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  1. Dean Pomerleau

    Read More, Live Longer

    All, This new study [1] (NY Times coverage) found that reading benefits survival. Researchers asked 3600+ older adults about their reading habits and then followed them for up to 12 years. They found that people who reported reading (even a little) were about 20% less likely to die during follow-up than those who reported reading not at all or only very rarely, even after adjusting for age, sex, race, education, comorbidities, self-rated health, wealth, marital status, and depression. Here are the survival graphs for the readers vs. non-readers: Reading books was better for survival than reading newspapers or magazines, but they too were associated with increased survival (about a 10% lower risk of dying). In additional analysis, they found that reading books was still associated with decreased mortality risk even once baseline cognitive ability was factored out. How much reading did it take? Not too much. People in the second tertile of reading amount (0.1 - 3.5 hours/week) benefited almost as much as those in the highest tertile (> 3.5 hours / week). Admittedly, it's hard to correct for every single potential confounder in this type of study, but it appears that independent of intelligence & cognitive abilities, and independent of a host of other potential confounders, reading is beneficial for longevity. --Dean ---------- [1] Soc Sci Med. 2016 Jul 18;164:44-48. doi: 10.1016/j.socscimed.2016.07.014. [Epub ahead of print] A chapter a day: Association of book reading with longevity. Bavishi A(1), Slade MD(1), Levy BR(2). Author information: (1)Yale University School of Public Health, Laboratory of Epidemiology and Public Health, 60 College Street, New Haven, CT 06510, USA. (2)Yale University School of Public Health, Laboratory of Epidemiology and Public Health, 60 College Street, New Haven, CT 06510, USA. Electronic address: becca.levy@yale.edu. Full text: http://sci-hub.cc/10.1016/j.socscimed.2016.07.014 Although books can expose people to new people and places, whether books also have health benefits beyond other types of reading materials is not known. This study examined whether those who read books have a survival advantage over those who do not read books and over those who read other types of materials, and if so, whether cognition mediates this book reading effect. The cohort consisted of 3635 participants in the nationally representative Health and Retirement Study who provided information about their reading patterns at baseline. Cox proportional hazards models were based on survival information up to 12 years after baseline. A dose-response survival advantage was found for book reading by tertile (HRT2 = 0.83, p < 0.001, HRT3 = 0.77, p < 0.001), after adjusting for relevant covariates including age, sex, race, education, comorbidities, self-rated health, wealth, marital status, and depression. Book reading contributed to a survival advantage that was significantly greater than that observed for reading newspapers or magazines (tT2 = 90.6, p < 0.001; tT3 = 67.9, p < 0.001). Compared to non-book readers, book readers had a 23-month survival advantage at the point of 80% survival in the unadjusted model. A survival advantage persisted after adjustment for all covariates (HR = .80, p < .01), indicating book readers experienced a 20% reduction in risk of mortality over the 12 years of follow up compared to non-book readers. Cognition mediated the book reading-survival advantage (p = 0.04). These findings suggest that the benefits of reading books include a longer life in which to read them. Copyright © 2016 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.socscimed.2016.07.014 PMID: 27471129
  2. 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.
  3. All, Over on the Body-mass index and all-cause mortality thread, TomB posted the following, asking about what we might learn from the lifestyle and biomarkers of the very old in order to optimize our own diets and lifestyles. TomB said (my emphasis): [Note: the blue highlights above will factor into the discussions below] That other Michael (i.e. Mike Lustgarten hereafter referred to as 'Mike' to avoid confusion) and I have had several debates on this subject before on the CR Facebook forum. Namely, Mike likes to look at the characteristics (e.g. BMI, or selenium level) of very long-lived people (i.e. who've made it into their 90s or 100s), declare "they must be doing something right!" and target those same biomarker levels, diet characteristics and/or lifestyle practices for himself, and advocate others do the same to maximize their chance of living a long time. But as I've tried to point out to him on several occasions (relatively unsuccessfully it would seem), this approach to diet and lifestyle optimization is naive and fraught with problems. Here are the reasons why. It all boils down to one overarching observation - we're not like very old people. But just how we are unlike them, and why it matters, will take some unpacking. Freakishly good gene combinations - Perhaps the most common way for people these days to reach a very ripe old age is to have freakishly good genes. This allows them to avoid the major killers, like heart disease and cancer, often despite bad diet and lifestyle habits. Think of this as the George Burns effect. Actor George Burns lived to 100 despite smoking 10-15 cigars per day for 70 years (ref). Don't try that at home sports fans! The same thing is happening when you hear on TV about the latest 110 year old who attributes their longevity to "eating two strips of bacon per day" or "drinking whisky". In short, just because someone with freakishly good genes got away with a bad habit and lived to a ripe old age, doesn't mean you could, or should, try to emulate them, since most of us have crappy, run-of-the-mill gene combos, by definition, which means emulating such behavior would kill us quick. Survivor bias - In addition to a few folks with freakishly good genes, in any large population, there will also be a few folks with average genes who get lucky, and live to a ripe old age, avoiding the major killers. In fact, they might have bad genes or lifestyle habits that would on average shorten lifespan, but because they got lucky, they lived a long time. Here are a couple great examples of survivor bias (and/or other explanations discussed below) from the study Tom posted above (PMID:25446984), and that I've highlighted in blue. Notice above in that study the people who lived a very long time, into their 90s and 100s, had significantly lower levels of calcium and iron than did middle-aged controls. What gives? Isn't calcium supposed to be good for bones and iron important for avoiding anemia-complications and having a healthy immune system? Those benefits of Ca and Fe may hold true for middle-aged folks, and even the average senior. But at the same time, calcium can calcify arteries, and iron can cause oxidative damage, both of which can exacerbate the major killers - heart disease and cancer. So if you are one of those very rare individuals with either good genes and/or very good luck, you can get away with keeping Ca and Fe on the low (deficient) side, and avoid Ca and Fe deficiency-related maladies that would kill off the average person early - like a hip fracture from weak bones or a respiratory infection from a weak immune system. If you get lucky and escape those downsides of low Ca and Fe, then you are golden because keeping them low will help you avoid heart disease and cancer and hence live a long time. But if you're like the average person, low Ca and/or Fe will lead to broken bones and/or infections that will cut your life short on average. In other words, low Ca and/or low Fe will harm most people, and only benefit a lucky few. Another good example here is directly related to immunity - namely white blood cell (WBC) count. Several studies (discussed in http://dx.doi.org/10.1371/journal.pone.0127550) have found that that oldest of the old have low WBC. This is great for them, since it enabled them to avoid the major diseases of aging, which are triggered by inflammation. But they very well may have gotten luck or had good genes, enabling them to avoid infections that would normally have killed an average person with such a low WBC. In short, it doesn't necessarily pay for the average person to try to emulate the blood chemistry profile of the very old. Late Life / Near Death Changes - It's not just good genes or survivor bias (i.e. freakish luck) that sets the oldest of the old apart from the rest of