6. Dean Pomerleau

    Optimal Late-Life BMI for Longevity

    Liz, Regarding the relative merits of lean body mass vs. fat mass for late-life survival in humans, from what I know/recall, there is pretty good evidence that having extra lean mass would be more beneficial than fat mass. But it may not be a causal relationship - i.e more lean mass means better physical condition / activity, more ability to take care of one's daily needs, less signs of aging (e.g. sarcopenia) and therefore less likelihood of dying. This isn't exactly your question but the famous ob/ob mice results [1] found that mice genetically prone to obesity lived shorter lives than normal mice when fed ad lib. But when both types of mice were restricted to the same # of calories per day, the ob/ob mice lived just as long as the normal mice (and had longer max lifespan), gaining more relatively lifespan (as a percent of their normal ad-lib fed lifespan) than did the normal mice. Here is the lifespan table with the details from the full text, for current and future reference (the +/+ mice are the normal ones): So having a natural tendency towards being overweight/obese, i.e. a so called "thrifty genotype", does not appear to be an obstacle to benefiting from CR. In fact some say it's an advantage, since (like the ob/ob mice), such people can retain more body fat for any given level of restriction, allowing for greater metabolic reserves in case of illness or injury. There is a whole thread on the genetics of obesity, on which some of us lament having a 'lean genotype" making CR harder to practice effectively, i.e. without losing too much weight. Cloud, Yes - in fact I included reference to the Longo study you point to, PMID 24606898, in this post. Based on it and other data, in that post I recommended: If possible, start CR in early or middle adulthood, when the body is more resilient. Ease into CR, to avoid a big shock, especially if starting relatively later in adulthood. Back off on the severity of one's CR practice (and perhaps add extra protein) when one's gets to be in the elderly range (65-70+), to avoid nutrient deficiencies and maintain some metabolic reserves so one can weather the 'slings and arrows' that will eventually come. For your and everyone's information, it's easy to find out if an article like the one you asked about has been discussed before by searching the forums using its PMID number. That is also why those of us who reference specific studies try to always include the PMID number if available, so discussions of it will be easy to find in the future. --Dean ---------- [1] Proc Natl Acad Sci U S A. 1984 Mar;81(6):1835-8. Effects of food restriction on aging: separation of food intake and adiposity. Harrison DE, Archer JR, Astle CM. Free Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC345016/pdf/pnas00607-0233.pdf Restricted feeding of rodents increases longevity, but its mechanism of action is not understood. We studied the effects of life-long food restriction in genetically obese and normal mice of the same inbred strain in order to distinguish whether the reduction in food intake or the reduction in adiposity (percentage of fatty tissue) was the critical component in retarding the aging process. This was possible because food-restricted obese (ob/ob) mice maintained a high degree of adiposity. In addition to determining longevities, changes with age were measured in collagen, immune responses, and renal function. Genetically obese female mice highly congenic with the C57BL/6J inbred strain had substantially reduced longevities and increased rates of aging in tail tendon collagen and thymus-dependent immune responses, but not in urine-concentrating abilities. When their weight was held in a normal range by feeding restricted amounts, longevities were extended almost 50%, although these food-restricted ob/ob mice still had high levels of adiposity, with fat composing about half of their body weights. Their maximum longevities exceeded those of normal C57BL/6J mice and were similar to longevities of equally food-restricted normal mice that were much leaner. Food restricted ob/ob mice had greatly retarded rates of collagen aging, but the rapid losses with age in splenic immune responses were not mitigated. Thus, the extension of life-span by food restriction was inversely related to food consumption and corresponded to the aging rate of collagen. These results suggest that aging is a combination of independent processes; they show that reduced food consumption, not reduced adiposity, is the important component in extending longevity of genetically obese mice. PMCID: PMC345016 PMID: 6608731
  7. Dean Pomerleau

    Optimal Late-Life BMI for Longevity

