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  1. https://www.youtube.com/watch?v=9nuoKbMNCbo&lc=Ugz6FWkNk7mMWATxO9x4AaABAg Papers referenced in the video: Sirtuins, Healthspan, and Longevity in Mammals https://www.sciencedirect.com/science... Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH https://pubmed.ncbi.nlm.nih.gov/24011... Resveratrol improves health and survival of mice on a high-calorie diet https://pubmed.ncbi.nlm.nih.gov/17086... Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice https://pubmed.ncbi.nlm.nih.gov/20974... Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer https://www.nature.com/articles/ncomm... Restoration of energy homeostasis by SIRT6 extends healthy lifespan https://pubmed.ncbi.nlm.nih.gov/34050... The sirtuin SIRT6 regulates lifespan in male mice https://pubmed.ncbi.nlm.nih.gov/22367... SIRT6 in Senescence and Aging-Related Cardiovascular Diseases https://pubmed.ncbi.nlm.nih.gov/33855... Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling https://pubmed.ncbi.nlm.nih.gov/26940... Ergothioneine oxidation in the protection against high-glucose induced endothelial senescence: Involvement of SIRT1 and SIRT6 https://pubmed.ncbi.nlm.nih.gov/27101... A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer’s Disease, Aging, Cancer, Inflammation, and Diabetes https://pubmed.ncbi.nlm.nih.gov/33920... Acute Exercise Leads to Regulation of Telomere Associated Genes and MicroR A Expression in Immune Cells https://pubmed.ncbi.nlm.nih.gov/24752... The effect of 12-week resistance exercise training on serum levels of cellular aging process parameters in elderly men https://pubmed.ncbi.nlm.nih.gov/32919...
  2. Dear colleagues, This Spring, as always, there was the annual Conference on Aging at UR. The keynote speaker was Matt Kaeberlein, of the University of Washington. I was particularly interested in attending his talk -- Prof. Kaeberlein spoke at one of the previous CR Society Conferences that I had attended. Matt's talk both surprised and interested me. Matt did not discuss Calorie Restriction -- but he did discuss studies involving the use of rapomycin as an anti-aging drug. He made the point that the side-effects of rapomycin that have been identified are minor (rapomycin is often used as a drug with transplant patients to reduce the likelihood of organ rejection, due to a lowering of the immune response). Dr. Kaeberlein pointed out that studies had not been done on healthy humans; he clearly would support that, but of course the FDA would not approve of such a study without extensive animal studies first. As we know, studies on fruit flies and rodents have shown both (average) lifespan and (possibly more important) healthspan increases. Dr. Kaeberlein has received approval for a study on large pet dogs. (Small dogs live on average much longer than large dogs, which have comparatively short lifespans.) Owners of large pet dogs can voluntarily enter the study -- some dogs will receive rapomycin, some a placebo. Since pet dogs are cared for by their owners, the cost of the study is greatly reduced from what a comparable study might cost if the dogs were in cages on site. After the talk, I asked Dr. Kaeberlein if he believed that CRON and taking rapomycin might work together synergystically. He told me that there were overlaps in the effects of both anti-aging procedures, but they were not identical. As to whether they would work well together, he answered truthfully that he had no idea -- he said that it would be impossible to get grant money to support such a study. I asked Dr. Kaeberlein if he still was on CR. He isn't; he said that he never had been. He "likes his food". 😋 -- Saul
  3. Just curious what thoughts are regarding cordyceps, and particularly this study showing it increases lifespan in normal mice. This study was done by NuSkin who sells a cordyceps product, so obviously questionable, but there are many other studies on cordyceps showing that it has purported anti-aging and longevity promoting effects. The lifespan-extending effect of Cordyceps sinensis Cs-4 in normal mice and its molecular mechanisms "All control mice died before 3 yrs of age while Cs-4 extended lifespan by10-66 days at 50% survival and 45-153 days at 10% survival. The age of the oldest surviving mice was extended 152 days (1.5 g/kg) and >210 days (both 0.5 and 1.0 g Cs- 4/kg BW)... The maximal lifespan (the average of the longest 10% lifespan) of mice was extended with C. sinensis CS-4 at doses of 0.5 g/kg (p<0.001) and 1.5 g/kg (p=0.047), respectively."