us, and which makes them poor models to emulate. Why? Because biomarkers change drastically later in life, and especially when you are approaching death, which centenarians almost invariably are. So their blood chemistry levels when they are old aren't necessarily reflective of what got them to a ripe old age. Serum cholesterol is a great example of this. For various reasons, ranging from intestinal parasites to cancer, serum cholesterol tends to drop precipitously as people get sick and approach death. This can result in several misleading observations. First, old people with the highest cholesterol often live longer (i.e. have a lower mortality rate) than old people with low cholesterol, due to reverse causality. That is, the folks with low cholesterol are low because they've got a disease that will soon kill them. This observation (i.e. mortality risk is lowest in elderly folks with high cholesterol) is often pointed to by saturated fat apologists who like to claim keeping cholesterol from getting too low is critical for health and that low cholesterol is as bad or worse than high cholesterol. Bogus argument. Conversely, the oldest of the old, e.g. centenarians or supercentenarians, who are almost invariably within a year or two of death, may exhibit freakishly low cholesterol, for the same "reverse causality" reason - i.e. they are close to death causing low cholesterol. In both cases, the cholesterol level these old or freakishly old folks exhibit when they get to their ripe old age tells us nothing about what cholesterol level is best to get you to old age. For that we can look at longitudinal studies, that show low cholesterol in middle age is associated with improved longevity, for obvious reasons. That's why, BTW, studies of the freakishly old often look at their offspring or (younger) siblings as well, to see what characteristics people with similar genes had when they were younger, to avoid these late life changes/biases. In summary, looking at the blood chemistry, diet and/or lifestyle of very old people and trying to emulate them is fraught with difficulty, and therefore ill-advised. This is unfortunate, since it makes us much more reliant on longitudinal studies in people and intervention studies in animals, which have their own pitfalls, as we are all well-aware. --Dean
  4. All, At the recent CR conference, Dr Richard Miller from the University of Michigan gave a great talk on the Interventions Testing Program, a NIA-sponsored, rigorous, multi-center effort to investigate the potential of various drugs, supplements and nutriceuticals to extend lifespan in mice. Dr. Miller shared with us some results which have now been published. Here is a good summary of the latest results. It looks like the most promising interventions were metformin+rapamycin, acarbose, and 17-α-estradiol (in males only). I'm not planning on running out to take any of these, but I find acarbose interesting. It works by blocking the breakdown of carbohydrates, and suppressing hunger - in many ways like eating extra dietary fiber (a controversial topic itself) as discussed here on the Dietary Fiber - Health Promoter or Anti-CR Hunger-Suppressor? thread. --Dean
  5. All, Here is an interesting new study [1] (popular press story) that I appreciated as much for its data as its conclusions. In it, researchers identified a group of ~1400 "Wellderly" individuals - which they defined as: ndividuals who are >80 years old with no chronic diseases and who are not taking chronic medications. As you might imagine, these folks are pretty rare, and so they wanted to compare their genomes with those of an average population of elderly people. But first, they did an interesting thing - they compared the longevity of the siblings of the Wellderly cohort (who share a lot of genetics, and probably some lifestyle factors too, with the Wellderly folks) to see how their lifespan compares with the average US population. Here are the "survival curves" for the Wellderly siblings (red) vs. average folks (blue): As you can see, the Wellderly siblings had a more square mortality curve, but their survival curve wasn't shifted right - i.e. their "maximum lifespan" wasn't any longer than the average folks. Instead, both curves hit (near) zero around 100 years. Like the Wellderly themselves, their siblings appear to avoid / postpone the diseases of aging, and so do better in the "middle years" of elderliness (65-85), but beyond that have a mortality rate similar to the population as a whole. They then looked at the Wellderly folks' genetics. Interestingly, they didn't find their genomes to be particularly enriched with so-called "longevity genes" - those that have been identified as more common in centenarians or other very long-lived people. In other words, these folks are healthy agers, but don't seem to be blessed with genes for extreme longevity, which I thought was interesting. It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings: [O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease. I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis... But what I found personally most interesting and helpful from this paper were two of their tables, listing the various genetic markers they tested for both longevity and Alzheimer's disease (AD). They quite explicitly listed the SNPs and which alleles of those SNPs are associated with longevity or AD. I've reproduced the two tables below, and added my own data, a friend's 23andMe data I have access to, and links to 23andMe so that any other 23andMe customers can check their own status for the corresponding SNPs. I've even added a tally at the bottom of each table with a genetic "score" - basically the number of "good" alleles one carries minus (in the case of the AD table) the number of "bad" alleles one carries. Although in the case of AD, it was the evil APOE4 allele that dominated - i.e. the biggest difference between the genes of the "Wellderly" folks and the average population was that the Wellderly were a lot less likely to carry APOE4 alleles. Anyway, here are the tables. First, the table with the SNPs and alleles previously identified (via other studies) to be associated with increased longevity. The "Longevity Allele" column shows that variant of the SNP that has been shown to be associated with increased longevity. The second column shows the gene the SNP is part of - as you can see many familiar names, including FOXO3, SIRT1, IL-6, IGF1, AKT (all of which I note have been associated with both CR and Cold Exposure in one way or another). The green letters show when I or "Person X" are carriers for the "good" longevity allele: Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs: https://www.23andme.com/you/explorer/snp/?snp_name=rs2802292 https://www.23andme.com/you/explorer/snp/?snp_name=rs1935949 https://www.23andme.com/you/explorer/snp/?snp_name=rs3758391 https://www.23andme.com/you/explorer/snp/?snp_name=rs5882 https://www.23andme.com/you/explorer/snp/?snp_name=rs1042522 https://www.23andme.com/you/explorer/snp/?snp_name=rs1800795 https://www.23andme.com/you/explorer/snp/?snp_name=rs2811712 https://www.23andme.com/you/explorer/snp/?snp_name=rs34516635 https://www.23andme.com/you/explorer/snp/?snp_name=rs2542052 https://www.23andme.com/you/explorer/snp/?snp_name=rs3803304 Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD): Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me): https://www.23andme.com/you/explorer/snp/?snp_name=rs190982 https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058 https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679 https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145 https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343 https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944 https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633 https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650 As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹ To wrap up, the researchers also also found that a few of the Wellderly folks were enriched with an ultra-rare variants of a gene that seems to be especially protective against AD, called COL25A1 but I couldn't figure out what SNPs or alleles they were talking about. As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores". --Dean ------- [1] Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.03.022 Whole-Genome Sequencing of a Healthy Aging Cohort Galina A. Erikson5, Dale L. Bodian5, Manuel Rueda, Bhuvan Molparia, Erick R. Scott, Ashley A. Scott-Van Zeeland, Sarah E. Topol, Nathan E. Wineinger, John E. Niederhuber, Eric J. Topol6, Ali Torkamani6 Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30278-1.pdf Summary Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype—healthy aging—to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. PMID: Unavailable
