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All: Diet quality may play into this, and the fact that the 27.4 ± 2.5 kg/m2 average BMI in the controls includes some significantly overweight people. And it's n-12, and only in the colon, where narrow diet effects might be most strongly observed (note that dietary influences on colorectal and GI cancers are more consistent than other tissues). But it seems pretty good evidence that human CR suppresses SC accumulation rather strongly, consistent with CR's tranlatability.

All, Over on this thread, Cloud did a helpful translation of a talk (in Italian) by everyone's favorite CR researcher, Luigi Fontana. In his talk, Luigi mentions a new paper [1] he and colleagues published this month in the open access journal Cell Reports (full text). It looks at several important biomarkers in some of us from the CR Society (mean BMI 19.2), as compared with endurance athletes (mean BMI 22.4) and normal weight controls (mean BMI 25.2). The CR group has significantly higher cortisol (15.6 ng/dl) than either the athletes (11.2) or the controls (12.3). The authors suggest this could be a good thing, since it may reduce systemic inflammation, and is consistent with elevated corticosteroids in CRed rodents. They didn't report any comparison of inflammation markers directly, but did show that one marker of inflammation, tumor necrosis factor alpha (TNF-a), was inversely correlated with cortisol levels across all subjects. This suggest to me that the change in TNF-a (or other markers of inflammation) probably wasn't significantly different across groups, or they would have reported it directly. Unfortunately, the rest of the paper only compares the CR group with the controls - they apparently didn't perform muscle biopsies on the athletes. Compared with controls, the CR folks had higher levels of stress-related biomarkers, like several heat shock proteins (HSPs), and markers of upregulated autophagy, "involved in cellular protein quality control and removal of dysfunctional proteins and organelles." Here is their conclusion: These CR-induced hormetic responses may play a key role in preserving protein quality control, preventing age-associated proteotoxicity, and increasing the capacity for degrading dysfunctional proteins and organelles, thereby preserving cell functionality and the capacity to adjust to a changing environment. These vital housekeeping homeostatic processes have been shown to protect against age-associated disease and may be involved in slowing the rate of aging in humans. Luigi & co. seem to be big into the health/longevity benefits of hormesis lately, including CR, intermittent fasting, exercise, and keeping abdominal fat low. See this thread for more on Luigi's current perspective, from Cloud's translated highlights from Luigi's recent talk. --Dean ------------- [1] Cell Reports 14, 1–7 January 26, 2016 http://dx.doi.org/10.1016/j.celrep.2015.12.042 Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle Ling Yang,1,11 Danilo Licastro,2,11 Edda Cava,3,4,11 Nicola Veronese,3,5 Francesco Spelta,3,6 Wanda Rizza,3,7 Beatrice Bertozzi,3 Dennis T. Villareal,3,8 Go¨ khan S. Hotamisligil,1 John O. Holloszy,3 and Luigi Fontana Full text: http://www.cell.com/cell-reports/pdf/S2211-1247(15)01483-7.pdf SUMMARY Calorie restriction (CR) retards aging, acts as a hormetic intervention, and increases serum corticosterone and HSP70 expression in rodents. However, less is known regarding the effects of CR on these factors in humans. Serum cortisol and molecular chaperones and autophagic proteins were measured in the skeletal muscle of subjects on CR diets for 3–15 years and in control volunteers. Serum cortisol was higher in the CR group than in age-matched sedentary and endurance athlete groups (15.6 ± 4.6 ng/dl versus 12.3 ± 3.9 ng/dl and 11.2 ± 2.7 ng/dl, respectively; p % 0.001). HSP70, Grp78, beclin-1, and LC3 mRNA and/or protein levels were higher in the skeletal muscle of the CR group compared to controls. Our data indicate that CR in humans is associated with sustained rises in serum cortisol, reduced inflammation, and increases in key molecular chaperones and autophagic mediators involved in cellular protein quality control and removal of dysfunctional proteins and organelles.

The CR Society International is excited to report our collaboration with Dr. Janko Nikolich-Žugich, MD, PhD, for a new study of the effects of CR in humans on markers of immunological aging, compared to a immunological "aging as usual" in a large sample of "normally"-aging humans. Details here!

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