  4. All, This NY Times article describes a new and disturbing study which found a growing disparity between the lifespans of rich people and poor people in the US. Here are a couple of the highlights (or lowlights): In the early 1970s, a 60-year-old man in the top half of the earnings ladder could expect to live 1.2 years longer than a man of the same age in the bottom half, according to an analysis by the Social Security Administration. Fast-forward to 2001, and he could expect to live 5.8 years longer than his poorer counterpart. New research released on Friday contains even more jarring numbers. Looking at the extreme ends of the income spectrum, economists at the Brookings Institution found that for men born in 1920, there was a six-year difference in life expectancy between the top 10 percent of earners and the bottom 10 percent. For men born in 1950, that difference had more than doubled, to 14 years. For women, the gap grew to 13 years, from 4.7 years. ... Overall, according to the Brookings study, life expectancy for the bottom 10 percent of wage earners improved by just 3 percent for men born in 1950 compared with those born in 1920. For the top 10 percent, though, it jumped by about 28 percent. (The researchers used a common measure — life expectancy at age 50, and included data from 1984 to 2012.) Here is the graph of life expectancy of 50 year-olds with different incomes has changed over the last 40 years: The data for poor women is particularly shocking - look how expected lifespan of the poorest women at age 50 has been declining steadily since the 1970s, while its been rising for the riches women. The researchers attribute some of the discrepancy to different rates of smoking and obesity between the rich and the poor. They say it is unclear how much of the disparity is attributable to the difference in access to cutting-edge healthcare between the rich and the poor, and therefore whether the Affordable Care Act with do much to close the widening gap. Overall it makes me doubt Aubrey de Grey's optimistic prediction that economic inequality won't hamper everyone benefiting from true life extension therapies when they become available, because he says it will be in everyone's interest to make it available to all. Aubrey says the longevity dividend will be so great that it would be "economic suicide" for a country not to make these technologies available to everyone for free. Here are Aubrey's exact words from the transcript (pdf) of the recent Intelligence2 debate on the topic "Are Lifespans Long Enough?" which we're discussing in this thread: In other words, the absence of these therapies is expensive. 90 percent or thereabouts of the medical budget of the Western world, including medical research but also medical budget, is spent on the ill health of old age in one way or another, not to mention of course all of the indirect costs, the fact that people are not contributing wealth to society anymore because they're no longer able bodied, the fact that their kids are not so productive because they're having to look after their sick parents, all those things add up to the fact that it would be economically suicidal for any country, even a tax averse country like the U.S.A., not to make sure that these therapies are available to everybody who is old enough to need them. It's going to be like basic education. It's going to be free. I think Aubrey is being a bit hyperbolic here, and exaggerating the degree to which people of the US will support large-scale redistributions of wealth (or expensive treatment), regardless of how rational such a policy might be or seem... --Dean
  5. Over on this thread, Rodney wrote: Have you decided whether or not to actually calorie restrict Paloma? I restrict my dog Zoe, and that's one reason I suspect she is always scrounging for food as well. Specifically, I limit her food to 80g/day, about 10% below the 90g/day recommended on the package for active dogs her size (11lbs) - she gets a lot of exercise for a small dog since she runs around while my wife and I walk her > 3 miles per day, which is long way for a small dog. From the dog food package, that amount of dog food equates to about 28 kcal / lb of bodyweight per day. If scaled to a 115lbs person like me - that would be about 3200 kcal/day, which is quite close to what I eat, when you factor in metabolizable energy! Interestingly, this 28kcal / lb BW per day is exactly the same amount of food fed to the control group of Labradors in the dog CR studies [1][2] that Al posted about recently, conducted by the Ralston Purina company about a decade ago. Unfortunately, the poor Labs were likely pretty sedentary, kept in cages their entire lives, without opportunity to take walks . From [1]: Dogs were housed in 2 X 19-m indoor-outdoor kennel runs with concrete floors for 8 years. The amount of exercise the dogs received was not controlled. According to the package on our dog food, relatively sedentary dogs