  6. http://www.theglobeandmail.com/news/world/worlds-oldest-person-dies-in-new-york-aged-116/article30008972/
  7. All, I was quite surprised to see in this study [1] posted by Al (thanks Al!) that among a population of nearly 1500 elderly people (age 75-96), two thirds said they didn't want to live to see 100. And these folks were apparently not institutionalized, but instead were "community dwelling" and recruited randomly by mail from the Helsinki's population registry. So they should have been a pretty good sample of older folks, if anything skewed towards being healthier than average rather than decrepit since they were able to respond to the survey. The two factors that correlated most strongly with desiring to make centenarian status were being male and being in good subjectively-reported health - so most of us have that goin' for us. For those who said no to the question of living to 100, their reasons were a litany of complaints about life and old age - pretty depressing actually: Among those not wishing to live to be 100, by far the largest proportion gave anticipatory explanations, seeming to believe that disease or poor functioning would be inevitable in a long life (n = 226): ‘Too many diseases!’ ‘Probably I would be too frail’ (Table 3). Emerging attitudes were mainly pessimistic. Many of the participants seemed to experience that life is meaningless (n = 111), ‘Not worth living’, or they conveyed indifference (n = 82) or even bitterness (n = 72): ‘Pointless suffering’; ‘Society is so cruel’. In addition, these old people were concerned about being a burden to others (n = 96): ‘It is a strain on yourself and your loved ones’. Some people expressed more positive attitudes, such as integrity (n = 16) or belief (n = 10): ‘I have led a rich life’; ‘I’m grateful every day’. In addition to rational reasons or attitudes, fear of the future was the third theme. Fear of loss of autonomy was striking (n = 98): ‘I’m afraid of frailty and helplessness’. Also loneliness (n = 23) and pain (n = 17) fed fear of the future. It shows how important it is to maintain one's health and especially a positive attitude. Obviously it's not so easy for the vast majority of people, at least in Finland - which is ironic, because Finland is perennially recognized as one of the happiest countries on Earth (#5 of 157), and it appears Finland has a darn good safety net for the elderly. I'm frightened to know what a survey of oldsters from the US (ranked #13) would reveal... --Dean --------- [1] Do you want to live to be 100? Answers from older people. Karppinen H, Laakkonen ML, Strandberg TE, Huohvanainen EA, Pitkala KH. Age Ageing. 2016 Apr 13. pii: afw059. [Epub ahead of print] PMID: 27076523 http://sci-hub.io/10.1093/ageing/afw059 Abstract BACKGROUND: little is known about the oldest-olds' views on ageing. OBJECTIVE: to investigate older people's desire and the reasons they give for wanting to live to 100. DESIGN: a postal questionnaire, analysed both quantitatively and qualitatively. SETTING: population based in Helsinki, Finland. SUBJECTS: a random sample (response rate 64%;N= 1,405) of community-dwelling older people (aged 75-96). METHODS: a structured self-completed questionnaire with an open-ended question on the reasons why/why not participants wished/did not wish to live to 100. RESULTS: one-third (32.9%) of home-dwelling older people wanted to live to be 100. Those who did were older, more often male and self-rated their health better than those who did not. Often the desire for long life was conditional: 'Yes, if I stay healthy'. Among the reasons is that many were curious to see what would happen. Many stated that they loved life, they had twinkle in their eye or significant life roles. Those who did not want to live extremely long lives gave various rationales: they would become disabled, life would be meaningless, they were reluctant to become a burden to others or they feared loss of autonomy or suffering pain or loneliness. Some people also shared the view that they should not intervene in destiny or they felt that they had accomplished what they wanted in life. CONCLUSIONS: one-third of the oldest-old participants wanted to live to 100. Identifying what motivated them to desire long life could be a resource in their care plans. KEYWORDS: centenarian; older people; oldest-old; qualitative; will-to-live
  8. Here is an interesting short blog post by our friend and evolutionary biologists, Josh Mitteldorf which he titles Aging is a Military Coup. In it he suggests two things, which I paraphrase thusly: Aging is not the passive process we used to think it was. Instead, aging is programmed into the body, and it is often a result of the body actively attacking itself in one way or another - commonly a result of the immune system response to inflammation. From a multi-level natural selection perspective, this self-destruction by individuals may be the way a community/society clears out its weaker members to make way for a new generation, and thereby promote the flourishing of the group. I don't think anyone can argue with #1 - aging, at least in the manifest forms Josh enumerates, does appear to be a very active, programmed response. But I'm much more skeptical about #2. It seems plausible, but far from proven. Here is how Josh describes it: If evolution found it necessary to regulate the individual’s life span for the larger good of the community or the ecosystem, there would be no need to invent a new and specialized death program. It would be far easier to coopt the body’s existing armies, and redirect them in a suicide mission. You can see where Josh gets the "military coup" metaphor in his title. But I think a better analogy is apoptosis. In Josh's model, the individual person is "self destructing" when they get old for the good of the community/society, in the same way an individual cell "self destructs" when it is damaged (via the process called apoptosis) for the good of body. Perhaps resources have been scarce enough in human history that it benefitted the group if older members died off to avoid consuming resources "unproductively". But it's not clear to me that there were enough long-lived, "parasitic" elders in our deep evolutionary history (when our ancestors rarely lived beyond age 30-40) to generate the kind of selection pressure in favor of "human apoptosis" that Josh postulates. Plus there is the "grandmother effect" which suggests older people (particularly women) may have been productive caregivers in a community even after their reproductive years. Regardless of whether his model is right or not, I don't believe that Josh thinks this human apoptosis is a good thing! --Dean
  9. All, It has been thought that CR lifespan benefits are likely to linearly increase with degree of CR, up to very severe CR, based on rodent data like the famous Weindruch study [2], data from which is highlighted on the CR Society home page, and reproduced in this graph: As you can see, compared with ad-lib fed mice, 25% CR provided some benefits. But severe CR, where mice ate 55% or even 65% less food than the AL group, lived much longer than the 25% restricted group. And note that this benefit was seen across the board. No sign of early mortality in the severely restricted mice - the survival curves for the 55% & 65% CR mice are completely to the right of the 25% CR mice survival curve, which in turn is completely right of the AL mice survival curve. From this it looks like the more CR the better. But the recent NIA/Wisconsin monkey data doesn't look so cut and dried. In fact, one plausible interpretation of the NIA monkey results (as we've discussed elsewhere, e.g. here), is that if eating a healthy diet, restricting calories beyond that required to avoid obesity doesn't provide additional longevity benefits. So how much CR is required to garner the benefits? Perhaps this new rodent study [1] sheds some light on the topic, as far as rodent studies can be extrapolated to humans (more on that below). What they did was restrict the calories of a common strain of rats (F344 - all male) in two groups - 10% and 40% restriction relative to AL-fed controls. Then they let them all live out their natural lifespan to see how longevity and causes of death compared between the 3 groups (AL, CR25, CR40). Here are the two important graphs and the most important table from the paper, illustrating the main lifespan