    Brian, I agree with you when you say that: and: There are many reasons why someone might be thin that have nothing to do with CR, and which aren't healthy (latent disease, smoking, heroin addiction, sarcopenia, digestive problems etc.). As a result, the observation that "thin people often die early" is not a good argument that CR doesn't work. Nevertheless, I think to dismiss the apparent advantage of having "extra meat on one's bones" late in life as entirely irrelevant to CR folks may be being a bit too hasty. You may not be doing this - but just in case you or others are, I think its worth considering. Frailty late in life has repeatedly been shown to predict mortality, as the study Al posted today [1] confirms. It can certainly be argued that thinness is not necessarily synonymous with frailty, and that CR may (hopefully) protect us from getting frail in our old age. But until aging can be halted, even CR folks will continue to fall victim to the negative effects of the aging process - perhaps a little more slowly, but we can't entirely escape things like sarcopenia, bone loss & fractures, loss of appetite, impaired nutrient digestion / absorption, impaired immunity, etc. So Brian, to make things concrete, I'd be interested in hearing what you would say to a hypothetical CR practitioner who is celebrating their 90th birthday today. Assume he/she has been practicing CR quite seriously for several decades, and have a thin physique to show for it (BMI ~18.5). For the last few years they've been feeling the effects of aging - no overt illnesses or disabilities yet, but they are starting to feel older and their biomarkers are starting to turn south. What would you tell them? Stay the course and continue hitting the CR hard? Or dial back and try to gain some weight? Admittedly we can't know for certain, since we don't (and won't in our lifetimes) have clear evidence from a large, controlled group of people in their situation, who have been practicing CR for many years and then experienced old age. But I would opt to advise the latter - dial their CR back and gain some weight (i.e. targeting a BMI of 20-22), since any additional longevity gains from continued CR are likely to be small, and the benefits of having extra "meat on their bones" may help them deal with the inevitable challenges of getting old. To support my contention, without human CR data, it seems that the best data we have to rely on is that of the general population, especially long-lived individuals from the general population, whose long lives suggest they've enjoyed the benefits of some combination of good genes and/or a healthy lifestyle that helped them avoid the typical diseases of aging that killed off most of their peers much earlier. If we look at the meta-analysis of BMIs for centenarians that Mike Lustgarten put together in the table above, the average BMI of these 1550 very long-lived individuals was 21.4. Certainly on the slim side, but not rail thin either. In fact, given that weight loss is virtually inevitable at such an advanced age, it seems likely they spent much of their elder years at a BMI significantly higher than 21.4. And as the study Al posted [1] shows, thinness is correlated with frailty, and frailty with mortality in the oldest of the old. The hypothetical 90-year-old in question might be one of the lucky few who escapes serious illness/injury as they get very old, and so not need the extra metabolic reserves. But the odds would seem to be against them, and eventually the inevitable (for now anyway) process of aging is going to catch up to them, so the safer bet in my eyes would be to dial it back. While obviously an argument from authority, I would also point to the fact that Luigi Fontana, perhaps the most knowledgeable researcher and proponent of human CR, has advised several of the CR cohort he's been studying (including me) that if he were in our shoes, he'd dial back on the CR somewhat (i.e. a BMI < 18 is too low) - since being as thin has many of us are comes with serious risks and offers uncertain benefits. Needless to say all of us are a lot younger than 90. I'm curious, what would you (or others) advise such a person? --Dean -------------- [1] Understanding Risk in the Oldest Old: Frailty and the Metabolic Syndrome in a Chinese Community Sample Aged 90+ Years. Hao Q, Song X, Yang M, Dong B, Rockwood K. J Nutr Health Aging. 2016;20(1):82-8. doi: 10.1007/s12603-015-0553-5. PMID: 26728938 http://download.springer.com/static/pdf/538/art%253A10.1007%252Fs12603-015-0553-5.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs12603-015-0553-5&token2=exp=1452293580~acl=%2Fstatic%2Fpdf%2F538%2Fart%25253A10.1007%25252Fs12603-015-0553-5.