should get only 66% as many calories as active dogs (e.g. 60g/day instead of 90g/day for a dog Zoe's size, or 18.66 kcal / lb BW per day). Plus, to make things even worse for the poor caged & sedentary Labs, the control dogs were fed ad lib from weaning until age 3.25 years - over 1/4 of their entire lifespan. Labs are fully grown and are supposed to have reached their adult weight by 2 years old, so the control dogs were fed ad lib until well into adulthood. In contrast, each CR dog was paired with one of the control dogs (of the same gender - 2/3rd were female), and fed 25% less than their pair-mate from weaning until death, so 25% less than ad lib for the first 3.25 years, and 21 kcal / lb BW per day - which is still above the 18.66kcal/lb BW recommended for sedentary dogs! The fact that they were fed ad lib until well past maturity, and likely had a sedentary lifestyle and so were overfed throughout their life by usual dog calorie recommendations, is reflected in the control dogs' weight. They don't have the weight trajectory data for the dogs, but by the 8th year the control dogs weighed an average of 74 lbs, which is 40% more than the CR dogs, who weighed 53 lbs on average. From here, the healthy weight range for female Labs (since these were mostly females) is 55-70 lbs. I'm not sure what the definition of obesity would be for relatively sedentary Labradors, but the control dogs were above the healthy weight range, and the CR dogs were right around the bottom end of the healthy range. So the control group might be the equivalent of about a human BMI of 26-27 (overweight but not quite obese) and the CR group would be around a human BMI equivalent of 18-18.5, right around many CR practitioners. Rapid growth and too much weight is bad news for dogs (and for people), but especially for Labs, because they are prone to cancer and especially joint problems / osteoarthritis, which is exacerbated by too much food and/or too much weight. So what were the lifespan results? From [2], the CR dogs lived 17% longer on average compared to the control dogs (13 vs. 11.1 years mean lifespan). The longest lived dog was a CR female, who died at 14.5 years, which was 9% longer than the longest lived control dog, another female who lived to 13.29. So not a whole lot of difference in max lifespan. While not in the original paper [1], I've created a graph of the survival curves for the two groups of dogs from Table 1 in the full text (yes - call me crazy). Here it is: Given how few dogs there were in each group (only 24), those survival curves are amazingly smooth and well-behaved! They also bear a striking resemblance to the AL and 10% CR groups of rats in PMID 26695614 that I discussed here two days ago, the survival graph from which I've reproduced below: If you ignore the CR40 survival curve, the two remaining rat survival curves (AL and CR10) look a whole lot like those of the two dog groups. Recall in that study, the median survival of the CR10 rats was 14% longer, and the median survival of the CR40 rats was 19% longer than AL-fed controls. In the dogs, the CR25 survival advantage was 17% relative to controls, right in the middle. Amazingly consistent! Given the striking similarity between the dog and the rat data, it would seem reasonable to extrapolate the dog data to predict that if there had been a CR10 group of dogs, they would have enjoyed a small bit less life extension relative to the CR25 dogs (e.g.. ~14% median life extension vs. 17% for CR25), and if there had been a CR40 group of dogs, they might have enjoyed a small bit more life extension relative to the CR25 dogs (e.g. ~19% vs. 17% median life extension for CR25). Put another way - the control dogs in this study were fed too much, given their caged lifestyle, so they grew fat. The CR dogs were fed an amount commensurate (or a bit higher) than is recommended by dog nutrition experts, remained slim and lived 17% longer than controls, enjoying nearly as much CR longevity benefit as can be hoped for in mammals, based on the rat data from PMID 26695614 discussed here. Bottom line? It appears from the rat, dog and primate CR data, that most of the CR benefits for the average animal come from avoiding overweight/obesity. Severe CR appears to provide seriously diminishing (perhaps negligible) marginal returns in terms of median lifespan, and may come at the cost of increased early mortality (based on the aforementioned rat data), and IMO probably not worth the risk given the disappointing 9% max lifespan advantage seen in the CR25 dogs relative to overweight controls. So my plan for myself and Zoe is to remain very active and eat only enough to stay quite slim. That way we both may be able to garner some CR benefits, and perhaps I at least can remain in good health long enough to be around for the arrival of longevity escape velocity, hopefully in several decades if we're lucky. Zoe is 5 years old. While her breed (Havanese) is long-lived for dogs (typically 13-15 years), she is unlikely to be around long enough to live forever. Perhaps I'll clone her or cryopreserve her, if either technology improves and comes down in price quickly enough. --Dean ----------- [1] J Am Vet Med Assoc. 