results, image originally from this analysis of the study on crvitality.com, red annotations are mine. As you can see from the survival curves and Table 1, both the CR10 and CR40 groups had mean longevity that was significantly longer than the AL group, but they did not significantly differ from each other, at 796 days for AL, 918 days for CR10 and 947 days for CR40. One way to look at this result is that on average, restricting enough to avoid obesity (i.e. CR10), resulted in a 15% increase in mean lifespan. Bumping it up to severe restriction (CR40) bought the rats an additional (non-significant) 4% of mean lifespan relative to obesity-avoiding 10% CR (15% vs. 19% increased lifespan, respectively). That seems like a pretty modest (if any - given its non-significance) lifespan gain for a lot more severe restriction. On the other hand, the longest lived 10% of the CR40 rats did indeed significantly outlive the CR10 rats, as can be seen from both the graph on the left above, and from the longevity table. Quantitatively, the longest lived 10% of the CR10 rats enjoyed a 37% longer life than the average AL rat, while the longest lived 10% of the CR40 rats enjoyed a 54% longer life than the average AL rat, a gain of 17% in lifespan from CR10 to CR40. That sounds pretty good, as long as you are one of the lucky, few longest-lived CR40 rats. From the survival graph, it looks like it was only the top ~20% of CR40 rats that enjoyed any longevity benefits relative to the CR10 rats, and it looks like this was almost (but perhaps not quite) fully counterbalanced by the bottom 20% of the CR40 rats dying before the CR10 rats (see red annotations on graph above for places where CR40 had an advantage and a disadvantage for lifespan relative to CR10). The Gompertz graph on the right above shows that rate of aging in the CR40 group appeared to be slowed relative to the other two groups, which didn't appear to differ from each other. In short, if you're lucky (and the rat data in [1] translates to humans - see below), this data suggests that going for severe CR might gain you an extra ~14 years relative to obesity avoiding mild CR. But if you're unlucky, severe CR might kill you off early by almost an equivalent amount. If you are average (mean or median), you can expect to do about the same in terms of lifespan with either mild CR (i.e. enough to avoid obesity) or severe CR. But wait a minute - one thing Michael always cautions about is the need to make sure the animal husbandry in a study is good, and the strain being used isn't one of those f**cked up ones that dies early, or is particularly fragile and therefore not a good candidate for CR research. From [3] (and from memory), it is apparent that the F344 strain of rats is one that is commonly used in CR research. Below is the mortality curves for F344 rats fed AL or 40% CR diets from [3]. The mortality curve for the AL-M (ad lib fed male) group looks about the same in [3] as in study we've been looking at [1], with median lifespan around 800 days and max around 1000 days. But if anything the 40% CR group of F344 (male) rats looks better in [1] than in [3] below - where (eyeballing it) the median lifespan looks to be around 900 days (vs. nearly 1000 in [1]) and max is around 1150 days (vs. 1400 in [1]). Note also that unlike in the mortality curves above from [1], the mortality curve for the 40% CR rats from [3] spends time below the AL curve from around 400 to 600 days (see red annotations below), representing early mortality in the CR rats, likely due to the stress of severe CR. So it doesn't look like there was any problem with strain or husbandry in [1] that might invalidate its results. In fact, based on the results of [3], it would seem that [1] may be overestimating the (max) longevity upside of severe CR, and underestimating the early mortality risk of severe CR, making severe CR in [1] seem like a better deal relative to a milder, obesity-avoiding level of CR that it actually may be. Unfortunately 10% CR wasn't tested in [3] - only AL and CR40. The author's of [1] seemed surprised by the modest benefits of severe CR40 relative to mild, obesity-avoiding CR10, saying: The data from this study clearly demonstrate that a 10% restriction of food significantly increases the lifespan of male F344 rats and, surprisingly, that the increase in lifespan is comparable to what was observed for rats that were restricted 40%. These data were surprising because of the general view that increasing the level of DR up to 40% would result in a continuous increase in lifespan, as reported by Weindruch et al.[2] for female C3B10RF1 mice in which a significant increase (over 20%) in the mean survival occurred between approximately 25% and 55% DR. ... These data in combination with the data from Duffy et al.,[4] 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. But what about translatability of such rodent data to humans? - a topic currently under discussion over on this thread, where just last night Michael said: So how good a model of human aging is the natural aging of these critters? Not very good it seems to me, if this study is typical of rodent causes of death (which I think it is), based on this table from the full text: As you can see from the table above, like most rodents, a clear majority died from various forms of cancer, with leukemia being by far the most common single cause. As we all know (and which is graphically illustrated here) cardiovascular disease in its various forms is the #1 killer of humans (at least in the US and other developed nations) - cancer only accounts for 23% of human death. Further, leukemia is only the 6th most common cancer killer in people, accounts for only 5% of all cancer deaths and only ~1% of all causes of death in the US. Based on this cause-of-death mismatch, these leukemia-prone rats, and cancer-prone rodents in general, don't seem like a very good model of the "diseases of aging" that kill people. As a corollary, the fact that CR40 significantly reduced leukemia deaths relative to CR10 in [1] seems unlikely to "move the bar" for human longevity, even if these results would translate directly to people. So the takeaway message from this one seems to be that even CR rodent results, which have always been the best data we have to support large additional lifespan benefits of 'serious' CR relative to simply avoiding obesity, may be open to question both in terms of the magnitude of the benefit, and their translatability to humans. Michael, if I'm missing something I'm sure I'll hear from you. --Dean ------- [1] 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 --------- [2] 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. --------- [3] J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. Turturro A(1), Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. PMID: 10619312 The collaborative Interagency Agreement between the National Center for Toxicological Research (NCTR) and the National Institute on Aging (NIA) was aimed at identifying and validating a panel of biomarkers of aging in rodents in order to rapidly test the efficacy and safety of interventions designed to slow aging. Another aim was to provide a basis for developing biomarkers of aging in humans, using the assumption that biomarkers that were useful across different genotypes and species were sensitive to fundamental processes that would extrapolate to humans. Caloric restriction (CR), the only intervention that consistently extends both mean and maximal life span in a variety of species, was used to provide a model with extended life span. C57BI/6NNia, DBA/2JNia, B6D2F1, and B6C3F1 mice and Brown Norway (BN/RijNia), Fischer (F344/NNia) and Fischer x Brown Norway hybrid (F344 x BN F1) rats were bred and maintained on study. NCTR generated data from over 60,000 individually housed animals of the seven different genotypes and both sexes, approximately half ad libitum (AL) fed, the remainder CR. Approximately half the animals were shipped to offsite NIA investigators internationally, with the majority of the remainder maintained at NCTR until they died. The collaboration supplied a choice of healthy, long-lived rodent models to investigators, while allowing for the development of some of the most definitive information on life span, food consumption, and growth characteristics in these genotypes under diverse feeding paradigms. ------------ [4] Duffy, P.H., J.E. Seng, S.M. Lewis, et al. 2001. The effects of different levels of dietary restriction on aging and survival in the Sprague–Dawley rat: implications for chronic studies. Aging Clin. Exp. Res. 13: 263–272.