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs12603-015-0553-5*~hmac=62d3c7f6498700f4d8c8ee8ae3ee8437a0cf428fe15a5b2b306134600544ed67 Abstract OBJECTIVES: To investigate the relationship between frailty and the metabolic syndrome and to evaluate how these contribute to mortality in very old people. DESIGN: Secondary analysis of data from the Project of Longevity and Aging in Dujiangyan. SETTING: Community sample from Sichuan Province, China. PARTICIPANTS: People aged 90+ years (n=767; baseline age=93.7±3.4 years; 68.0% women. MEASUREMENTS: After a baseline health assessment, participants were followed for four years (54.0% died). A frailty index (FI) was calculated as the sum of deficits present, divided by the 35 health-related deficits considered. Relationships between the FI and the metabolic syndrome were tested; their effect on death was examined. RESULTS: The mean FI was 0.26±0.11. Higher FI scores were associated with a greater risk of death, adjusted for age, sex, education, and metabolic syndrome items. The hazard ratio was 1.03 (95% confidence interval 1.02, 1.04) for each 1% percent increase of the FI. The mortality risk did not change with the metabolic syndrome (odds ratio=0.99; 0.71-1.36). CONCLUSIONS: In the oldest old, frailty was a significant risk for near-term death, regardless of the metabolic syndrome. Even using age-adjusted models, the epidemiology of late life illness may need to account for frailty routinely. ----------------- [2] Ann N Y Acad Sci. 2015 Dec 22. doi: 10.1111/nyas.12982. [Epub ahead of print] Significant life extension by ten percent dietary restriction. Richardson A(1,)(2), Austad SN(3), Ikeno Y(4), Unnikrishnan A(1), McCarter RJ(5). Free full text: http://onlinelibrary.wiley.com/doi/10.1111/nyas.12982/epdf Although it is well documented that dietary restriction (DR) increases the life span of rodents and other animals, this increase is observed at relatively high levels of DR, in which rodents are typically fed 40% less than that consumed by rodents fed ad libitum. It is generally assumed that lower levels of DR will have a lesser impact on life span; however, there are very little published data on the effect of low levels of DR on life span. In this study, we show that 10% DR increased life span to almost the same extent as 40% DR. While both 10% and 40% DR resulted in similar changes in non-neoplastic lesions, 10% DR had no significant effect on the incidence of neoplasia (except for pituitary adenoma), and 40% DR resulted in a significant reduction (40%) in neoplasia. These data clearly demonstrate that the life span of F344 rats does not increase linearly with the level of DR; rather, even a low level of DR can substantially affect life span. This rodent study has important translational implications because it suggests that a modest reduction in calories might have significant health benefits for humans. PMID: 26695614
  8. All, Keeping one's immune system healthy is important for everyone, but this is especially true for CR practitioners. Anecdotally we appear to have a very competent immune system, and this has been shown to be true clinically in early stage anorexics. But at the same time we have fewer metabolic reserves to fight off infections if/when we do get sick. With that background, Dr. Greger has an amusing and informative video out today on the impact of various social behaviors on immune system function. It turns out that laughing (or crying) as a result of watching funny (or sad) videos boosts immune system response for at least 24 hours. But you actually have to laugh or cry to get the effect; just watching the video doesn't cut it. What's more, kissing and sex also work to improve allergic responses in people with allergies. I've found that CR has had a tempering influence on both my positive and negative affective states (to put it rather clinically), so I don't find these insights to be too personally relevant, but they are interesting nonetheless. I've included the transcript and references (with links) below, for people who hate watching videos. --Dean Transcript: Laughter as Medicine The study I explored about how listening to Mozart can reduce allergic reactions reminded me of a similar study on humor. Took a bunch of people with dust mite allergies; half watched Charlie Chaplin; half watched the weather channel. Then, they injected them with dust mite poop, and the allergic response was significantly reduced after viewing the humorous video for a matter of hours, suggesting that the induction of laughter may play some role in alleviating allergic diseases. But, might it suppress our immune system too much? No. Say we have people watch a comedian for an hour, and their natural killer cell activity goes up, compared to watching nothing. And, their white blood count goes up, the number of immune cells in their bloodstream, the level of immune-boosting interferon goes up and stays up the next day, and the same with antibody