2000 Dec 1;217(11):1678-80. Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. Kealy RD(1), Lawler DF, Ballam JM, Lust G, Biery DN, Smith GK, Mantz SL. Author information: (1)Pet Nutrition Research Department, Ralston Purina Company, St Louis, MO 63164, USA. Free full text: https://www.avma.org/News/Journals/Collections/Documents/javma_217_11_1678.pdf OBJECTIVE: To determine prevalence of radiographic evidence of osteoarthritis in 4 diarthrodial joints of dogs with restricted feed intake, compared with dogs without restricted feed intake. DESIGN: Paired feeding study. ANIMALS: 48 Labrador Retrievers. PROCEDURE: Dogs in litters from 7 dams and 2 sires were paired by sex and weight within litters and randomly assigned to a control-fed group or a limit-fed group that received 25% less food than the control-fed group. Radiographic evaluation of prevalence and severity of osteoarthritis in the hip, shoulder, elbow, and stifle joints was performed when dogs were 8 years of age. RESULTS: Radiographic evidence of osteoarthritis that affected multiple joints was significantly more common in the control-fed group than in the limit-fed group. Prevalence of lesions in the hip joint was 15/22 in the control-fed group and 3/21 in the limit-fed group. Prevalence of lesions in the shoulder joint was 19/22 in the control-fed group and 12/21 in the limit-fed group; lesions in this joint were generally mild. Severity, but not prevalence, of osteoarthritis in the elbow joint was greater in the control-fed group than in the limit-fed group. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence and severity of osteoarthritis in several joints was less in dogs with long-term reduced food intake, compared with control dogs. Food intake is an environmental factor that may have a profound effect on development of osteoarthritis in dogs. PMID: 11110459 -------------- [2] J Am Vet Med Assoc. 2005 Jan 15;226(2):225-31. Influence of lifetime food restriction on causes, time, and predictors of death in dogs. Lawler DF(1), Evans RH, Larson BT, Spitznagel EL, Ellersieck MR, Kealy RD. Author information: (1)Néstle Purina PetCare Research, 835 S 8th St, St Louis, MO 63164, USA. Free full text: https://www.avma.org/News/Journals/Collections/Documents/javma_226_2_225.pdf OBJECTIVE: To describe effects of lifetime food restriction on causes of death and the association between body-mass characteristics and time of death in dogs. DESIGN: Paired-feeding study. ANIMALS: 48 dogs from 7 litters. PROCEDURES: Dogs were paired, and 1 dog in each pair was fed 25% less food than its pair mate from 8 weeks of age until death. Numerous morphometric and physiologic measures were obtained at various intervals throughout life. Associations of feeding group to time and causes of death were evaluated, along with important associated factors such as body composition components and insulin-glucose responses. RESULTS: Median life span was significantly longer for the group that was fed 25% less food, whereas causes of death were generally similar between the 2 feeding groups. High body-fat mass and declining lean mass significantly predicted death 1 year prior to death, and lean body composition was associated with metabolic responses that appeared to be integrally involved in health and longevity. CONCLUSIONS AND CLINICAL RELEVANCE: Results were similar to results of diet restriction studies in rodents and primates, reflecting delayed death from species- and strain-specific intrinsic causes. Clinicians should be aware that unplanned body mass changes during mid- and later life of dogs may indicate the need for thorough clinical evaluation. PMID: 15706972
  6. 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
  7. Al Pater posted this review article [1] from way back in 2002 on the question of whether or not worldwide life expectancy is really beginning to level off, or is marching higher at the same 1/4 of a year per year rate that it has for the last 150 years. Here are two graphs from the paper, the first showing how striking and consistent the trend towards a higher lifespan has been, and how virtually everyone predicts it is going to level off (dashed red lines at the top): The authors postulate that the impression people have that lifespan is constantly on the verge of plateauing is an illusion with a few different causes. One interesting one is political. Politicians tend to low-ball when it comes to estimating future gains in life expectancy to make the cost of social programs, particularly those directly at the elderly like social security, medicare, look less costly and burdensome on the future. More interestingly, and with more evidence it would seem, they suggest the apparent leveling off in life