  10. All, Sithra (thanks Sithra!) was the first to alert us of this brand new study [1] out yesterday in Nature, now getting lots of attention in the popular press (e.g. here, here and here). He made relatively casual mention of it, deep in this thread on Intrinsic Aging, so at first I didn't realize its significance. Now that I do, I think it definitely deserves its own thread. It could be the kind of "out of the blue" breakthrough mentioned here that just might rapidly advance the science of human longevity, or at least put us on the road to longevity escape velocity to give Aubrey and Co. time to solve the plethora of other problems (discussed here and here) which cause aging... With that build-up, what was the study about, and what did they find? It was a study in mice, and the effects on health & longevity of killing off of senescent cells - old dysfunctional cells that are no longer dividing, but that refuse to die and as a result spew out reactive oxygen species (ROSs) and inflammatory chemicals into the body. It has long been suspected that senescent cells contribute to aging, but it has been hard to prove it. It seems that the researchers in this study may have done that, and opened up new research directions for anti-aging therapy. What they actually did is rather complicated. But in a nutshell, as I understand it, here is what they did. It seems that in addition to all other crap that senescent cells spew out, they generate a tumor suppressing protein called p16Ink4a, which I'll abbreviate as p16. From this popular press article: You can think of [p16] as basically [the senescent cells'] calling card. By rewriting a tiny portion of the mouse genetic code, Baker and van Deursen's team developed a genetic line of mice with cells that could, under the right circumstances, produce a powerful protein called caspase when they start secreting p16. Caspase acts essentially as a self-destruct button; when it's manufactured in a cell, that cell rapidly dies [via apoptosis]. So what exactly are these circumstances where the p16 secreting cells start to create caspase and self-destruct? Well, only in the presence of a specific medicine the scientists could give the mice. With their highly-specific genetic tweak, the scientists had created a drug-initiated killswitch for senescent cells. So the researchers took mice genetically modified to carry this senescent cell "kill switch" and started injecting them with the kill switch activator at 12 months of age (around the human equivalent of 45 years old). This resulted in the death of a large fraction of senescent cells in various parts of the mice with the kill switch. As a result, in two strains of mice, both males and females median lifespan was significantly extended by about 25%. Here are the male-only survival curves of controls without the kill switch but treated with the activator (C57 +AP), controls with the kill switch but without activating it (ATTAC -AP) and the treatment group with the kill-switch which was activated (ATTAC +AP) to kill off the senescent cells, for the commonly-employed C57BL/6 strain of mice: The magenta curve shows administering the activator alone doesn't improve or harm the survival of natural mice without the genetically-engineered kill-switch (C57 +AP). The dark blue (solid) curve shows the genetic modification, without the activator, doesn't improve or harm mice survival either (ATTAC -AP). The light blue (dashed) curve shows that in mice with the kill-switch and treated with the kill-switch activator (ATTAC +AP), lived significantly longer on average, by in this case, a whopping 35%. The "xxx d" numbers associated with each curve represent the different groups' median lifespan. Now before we jump to any conclusions, we should do as Michael always says, and check the longevity of these mice against other studies of the same strain, and especially compare their longevity with the results of CR. From this study [2], discussed here, the median lifespan of male-only C57BL/6 is 26.3 months for AL fed mice and 32.6 months for CR fed mice. At an average of 30.4 days per month, that is a median lifespan of 800 days for AL mice, and 991 day for CR mice (24% life median life extension for CR). Hmmm... That calls these results into question a bit. Why? Because well-cared-for C57BL/6 mice fed ad lib appear to live 800 days in other labs, whereas the equivalent so-called "controls" in this study lived only 626 days. Killing off the senescent cells eliminated this early death effect observed in the so-called controls, boosting the treated mice to a median lifespan of 843 days. But this 843 days is only marginally longer (if at all) than the median lifespan of well-cared-for ad lib controls in this strain (800 days), and nowhere near the median lifespan of male C57BL/6 mice subjected to CR (991 days). The other important thing to notice is that in the above survival curve, the median lifespan of the treated mice was increased, but not the maximum lifespan. The two blue curves hit zero on the x-axis at the exact same age. This is in contrast with the effect of CR in this strain, where the median and maximum lifespan of CRed mice is greatly extended, as can be seen from the survival curve from [2]: Whether it was due to poor animal husbandry, or something in the genetic manipulation, treatmetn and/or kill-switch activator compound itself, something was killing off the control animals early in this new study. The treatment appears to restore their median longevity to the natural median lifespan of well-cared-for ad lib-fed controls, but even there the maximum lifespan of well-cared-for ad lib-fed controls was 1042 days (34.3 months), while the treated animals in this study lived to a maximum of only 900 days. So the treated mice didn't even come close to the maximum lifespan of ad lib fed well-cared-for mice, to say nothing of the 1300 day maximum lifespan of the well-cared-for CR C57BL/6 mice. This may explain several anomalies between the popular press reports of this study and the full text of the study itself. First of all, compare the gushing popular press headlines: In New Anti-Aging Strategy, Clearing Out Old Cells Increases Life Span of Mice by 25 Percent - MIT Technology Review AGEING BREAKTHROUGH: RESEARCHERS ADD UP TO A THIRD TO MICE’S LIFESPANS BY CLEARING OLD CELLS - Factor-tech.com Scientists Can Now Radically Expand the Lifespan of Mice—and Humans May Be Next - Popular Mechanics with the much more modest title from the Nature paper itself on which they are reporting: Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan - Nature I've underlined the key difference - "shortens" vs. "increases", "adds up to a third" or "radically expands". With the very title of their paper the authors are conceding that they haven't actually increased the median (to say nothing of maximum) lifespan of mice relative to normal, ad lib controls of the same strain with their treatment for killing off senescent cells. In the discussion section of the full text of the paper, the authors clarify what might be going on with this passage: It will be useful to optimize senescent cell removal protocols and methods further because the longevity of male C57BL/6 mice seemed negatively affected by repetitive vehicle injection stress, and because clearance was partial and several key tissues were refractory to clearance, including liver and colon. In short, so far the 'cure' (killing off senescent cells) seems worse (or at least not significantly better) than the 'disease' (living with senescent cells). Plus, remember the mice had to be genetically engineered so that their p16-expressing senescent cells would be targeted by the apoptosis-activating compound, a genetic modification that a technology like CRISPR might one day be able to pull-off in humans, but that day is a long way off. So not for the first time, I started off a post with a flourish of enthusiasm, only to discover the popular press has seriously overhyped the significance of the research. I considered going back and curbing the enthusiasm I expressed in the introductory paragraphs of this post. But I figured it was better not to - since this way it serves as a nice case-study in the value and importance of careful reading and analyzing the original source. Overall, the results are certainly suggestive that senescent cells are bad news for health & longevity, but we pretty much knew that already. Getting rid of senescent cells may indeed extend longevity, at least on average. But true (maximum) human lifespan extension, still seems to remain a long way off... But this hasn't stopped the researchers involved from partnering with the Buck Institute to form a biotech startup called Unity Biotechnology to try to push towards commercializing methods to clear senescent cells. --Dean ------- [1] Nature. 