production; pumping out more antibodies because yesterday you saw some video. So, humor seems to offer the best of both worlds at preventing the over reactive allergic response while boosting immune protection. But, you actually have to laugh. The more you laugh, the better your natural killer cell activity gets, but exposure to a humorous video alone did not significantly affect immune function. Those that didn’t laugh—maybe because it was a Bill Cosby video, did not benefit, reinforcing that it is not the funny video that improved immune function, but our laughter in response. Because of the role natural killer cells play in viral illness and various types of cancer, the ability to significantly increase their activity in a brief period of time using a noninvasive method could be clinically important the next time you have a cold or cancer. Laughter, like music or healthy food, offers potential benefits without any risk, or almost any risk. You’ve heard of side-splitting laughter? 67-year old woman attending laughter therapy sessions and evidently, rapture led to rupture. Thankfully, you can’t actually laugh your head off, but you can laugh until you wet yourself, called "giggle incontinence" in the medical literature—it's actually quite common in women, and no laughing matter. So, the next time you’re in the theater, should you choose the comedy over the tear-jerker? Not necessarily. If you take people with latex allergy and have them watch a weather video versus a heart-warming drama, viewing the weather information video did not cause emotion with tears, and it failed to modulate allergic responses. The tear-jerker, however, successfully reduced the allergic response, but only in those whose tears were actually jerked. So, to improve allergies laughing works, crying works. I laughed, I cried; it was better than Cats— especially if you have a cat allergy. Anything else you can do? Kissing! There’s actually a whole science of kissing, which sounds a pleasant enough college major, until you realize it’s about all the diseases you can get. But, if you take people with seasonal pollen allergies, or dust mite allergies, and have them kiss someone in a room for 30 minutes, they have a significant reduction in their allergic reactions, for both the pollen and the dust mites, whereas, if you just have them hug for a half-hour instead - no benefit. Bottomline, kissing significantly reduced allergic responses in patients with both allergic rhinitis (runny nose, itchy eyes) or allergic dermatitis. Collectively, these findings indicate that the direct action of love may be beneficial, though evidently cuddling wasn’t quite direct enough. With all the side-effects of antihistamine drugs, you’d think it would be easy to get people to sign up for the study, but this was done in Japan where, evidently, they do not kiss habitually. The follow-up study, which found similar benefit for an action of love that was even more direct, was also performed by researchers for whom English may not be their primary language, as evidenced by their speculation about females having more, “organisms.” Video Sources H Kimata. Listening to mozart reduces allergic skin wheal responses and in vitro allergen-specific IgE production in atopic dermatitis patients with latex allergy. Behav Med. 2003 Spring;29(1):15-9. H Kimata. Effect of humor on allergen-induced wheal reactions. JAMA. 2001 Feb 14;285(6):738. L S Berk, S A Tan, W F Fry, B J Napier, J W Lee, R W Hubbard, J E Lewis, W C Eby. Neuroendocrine and stress hormone changes during mirthful laughter. Am J Med Sci. 1989 Dec;298(6):390-6. L S Berk, D L Felten, S A Tan, B B Bittman, J Westengard. Modulation of neuroimmune parameters during the eustress of humor-associated mirthful laughter. Altern Ther Health Med. 2001 Mar;7(2):62-72, 74-6. M P Bennett, J M Zeller, L Rosenberg, J McCann. The effect of mirthful laughter on stress and natural killer cell activity. Altern Ther Health Med. 2003 Mar-Apr;9(2):38-45. H Sharma, N S Shekhawat, S Bhandari, Breda Memon, M A Memon. Rectus sheath haematoma: a rare presentation of non‐contact strenuous exercises. Br J Sports Med. 2007 Oct; 41(10): 688–690. M P Rogers, R F Gittes, D M Dawson, P Reich. Giggle incontinence. JAMA. 1982 Mar 12;247(10):1446-8. H Kimata. Emotion with tears decreases allergic responses to latex in atopic eczema patients with latex allergy. J Psychosom Res. 2006 Jul;61(1):67-9. H Kimata. Kissing reduces allergic skin wheal responses and plasma neurotrophin levels. Physiol Behav. 2003 Nov;80(2-3):395-8. L Z G Touyz. Kissing and hpv: honest popular visions, the human papilloma virus, and cancers. Curr Oncol. 2014 Jun; 21(3): e515–e517. J S Alpert. Philematology: the science of kissing. A message for the marital month of june. Am J Med. 2013 Jun;126(6):466.
