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I'm doing a lot of reading on sarcopenia and other muscle-related topics lately. I'm 65, which is the threshold of the steep decline in muscle mass, so I've developed an almost unhealthy interest in the topic. As part of my reading I've begun Bruce Grierson's book What Makes Olga Run? Olga Kotelko died at 95 a couple of years ago (of a cerebral hemorrhage), but up until her last year of life she was involved in track and field competitions. The notable thing is that she maintained a great deal of her muscle mass into her 90s. I remember reading a few years ago that researchers at McGill University were running tests on her to try to determine why sarcopenia largely spared her. Kotelko herself expressed as much curiosity as anyone else about why her muscle mass and athletic performance declined so little, but guessed that it was a combination of genetics and continued activity.
Here is a new 20min video interview of Aubrey de Grey on Youtube in which he covers some interesting topics, including: The self-experimentation Liz Parrish from Bioviva has done to modify expression of genes telomerase & for preventing sarcopenia. Aubrey says there some evidence these modifications could be beneficial. But both have their potential downsides as well (e.g. cancer for telomerase). He admires Parrish for her boldness, and for bringing the possibility of genetic manipulation in humans for health / longevity to the public debate. But he worries that it will be very difficult to identify any measureable benefits that might result from these interventions, since Parrish is young and healthy The newly FDA-approved study of metaformin as a potential anti-aging drug. He is skeptical of CR mimetics like metaformin, due to his skepticism that CR will have much longevity benefit in long-lived species. He applauds the effort to study aging as a disease that can be treated, as this study attempts. CRISPR-cas9 gene editing technology He sees lots of potential for this technology to facilitate the kind of health / longevity interventions his SENS Foundation is investigating He doesn't see a lot of benefits/advantages (yet) for using the other recently publicized DNA technology, DNA_Origami, for drug delivery relative to other drug delivery methods. --Dean
[Note: This is another post that would fit best on a "Non-CR health science" forum. I'm posting it here on "CR Practice" because it has to do with a concern of people practicing CR.] Excessive muscle loss and wasting (sarcopenia) is a concern as people age, and since CRers weigh less, they also (generally) have less muscle mass to lose as they age, so it is a potential issue for us too. This new study , described in this popular press article, provides new understanding of this problem. It describes research identifying a protein (ATF4) that appears to be causally related to muscle wasting. Here is the main points of the research, summarized in the article: The protein, ATF4, is a transcription factor that alters gene expression in skeletal muscle, causing reduction of muscle protein synthesis, strength, and mass. The UI study also identifies two natural compounds, one found in apples and one found in green tomatoes, which reduce ATF4 activity in aged skeletal muscle. The findings, which were published online Sept. 3 in the Journal of Biological Chemistry, could lead to new therapies for age-related muscle weakness and atrophy. Previously, Adams and his team had identified ursolic acid, which is found in apple peel, and tomatidine, which comes from green tomatoes, as small molecules that can prevent acute muscle wasting caused by starvation and inactivity. An example of the previous work by these authors that identified ursolic acid and tomatidine as protective against muscle wasting is this publication . The possible downside of these compounds is that they appear to have their effect by "enhancing skeletal muscle insulin/IGF-I signaling", which CR is known to downregulate, an effect which may very well be important for CR's health/longevity benefits. In the meantime, I'm going to continue exercising, eating apple peels and tomatoes (although usually red rather than green), to hopefully maintain skeletal muscle mass and health. --Dean ------------  J Biol Chem. 2015 Sep 3. pii: jbc.M115.681445. [Epub ahead of print] Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Ebert SM(1), Dyle MC(1), Bullard SA(1), Dierdorff JM(1), Murry DJ(1), Fox DK(1), Bongers KS(1), Lira VA(1), Meyerholz DK(1), Talley JJ(2), Adams CM(3). Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy, as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs are repressed by ursolic acid and tomatidine in aged muscle are positively regulated by the transcription factor ATF4. Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. Copyright © 2015, The American Society for Biochemistry and Molecular Biology. PMID: 26338703 ----------------------------  Cell Metab. 2011 Jun 8;13(6):627-38. doi: 10.1016/j.cmet.2011.03.020. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Kunkel SD(1), Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, Adams CM. Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases. PMCID: PMC3120768 PMID: 21641545