2016 Feb 3. doi: 10.1038/nature16932. [Epub ahead of print] Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Baker DJ(1), Childs BG(2), Durik M(1), Wijers ME(1), Sieben CJ(2), Zhong J(1), A Saltness R(1), Jeganathan KB(1), Verzosa GC(3), Pezeshki A(4), Khazaie K(4), Miller JD(3), van Deursen JM(1,)(2). Author information: (1)Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. (2)Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. (3)Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. (4)Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. Full text: http://www.nature.com.sci-hub.io/nature/journal/vaop/ncurrent/full/nature16932.html Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan. PMID: 26840489 ----------- [2] Genotype and age influence the effect of caloric intake on mortality in mice. Forster MJ, Morris P, Sohal RS. FASEB J. 2003 Apr;17(6):690-2. Epub 2003 Feb 5. PMID: 12586746 Free PMC Article http://www.ncbi.nlm....les/PMC2839882/ http://www.ncbi.nlm....nihms182370.pdf Abstract Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/2, and B6D2F1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22–24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL==>AL, AL==>CR, CR==>CR, and CR==>AL, designated according to long-term and short-term caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL==>CR increased mortality in 17- and 24-month-old mice, whereas the shift from CR==>AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age. Keywords: caloric restriction, aging, C57BL/6, DBA/2, B6D2F1
  11. All, There is a new study [1] out this week getting lots of media attention with headlines like Study: Obesity more dangerous to health than lack of fitness and 'Fat but fit' counts for nothing scientists say. After reading the full text (via sci-hub.io) it appears this is a gross oversimplification, if not outright distortion of what the study really says. In the study, researchers looked at the aerobic fitness and weight of 1.3 million Swedish men at the time of their military conscription (mean age 18). Aerobic fitness was tested by seeing how long the men could keep pedalling on a stationary bike whose resistance was increased at a rate of 2.5 watts/min. The subjects were then followed for an average of 29 years (to around age 47 - so still relatively young), during which 44K of them died. They then compiled statistics about mortality rate as a function of both baseline weight and baseline aerobic fitness. The results of the entire study are nicely summarized in a single graph (don't you love it when that happens?!). Here it is: There are several interesting things that can be gleaned from this graph: Being more aerobically fit resulted in reduced mortality across all four BMI categories. There was virtually no difference in the mortality rate of men with low BMI (< 18.5) vs. normal BMI (18.5 - 25). The fact that the researchers did not correct for smoking would seem to make this lack of difference even more significant, since it is likely that the skinny group smoked more than the normal weight group, and so would be expected to have a higher mortality rate, based on many other studies. The most fit obese men were significantly more likely to die than the least fit normal or even overweight individuals. It is only the last of these three points which seem to have sparked all the media attention. But as you can see, the study has much more interesting information than just that, particularly for us CR practitioners - namely that when it comes to reducing mid-life mortality, being skinny isn't bad and being more aerobically fit is good. --Dean --------- [1] International Journal of Epidemiology, 2015, 1–10 doi: 10.1093/ije/dyv321 Aerobic fitness in late adolescence and the risk of early death: a prospective cohort study of 1.3 million Swedish men Gabriel Hogstrom, Anna Nordstrom and Peter Nordstrom Full text (via sci-hub.io): http://ije.oxfordjournals.org.sci-hub.io/content/early/2015/12/20/ije.dyv321.full Abstract Background: Fitness level and obesity have been associated with death in older populations. We investigated the relationship between aerobic fitness in late adolescence and early death, and whether a high fitness level can compensate the risk of being obese. Methods: The cohort comprised 1 317 713 Swedish men (mean age, 18 years) that conscripted between 1969 and 1996. Aerobic fitness was assessed by an electrically braked cycle test. All-cause and specific causes of death were tracked using national registers. Multivariable adjusted associations were tested using Cox regression models. Results: During a mean follow-up period of 29 years, 44 301 subjects died. Individuals in the highest fifth of aerobic fitness were at lower risk of death from any cause [hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.47–0.51] in comparison with individuals in the lowest fifth, with the strongest association seen for death related to alcohol and narcotics abuse (HR, 0.20; 95% CI, 0.15–0.26). Similar risks were found for weight-adjusted aerobic fitness. Aerobic fitness was associated with a reduced risk of death from any cause in normalweight and overweight individuals, whereas the benefits were reduced in obese individuals (P< 0.001 for interaction). Furthermore, unfit normal-weight individuals had 30% lower risk of death from any cause (HR, 0.70; 95% CI, 0.53–0.92) than did fit obese individuals. Conclusions: Low aerobic fitness in late adolescence is associated with an increased risk of early death. Furthermore, the risk of early death was higher in fit obese individuals than in unfit normal-weight individuals. Key words: Fitness, obesity, death PMID: 26686843
  12. There is a really interesting new meta-analysis [1] in this week's issue of The Lancet on the association between height and health/longevity. Here is a popular press article on the study, with the title Big And Tall: Nutritious Meals May Make Us Taller But They Could Also Increase Our Cancer Risk. The researchers looked at 121 epidemiological studies of over a million people that assessed the association of height with health and lifespan. The heart of the paper are these two graphs: showing how in both men and women, being taller reduces risk of coronary heart disease, but increases risk of cancer. Here is a graphical representation of the over/undernutrition-based mechanisms the authors postulate to explain the observations: The link to cancer via higher insulin in people who eat a lot (and hence grow taller) is familiar. What was a bit surprising was their suggestion that increased levels of grow factors like IGF-1 in taller people may actually improve insulin sensitivity and hence reduce diabetes and cardiovascular disease. --Dean ------------- [1] The Lancet Diabetes & Endocrinology Available online 28 January 2016 DOI: http://dx.doi.org/10.1016/S2213-8587(15)00474-X| Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications Norbert Stefan, MD, Hans-Ulrich Häring, MD, Frank B Hu, MD, Dr Matthias B Schulze, DrPHcorrespondenceemail Full text: http://dx.doi.org.sci-hub.io/10.1016/S2213-8587(15)00474-X Summary Among chronic non-communicable diseases, cardiometabolic diseases and cancer are the most important causes of morbidity and mortality worldwide. Although high BMI and waist circumference, as estimates of total and abdominal fat mass, are now accepted as predictors of the increasing incidence of these diseases, adult height, which also predicts mortality, has been neglected. Interestingly, increasing evidence suggests that height is associated with lower cardiometabolic risk, but higher cancer risk, associations supported by mendelian randomisation studies. Understanding the complex epidemiology, biology, and pathophysiology related to height, and its association with cardiometabolic diseases and cancer, is becoming even more important because average adult height has increased substantially in many countries during recent generations. Among the mechanisms driving the increase in height and linking height with cardiometabolic diseases and cancer are insulin and insulin-like growth factor signalling pathways. These pathways are thought to be activated by overnutrition, especially increased intake of milk, dairy products, and other animal proteins during different stages of child development. Limiting overnutrition during pregnancy, early childhood, and puberty would avoid not only obesity, but also accelerated growth in children—and thus might reduce risk of cancer in adulthood.