  9. Dean Pomerleau

    CR, immunity and under-nutrition, and Rhesus LS

    Hi Khurram, I think I see what you are saying. Living in the "wild" as we humans do (sort of... more on that below), and as animals exposed to true famines do, might result in greater lifespan extension than animals subjected to lab-induced famines (i.e. in CR experiments), because in the lab both the CR and the control animals enjoy (relatively) germ-free conditions, and so the immunity boosting benefits of CR don't get reflected (much) in survival data. You may be right, but I'll play devil's advocate, just for fun. First, I'll grant you that famine likely improves some aspects of immune function (although see below). See this post on the recent Fontana paper (PMID: 25500208) showing anorexics have better immune system efficiency. But there is also a downside to CR's impact on the immune system. Specifically, when infections like flu/pneumonia are most likely to kill us (i.e. when we are old), a very thin CR practitioner might be somewhat less susceptible to contracting such an illness, but more susceptible to dying from it, due to fewer metabolic reserves to fight it once a serious infection is contracted. This hypothesis that CR may be a serious problem once infected, is supported by this recent rodent study [1], where more young and old CR mice than controls died when exposed to the flu. Fortunately, refeeding before the illness improved the ability of the mice to recover, but that sort of defeats the purpose of CR, and is likely to reverse the CR benefit of reduced susceptibility! So damned if you do, and damned if you don't. But perhaps another reason to consider backing off serious CR when one gets old... BTW, "flu and pneumonia" are the 3rd leading killer of centenarians. Also - sure relative to eating a crappy SAD diet CR seems likely to provide an immunity advantage. But it's not clear that the CR immunity advantage would be significant relative to an obesity-avoiding healthy diet and lifestyle. And with vaccines and modern antibiotics, it might be argued that we're living more in sheltered laboratory conditions than the "wild" of our ancestors, where having a stronger immune system and thereby avoiding infections during famine via CR might have indeed been a win, since once you got infected in such a Hobbesian "state of nature", you were as good as dead, whether CRed or not - if not from the infection itself than from some bully coming and beating you to death to take your stuff. Finally, see my upcoming post on the cold exposure thread on cold exposure and immune system function. --Dean -------------- [1] J Nutr. 2010 Aug;140(8):1495-501. doi: 10.3945/jn.110.122408. Epub 2010 Jun 9. Short-term re-feeding of previously energy-restricted C57BL/6 male mice restores body weight and body fat and attenuates the decline in natural killer cell function after primary influenza infection. Clinthorne JF(1), Adams DJ, Fenton JI, Ritz BW, Gardner EM. Author information: (1)Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA. A hallmark of energy restriction (ER) is a decrease in total body fat, which is thought to increase lifespan and maintain immune function. However, we have shown that during primary influenza infection, ER induces rapid weight loss, impairs natural killer (NK) cell function, and increases mortality in young and aged mice. To determine whether influenza-induced NK cell function could be restored in ER mice, young adult (6 mo) male C57BL/6 mice were fed an ER diet or re-fed (RF) control diet ad libitum for 2 wk before infection with PR8 influenza A. An initial hyperphagic response was observed in RF mice, characterized by increased food intake, rapid weight gain, and restoration of body fat and fat depots by 5-7 d of re-feeding to levels comparable to control ad libitum (AL) mice. Re-feeding improved survival and attenuated the decline in NK cell function during infection, evidenced by increased numbers, percentages, and CD69 expression by d 3 postinfection in RF mice. Interestingly, an altered metabolic phenotype was observed during infection of RF mice, with plasma leptin concentrations greater than in ER mice but less than in AL mice. In contrast, adiponectin concentrations of RF mice were lower than those of both ER and AL mice. These data suggest that re-feeding for a defined period before, and perhaps throughout, influenza season may provide the energy needed to counter the deleterious effects of ER on NK cell function, especially during exposure to newly emerging strains of influenza, for which vaccines are limited or unavailable. PMCID: PMC2903303 PMID: 20534876