expectancy gains is a result of the fact that the leading nation in life expectancy improvements keeps changing, with some countries (like the US) falling off the cutting edge, while other countries, like Japan, pick up the torch and push life expectancy higher at the same old rate of 1/4 of a year per year. So for the citizen in most countries, they fact is that lie expectancy improvements have levelled off. They give as evidence for this effect this graph: As you can see, Japan comes up after WWII to overtake the rest of the world in life expectancy, and keep us on the linear curve of life expectancy increases. Here are the authors' three rather bold assertions in the concluding paragraph of the paper: This mortality research has exposed the empirical misconceptions and specious theories that underlie the pernicious belief that the expectation of life cannot rise much further. Nonetheless, faith in proximate longevity limits endures, sustained by ex cathedra pronouncement and mutual citation (1, 8, 9). In this article we add three further lines of cogent evidence. First, experts have repeatedly asserted that life expectancy is approaching a ceiling: these experts have repeatedly been proven wrong. Second, the apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind. Third, if life expectancy were close to a maximum, then the increase in the record expectation of life should be slowing. It is not. For 160 years, best-performance life expectancy has steadily increased by a quarter of a year per year, an extraordinary constancy of human achievement. As I said - bold words. So that was in 2002. It's been almost a decade and a half since the paper was written. Have gains in life expectancy continued their "steadily increased by a quarter of a year per year" that the authors observe happening for the last 160 years? Nope - Not quite at least. Japan remains #1, and here is a graph of Japanese life expectancy that includes the period between 2002 through 2014: The paper reports in 2002 the life expectancy of a Japanese female was "almost 85 years", and in 2014 it was almost 87 years. So that is a life expectancy increase of 2 years in 12 years, or one sixth of a year per year, rather than the quarter of a year per year trend the authors point to. That equates to an average yearly shortfall in lifespan gains of 33% relative to the authors' prediction. Of course, this may be just a short-term deviation away from the long-term trend. Perhaps new advances in treatments or therapies for the diseases of aging (e.g. stem cell therapy, CRISPR-based gene therapy) will come along and keep us on the curve. It reminds me of the supposedly inexorable Moore's Law that futurist and immortality-optimist Ray Kurzweil likes to point to, namely that computer power (actually transistor count) doubles every two years, like clockwork, and has been for at least the last 40-50 years, and much longer than that if you ask Kurzweil. Unfortunately, I looks like we're falling off that curve too, according to this recent article in Nature (Feb '16): Next month, the worldwide semiconductor industry will formally acknowledge what has become increasingly obvious to everyone involved: Moore's law, the principle that has powered the information-technology revolution since the 1960s, is nearing its end. Similarly, at this point we seem to be slowing down rather than speeding up increases in life expectancy which would move us toward longevity escape velocity, where life expectancy increases by (at least) one year per year. --Dean ---------- [1] Science. 2002 May 10;296(5570):1029-31. No abstract available. Demography. Broken limits to life expectancy. Oeppen J, Vaupel JW. Free Full text: http://www.econ.ku.dk/okocg/VV/VV-Economic%20Growth/articles/artikler-2006/Broken-limits-to-life-expectancy.pdf Summary Is human life expectancy approaching its limit? Many--including individuals planning their retirement and officials responsible for health and social policy--believe it is, but the evidence presented in the Policy Forum suggests otherwise. For 160 years, best-performance life expectancy has steadily increased by a quarter of a year per year, an extraordinary constancy of human achievement. Mortality experts have repeatedly asserted that life expectancy is close to an ultimate ceiling; these experts have repeatedly been proven wrong. The apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind. PMID: 12004104
  8. Hi, everyone, reading some recent books and papers I've gathered some clues that not caloric restriction in general but the blood sugar control/insulin control might be the major cornerstone for longevity - so I wonder if low-carb, low-glycemic (but fructose-limited) oder even low-carb high-fat (good fats like Omega-3 rich plant oils) diets could give the same fine results like caloric restriction. Is there any recent reseach available focussing this issue? Any ideas/hints or publications are much appreciated! Thanks! Max