  13. This new study in the Lancet [1] (popular account here) is sad news for us happy people. In the study, researchers polled 700,000 women in 1996-2001 about their level of happiness, and other health markers. Then the followed up in 2012 to see how many had died, and if there was a correlation between self-reported happiness and mortality that was independent of baseline health and other (socioeconomic) factors. From the full text, here is an interesting chart of what lifestyle and health parameters made these women the most happy or unhappy - i.e. factors that correlated with self-reported happiness. The most happiness-inducing was being married with children. The most unhappiness-inducing was sleeping less than 7h per night. If I'm reading it right, it also appears the more education the women had, the less happy they reported themselves to be. Anyway, what these researchers were interested was the relationship of happiness and health/longevity. First, they eliminated women who reported having "life threatening health disorders" (e.g. cancer, heart disease, etc.) at baseline, to avoid their (presumed) unhappiness from interfering with the analysis. In the disease-free women that remained, they found unhappy women were 30% more likely to die than those who reported being happy "most of the time" or "usually happy": In crude analyses adjusted only for age, unhappiness remained associated with increased mortality (RR 1·29, 95% CI 1·25–1·33) But they found that women who self-rated their health as fair or poor were 67% more likely to die during follow-up than those who rated it good or excellent. Once they adjusted for the correlation between self-rated health and happiness, the association between happiness and reduced mortality disappeared: ]O]nce we adjusted for self-rated health, unhappiness was no longer significantly associated with all-cause mortality (RR 1·02, 0·98–1·05; table). Here is the most relevant graph, showing just how flat the mortality rate (vertical axis) is across different levels of reported happiness (horizontal axis), but that people with poor self-reported health have a mortality curve shifted much higher than those reporting themselves to be in good or excellent health: In short, this study appears to suggest that self-rated poorer health, even among women free from life threatening health conditions, was a predictor of unhappiness at the time of the survey and increased subsequent mortality. But self-reported (un)happiness itself was not an independent predictor of mortality. Another measure of well-being the researchers surveyed, and found not to be independently associated with reduced subsequent mortality was whether the women reported feeling "in control, relaxed, or not stressed". So it looks like from this study being happy and stress-free makes one's life more pleasant, but not any longer. --Dean ---------- [1] The Lancet 09 December 2015 http://dx.doi.org/10.1016/S0140-6736(15)01087-9 Does happiness itself directly affect mortality? The prospective UK Million Women Study Bette Liu, Sarah Floud, Kirstin Pirie, Prof Jane Green, Prof Richard Peto, Prof Valerie Beral Free full text: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01087-9/fulltext Summary Background Poor health can cause unhappiness and poor health increases mortality. Previous reports of reduced mortality associated with happiness could be due to the increased mortality of people who are unhappy because of their poor health. Also, unhappiness might be associated with lifestyle factors that can affect mortality. We aimed to establish whether, after allowing for the poor health and lifestyle of people who are unhappy, any robust evidence remains that happiness or related subjective measures of wellbeing directly reduce mortality. Methods The Million Women Study is a prospective study of UK women recruited between 1996 and 2001 and followed electronically for cause-specific mortality. 3 years after recruitment, the baseline questionnaire for the present report asked women to self-rate their health, happiness, stress, feelings of control, and whether they felt relaxed. The main analyses were of mortality before Jan 1, 2012, from all causes, from ischaemic heart disease, and from cancer in women who did not have heart disease, stroke, chronic obstructive lung disease, or cancer at the time they answered this baseline questionnaire. We used Cox regression, adjusted for baseline self-rated health and lifestyle factors, to calculate mortality rate ratios (RRs) comparing mortality in women who reported being unhappy (ie, happy sometimes, rarely, or never) with those who reported being happy most of the time. Findings Of 719 671 women in the main analyses (median age 59 years [iQR 55–63]), 39% (282 619) reported being happy most of the time, 44% (315 874) usually happy, and 17% (121 178) unhappy. During 10 years (SD 2) follow-up, 4% (31 531) of participants died. Self-rated poor health at baseline was strongly associated with unhappiness. But after adjustment for self-rated health, treatment for hypertension, diabetes, asthma, arthritis, depression, or anxiety, and several sociodemographic and lifestyle factors (including smoking, deprivation, and body-mass index), unhappiness was not associated with mortality from all causes (adjusted RR for unhappy vs happy most of the time 0·98, 95% CI 0·94–1·01), from ischaemic heart disease (0·97, 0·87–1·10), or from cancer (0·98, 0·93–1·02). Findings were similarly null for related measures such as stress or lack of control. Interpretation In middle-aged women, poor health can cause unhappiness. After allowing for this association and adjusting for potential confounders, happiness and related measures of wellbeing do not appear to have any direct effect on mortality. PMID: 26684609
  14. Al Pater posted this older paper [1] that I don't believe has been discussed here before - perhaps on the email list, but unfortunately those archives aren't available... It has the pessimistic title: "Why dietary restriction substantially increases longevity in animal models but won't in humans". In it, the authors develop a simple (simplistic?) linear model of the impact of calorie restriction on rodent longevity - as long as calories remain above a certain minimum needed for survival, their model say a given percentage decrease in calories will result in the same percentage increase in lifespan. They use rodent CR data from a range of experiments to create this model, and claim their model fits the data pretty well - which isn't too surprising. Although recent data and analysis discussed here, suggests that in rodents (and primates) that a disproportionate fraction of CR longevity benefits may be achieved via modest (e.g. 10%) restriction, suggesting such a linear model of benefits may not be appropriate. Then they try to apply the same model to humans, by fitting a linear model to three different populations of Japanese people whose calorie intake and lifespan information we know - long-lived male Okinawans who eat ~1900kcal/day, medium-lived average Japanese men who eat 2300kcal/day, and short-lived Sumo wrestlers who eat 5500kcal/day. By their best estimate, fitting a line between the Sumo wrestlers and the normal japanese men, they come up with a very modest, 7% (or 5 year) lifespan extension for lifelong, maximal CR (which they estimated to be 1500kcal/day) relative to lifespan eating a normal diet of 2300 kcal/day. They argue that the reason rodents see such a large benefit (up to 64% life extension) from CR while humans will likely enjoy such a small benefit is because of the different fractions of energy the two species devote to reproduction. In short, relative to "normal" fecund & well-fed rodents, CRed rodents can tolerate a crushing 66% CR (yes - only 33% of "normal" calorie intake), because of all the energy they can save by not 'wasting' energy on reproductive functions. In contrast, humans devote a much smaller fraction of our energy budget to reproduction, and so can tolerate a much smaller degree of CR