  10. Dean Pomerleau

    CR-induced elevated cortisol and sleep

    In light of the discussion in this thread about just how much contribution elevated cortisol has in CR-related sleep difficulties, the results of this new meta-analysis [1] just posted by Al Pater on the relation between CR and cortisol in humans seem quite relevant. Two findings from the analysis seem particularly relevant to these discussions: Fasting (for what appears to be 3-6 days based on graph below) resulted in elevated cortisol, but a low calorie diet (LCD, defined as > 800kcal/day) or very low calorie diets (VLCD defined as < 800kcal/day) did not, especially if extended in duration (see #2). The http://www.tandfonline.com.sci-hub.io/doi/abs/10.3109/10253890.2015.1121984hasforest plots for the three conditions - I haven't included them here. It appeared that subjects' cortisol level returned to baseline after they've been following a LCD or VLCD for an extended duration. The details are illustrated in the graph from the paper included below, showing that at least by three weeks (and perhaps earlier), subjects in studies for LCD or VLCD has cortisol levels indistinguishable from baseline. So it is curious Zeta that you continue to exhibit symptoms (and measurements it sounds as well) of elevated cortisol, given that your overall calorie intake is not particularly restricted, and even on your "fasting" days you're still consuming 500 kcal, which would qualify as a VLCD (rather than fasting) by these authors' definition. Of course the subjects in the studies included in this analysis were almost certain to be overweight/obese (as most adults in the developed world are, and as you would expect participants in most diet studies to be) or at least normal weight - and hence possessed more metabolic reserves than we CR folks. It seems reasonable to think that eating few(er) calories may have more of an impact on cortisol levels when someone has less fat to burn, particularly in the early morning when the body has gone without food for many hours, resulting in early waking as you Zeta, and quite a few of us other CR folks as well, experience. --Dean ------------ [1] Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction. Nakamura Y, Walker BR, Ikuta T. Stress. 2015 Nov 19:1-21. [Epub ahead of print] PMID: 26586092 http://www.tandfonline.com.sci-hub.io/doi/abs/10.3109/10253890.2015.1121984 Abstract Elevated plasma cortisol has been reported following caloric restriction, and may contribute to adverse effects including stress-induced overeating, but results from published studies are inconsistent. To clarify the effects of caloric restriction on plasma cortisol, and to assess cortisol as an indicator of stress during caloric restriction, we conducted a systematic review and meta-analysis of published studies in which cortisol was measured following caloric restriction without other manipulations in humans. We further compared effects of fasting, very low calorie diet (VLCD), and other less intense low calorie diet (LCD), as well as the duration of caloric restriction by meta-regression. Overall, caloric restriction significantly increased serum cortisol level in thirteen studies (357 total participants). Fasting showed a very strong effect in increasing serum cortisol, while VLCD and LCD did not show significant increases. The meta-regression analysis showed a negative association between the serum cortisol level and the duration of caloric restriction, indicating serum cortisol is increased in the initial period of caloric restriction but decreased to the baseline level after several weeks. These results suggest that severe caloric restriction causes activation of the hypothalamic-pituitary-adrenal axis, which may be transient, but results in elevated cortisol which could mediate effects of starvation on brain and metabolic function as well as ameliorate weight loss. KEYWORDS: Caloric restriction; Cortisol; Hypothalamic-pituitary-adrenal axis; Meta-analysis; Stress; diet; endocrinology; weight control
  11. Dean Pomerleau

    Low Testosterone via CR - Good or Bad?

    Todd A., Welcome to the CR Society Forums! Sorry about your health challenges, but you've come to the right place to ask about CR. Yes and no. Chronic CR usually reduces testosterone, and importantly for you free testosterone [1], and (more controversially) libido in most (but not all) adult men. But I don't know of any dose/response data on how (or even if) degree of CR correlates with magnitude of testosterone drop. But I will note that none of the men (including me) in [1] were nearly as CRed as you indicate that you are (see below). But perhaps as significantly for you, CR not only reduces free & total testosterone, it also activates SIRT1, which appears beneficial for spinal and bulbar muscular atrophy (SBMA) [2] through the deacetylation of androgen receptors (ARs),. Deacetylation of your ARs deactivates them, which in your case is a good thing since your ARs are mutated and therefore apparently deleterious for cells in your motor cortex when bound with testosterone. But maybe you already knew that, and that's why you're here... My suggestion is to give it time. You haven't shared your starting point (age, BMI, etc), but unless you're naturally very thin with little body fat, you've probably got plenty of metabolic reserves, so you're body may not yet realize how much of a calorie deficit you are running. This can definitely result in an "buzz" in the early days of CR that many of us experience. If you can deal with the hunger, it can feel pretty good on the way down. BTW, 1200kcal/day is almost certainly not sustainable in the long run, and could lead to rapid muscle catabolism, especially if your condition is such that it makes it hard for you to exercise. Given that SBMA is associated with degeneration of certain skeletal muscles already, extreme CR (like 1200kcal/day for a man) could make matters worse. So if I were you I wouldn't cut calories nearly as drastically as you appear to be doing. One other caveat. Another consistent and major effect of CR is to reduce Insulin Like Growth Factor 1 (IGF-1). Although it is not without controversy, this effect is generally thought to be beneficial in healthy people, since IGF-1 is an anabolic hormone associated with the promotion of cancer grown and possibly accelerated aging. But in your case, anabolic hormones besides testosterone, and in particularly IGF-1, are potentially beneficial, both for maintaining motor neurons and muscle cells generally, and specifically by inhibiting your messed up ARs. From review article [3]: The neurodegenerative disease SBMA is caused by expansion of a CAG repeat encoding polyglutamine in the androgen receptor (AR) gene, resulting in accumulation of AR and loss of motor neurons in the brainstem and spinal cord. Augmentation of IGF-I levels in the muscle increases AR clearance through the ubiquitin-proteasome system and AR phosphorylation by Akt [4], and in a mouse model of SBMA, muscle-specific overexpression of IGF-I was able to improve motor performance and body weight [4]. Collectively, these data suggest that IGF-I has a direct inhibitory effect on mutant AR, which might help prevent motor neuron degeneration in SBMA. So while CR-induced reduction in free testosterone may be good in your case, CR-induced reduction in IGF-1 may be bad. Finally, it goes without saying this should not be interpreted as medical advice. I'm just some random guy on the internet trying to help, without medical training and without any knowledge about your specific situation. I also have only the cursory understanding of your disease and the potential impact CR might have on it that an hour of targeted internet searching and reading can provide. Heck, up until a couple hours ago I'd never even heard of SBMA. In short, don't listen to me. Talk to your doctor(s) if you haven't already about whether CR makes sense for your condition and your situation. By all means bring printouts of these abstracts/papers, and if he/she dismisses the idea of CR out of hand, look for another specialist who will at least give it careful consideration before advising for or against it. BTW, this blog looks like a pretty good resource for Kennedy's disease (aka SBMA) sufferers, if you haven't found it already. Good luck and all the best. Please keep us updated on what you decide in consultation with your doc, and how it works out. --Dean ------------ [1] Aging Cell. 2010 Apr;9(2):236-42. doi: 10.1111/j.1474-9726.2010.00553.x. Epub 2010 Jan 20. Long-term effects of calorie restriction on serum sex-hormone concentrations in men. Cangemi R(1), Friedmann AJ, Holloszy JO, Fontana L. Author information: (1)Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA. Calorie restriction (CR) slows aging and consistently reduces circulating sex hormones in laboratory animals. However, nothing is known regarding the long-term effects of CR with adequate nutrition on serum sex-hormone concentration in lean healthy humans. In this study, we measured body composition, and serum total testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5 +/- 13 years), who had been practicing CR with adequate nutrition for an average of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and 24 age-matched sedentary controls eating Western diets (WD). We found that both the CR and EX volunteers had significantly lower body fat than the WD volunteers (total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P = 0.0001). Serum total testosterone and the free androgen index were significantly lower, and SHBG was higher in the CR group than in the EX and WD groups (P < or = 0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both significantly lower in the CR and EX groups than in the WD group (P < or = 0.005). Serum DHEA-S concentrations were not different between the three groups. These findings demonstrate that, as in long-lived CR rodents, long-term severe CR reduces serum total and free testosterone and increases SHBG concentrations in humans, independently of adiposity. More studies are needed to understand the role of this CR-mediated reduction in sex hormones in modulating the pathogenesis of age-associated chronic diseases such as cancer and the aging process itself. PMCID: PMC3569090 PMID: 20096034 ------------------ [2] J Neurosci. 