than rodents. Not to mention we have free access to food and the rodents can only eat what the cruel researchers put in their cages - one rodent per cage to avoid cannibalism... They go on to editorialize about the relatively futility of human CR, saying: Caloric restriction is likely to be almost universal in its beneficial effects on longevity. This does not, however, warrant an expectation that there will be a quantitative equivalence between DR in humans and DR in rodents. Instead, if our quantitative analysis is to be taken at face value, the quantitative benefit to humans from caloric restriction is going to be small, even if human subjects restrict their caloric intake substantially and over long periods of time... To undergo decades of CR, suffering chronically reduced fertility and increased hunger, for the sake of a much smaller proportionate increase in longevity than is seen in rodents seems unappealing and ill-advised. Our conclusion is that it is reasonably prudent assuming that caloric restriction is unlikely to be a panacea for human aging. Boy they are Debbie Downers aren't they... --Dean ------------- [1] Ageing Res Rev. 2005 Aug;4(3):339-50. Why dietary restriction substantially increases longevity in animal models but won't in humans. Phelan JP(1), Rose MR. Author information: (1)Life Sciences Core Curriculum Program, UCLA, Los Angeles, CA 90095-1606, USA. jay@ucla.edu Full text: http://roselab.bio.uci.edu/Publications/75%20Phelan%20Rose%202005.pdf Caloric restriction (CR) extends maximum longevity and slows aging in mice, rats, and numerous non-mammalian taxa. The apparent generality of the longevity-increasing effects of CR has prompted speculation that similar results could be obtained in humans. Longevity, however, is not a trait that exists in a vacuum; it evolves as part of a life history and the physiological mechanisms that determine longevity are undoubtedly complex. Longevity is intertwined with reproduction and there is a cost to reproduction. The impact of this cost on longevity can be age-independent or age-dependent. Given the complexity of the physiology underlying reproductive costs and other mechanisms affecting life history, it is difficult to construct a simple model for the relationship between the particulars of the physiology involved and patterns of mortality. Consequently, we develop a hypothesis-neutral model describing the relationship between diet and longevity. Applying this general model to the special case of human longevity and diet indicates that the benefits of caloric restriction in humans would be quantitatively small. PMID: 16046282
  15. Dean Pomerleau

    Telomeres, Diet & Longevity

    It's not clear whether telomere shortening is a cause or a side-effect of aging, and Aubrey de Grey is concerned that direct manipulation of telomeres to make them longer (i.e. via increased expression of the telomerase enzyme) is likely to be a bad idea due to concern about allowing cancer cells to replicate more readily. But longer leukocyte telomeres do seem to be associated with longevity: study [2] found that centenarians have leukocyte telomeres as long as people who are much younger than themselves (and therefore unlikely from a statistical perspective to make it to 100), and the offspring of centenarians have longer telomeres than age and gender matched offspring of parents who died at a "normal" age. So having longer telomeres might be a sign of healthy aging (I can hear Michael Rae revving up his engines now :)). With this in mind this new study [1] (provided to me by Al Pater - thanks Al !), found that components of a person's diet was predictive of their telomere length 10 years later. From the abstract: The first factor labeled 'prudent dietary pattern' was characterized by high intake of whole grains, seafood, legumes, vegetables and seaweed, whereas the second factor labeled 'Western dietary pattern' was characterized by high intake of refined grain, red meat or processed meat and sweetened carbonated beverages. In a multiple linear regression model adjusted for age, sex, body mass index and other potential confounding variables [including from the full text - income status, smoking status, alcohol consumption status, physical activity and calorie intake, and presence of hypertension, diabetes mellitus or hypercholesterolemia], the prudent dietary pattern was positively associated with [leukocyte telomere length - LTL]. In the analysis of particular food items, higher consumption of legumes, nuts, seaweed, fruits and dairy products and lower consumption of red meat or processed meat and sweetened carbonated beverages were associated with longer LTL. So for what is may be worth (he says, expecting to be corrected and chastised by Michael :) for oversimplifying and ignoring important evidence...), eating what is considered by most to be a healthy diet may help to preserve your telomeres, and improve your chances of healthy aging. --Dean ----------- [1] Eur J Clin Nutr. 2015 Sep;69(9):1048-52. doi: 10.1038/ejcn.2015.58. Epub 2015 Apr 15. Association between dietary patterns in the remote past and telomere length. Lee JY(1), Jun NR(1), Yoon D(2), Shin C(2,)(3), Baik I(1). BACKGROUND/OBJECTIVES: There are limited data on the association between dietary information and leukocyte telomere length (LTL), which is considered an indicator of biological aging. In this study, we aimed at determining the association between dietary patterns or consumption of specific foods and LTL in Korean adults. SUBJECT/METHODS: A total of 1958 middle-aged and older Korean adults from a population-based cohort were included in the study. Dietary data were collected from a semi-quantitative food frequency questionnaire at baseline (June 2001 to January 2003). LTL was assessed using real-time PCR during the 10-year follow-up period (February 2011 to November 2012). RESULTS: We identified two major factors and generated factor scores using factor analysis. The first factor labeled 'prudent dietary pattern' was characterized by high intake of whole grains, seafood, legumes, vegetables and seaweed, whereas the second factor labeled 'Western dietary pattern' was characterized by high intake of refined grain, red meat or processed meat and sweetened carbonated beverages. In a multiple linear regression model adjusted for age, sex, body mass index and other potential confounding variables, the prudent dietary pattern was positively associated with LTL. In the analysis of particular food items, higher consumption of legumes, nuts, seaweed, fruits and dairy products and lower consumption of red meat or processed meat and sweetened carbonated beverages were associated with longer LTL. CONCLUSIONS: Our findings suggest that diet in the remote past, that is, 10 years earlier, may affect the degree of biological aging in middle-aged and older adults. PMID: 25872911 -------------------------- [2] Exp Gerontol. 2014 Oct;58:90-5. doi: 10.1016/j.exger.2014.06.018. Epub 2014 Jun 27. Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring. Tedone E(1), Arosio B(2), Gussago C(3), Casati M(4), Ferri E(3), Ogliari G(3), Ronchetti F(3), Porta A(3), Massariello F(3), Nicolini P(4), Mari D(2). Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age. PMID: 24975295
  16. All, Here is a short video (1:30) and a longer one (13min) profiling a Ellsworth Wareham, 100-year vegan man who appears to be still going strong, both physically and mentally. He was a heart surgeon who didn't retire until 95. He is (not surprisingly) one of those long-lived, clean-living Seventh Day Adventists from Loma Linda California. He attributes his longevity to his low-fat vegan diet (which he adopted ~50 years ago) and his ability to avoid stress. His total cholesterol is 117, which he says makes him very unlikely to develop heart disease. He now sees it as his mission to educate people about preventative medicine. Here is his wikipedia page for more information. He is quite an inspiration and the kind of person I think CR practitioners should aspire too! --Dean