2011 Nov 30;31(48):17425-36. doi: 10.1523/JNEUROSCI.3958-11.2011. SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. Montie HL(1), Pestell RG, Merry DE. Author information: (1)Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially modified, in response to hormone binding, by phosphorylation, sumoylation, and acetylation; these modifications might thus contribute to DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is neuroprotective in many neurodegenerative disease models. Our studies reveal that SIRT1 also offers protection against polyQ-expanded AR by deacetylating the AR at lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent studies revealed that the polyQ-expanded AR is hyperacetylated and that pharmacologic reduction of acetylation reduces mutant AR aggregation. Moreover, genetic mutation to inhibit polyQ-expanded AR acetylation of lysines 630/632/633 substantially decreased its aggregation and completely abrogated its toxicity in cell lines and motor neurons. Our studies also reveal one means by which the AR acetylation state likely modifies polyQ-expanded AR metabolism and toxicity, through its effect on DHT-dependent AR stabilization. Overall, our findings reveal a neuroprotective function of SIRT1 that operates through its deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and AR acetylation as powerful therapeutic targets in SBMA. PMID: 22131404 ------------ [3] Trends Endocrinol Metab. 2013 Jun;24(6):310-9. doi: 10.1016/j.tem.2013.03.004. Epub 2013 Apr 27. The therapeutic potential of IGF-I in skeletal muscle repair. Song YH(1), Song JL, Delafontaine P, Godard MP. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732824/ Skeletal muscle loss due to aging, motor-neuron degeneration, cancer, heart failure, and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury, and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery methods. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches. Copyright © 2013 Elsevier Ltd. All rights reserved. PMCID: PMC3732824 PMID: 23628587 ----------- [4] Neuron. 2009 Aug 13;63(3):316-28. doi: 10.1016/j.neuron.2009.07.019. Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Palazzolo I(1), Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735765/ Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA. PMCID: PMC2735765 PMID: 19679072
  12. Dean Pomerleau

    Fasting

    Sthira, Glad you made it and are still with us. Sorry to hear this fast didn't go so well. If you look at Ray Cronise in the above video, he doesn't even look that thin at day 23 of a water-only fast. I think your experience suggests that those of us who are already rail-thin probably need to be very careful when it comes to extended water-only fasts, since we have so little in the way of metabolic reserves. I'm glad you're giving time-restricted eating a try. Eating as early in the day as I do is clearly unnecessary. But avoiding eating too close to bedtime is a good idea, for reasons Tom and I were just discussing in this thread. Let me know if you this needs further clarification. I really wish you were going to be at the conference. It seems like you'd be a lot of fun to hang out with, and you could benefit from some socializing with other folks as crazy as you! --Dean
  13. Hi Casey, As far as I know, there is no evidence for the former (i.e. starting CR young means more serious CR is required to have benefits). I think you may be mistaking the pretty well-supported idea that a greater degree of CR can be tolerated, at least in rodents and possibly in primates too, when started at a young age than when started later in adulthood, when the body isn't so resilient. As for benefits, if anything the evidence suggest that it is cumulative years of CR (at whatever degree of restriction works for you) that count towards total health/longevity benefits. In other words, starting younger will result in more benefit than starting later with the same degree of restriction. See this post for evidence suggesting that starting earlier appeared to be better for CR monkeys. As for the latter (being naturally thin may make it harder to attain CR benefits) - this one may have some validity to it, if only because being naturally thin makes it harder to practice CR safely (i.e. while maintaining sufficient metabolic reserves that may be required if you become sick or injured). But the jury is still out on this one. Once latent disease and unhealthy causes of thinness (e.g. smoking) are factored out, it doesn't appear that thin people in the general population (i.e. BMI < 18.5) are at a disadvantage relative to 'normal' weight people when it comes to health and longevity. Here is an entire thread on the topic of the benefits (reduced or otherwise) of CR for naturally thin people. --Dean
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