Dean Pomerleau posted a topic in CR PracticeLose of muscle mass (sarcopenia) is a problem that humans other primates and rodents suffer as a result of aging. CR has long been known to attenuate this muscle loss, including in CR primates . But on the other hand, CR animals and humans typically enter old age with less muscle to start with, so excessive muscle loss is still an issue for CR practitioners to be concerned about. This new study  posted by James Cain (thanks James!) found once again that CR prevented sarcopenia in mice, but as usual, the CR mice had less lean mass throughout most of their life. As a result of these competing influences, by the time the mice were quite old (28 months), the amount of muscle in the CR and control animals were similar, as was their strength: Particularly at the age of 28 months, differences in muscle mass between the two intervention groups are relatively small, specifically when compared with the large difference present in body weight at all time points. .... In contrast to mice that have received the control diet, in the caloric-restricted group, no age-related decline in muscle mass was observed, which could be interpreted as protecting against sarcopenia. Absolute muscle masses were approximately similar in both groups at 28 months of age as were grip strength measurements. The CR mice also showed improved insulin sensitivity relative to controls (no surprise). They also had a lot less fat (also not surprising) but what was surprising was that the CR mice had higher bone mineral density at both 14 and 23 months, which is encouraging! Here is the BMD graph: But perhaps the most interesting thing about the study is the author's discussion of why they think muscle mass may have been preserved. They talk about a bunch of biochemical and gene expression differences between aged CR and control mice that might have contributed to reduced sarcopenia in the CR group. But they also focus a lot on the role of activity (e.g. exercise) and its timing relative to eating in preserving muscle mass. As you can see from this graph comparing daily activity of the control and CR animals at 12 months and 23 months, the controls were more active at 12 months than the CR group, but their activity declined precipitously. In contrast, the CR mice maintained, and perhaps even increased their activity between 12 and 23 months. So by 23 months the two groups had about the same level of daily activity: And after 24 months of age, the control mice daily activity fell off a cliff, to the point where the total daily activity of the CR mice greatly exceeded that of the fat, sick control mice. Here is the graph daily activity of old (28 month) control and CR mice compared with young mice: Maintaining a high level of activity likely helped the CR mice maintain their lean muscle mass (and strength) while the controls lost their muscles and strength. So this suggests the ability to remain active into old age as a result of staying lean and healthy on CR can help us maintain muscle mass relative to people eating a crappy, high caloric diet. The authors go on to hypothesize that increased exercise in the old CR group relative to the old controls may not be the only behavioral contributor to muscle preservation. They suggest that timing and intensity of the exercise may play a role as well. As is apparent in this graph of the timing of daily activity in young control, old control, and old CR mice, the old CR mice had a burst of high intensity exercise in the 2 hours prior to feeding, while the other two groups had exercise spread throughout the day (with the old controls having much less activity than the other two groups). The authors suggest that this bout of intense exercise just prior to the bolus of food (protein) given at mealtime may have been especially beneficial for muscle building / maintenance relative to lower intensity exercise spread throughout the day as seen in the control animals. Here is how the authors (rather awkwardly) describe it: Mice on a CR diet have more hunger and therefore show an increased [Food Anticipatory Activity]. This behaviour stays for the rest of their life if CR maintains. This activity is different from normal daily activity in a way that it is more intense: more running and climbing. The animals compensate for the activity [by being less active] during the rest of the day, which might result in a decreased total daily activity. Furthermore, it is hypothesized that the increase in activity just before the meal is provided, increases the insulin sensitivity of the body and assumedly of the muscle. A lower total provided load of carbs and fat due to the CR can further contribute to an improved insulin sensitivity. Next to that triggers the bout of activity an anabolic response of the skeletal muscles involved in this activity. We moreover speculate that the increased insulin sensitivity combined with the activity-induced anabolic response lower the threshold needed for protein synthesis and therefore make maintenance of muscle protein possible. Here is their conclusion: Control animals showed an age-dependent sarcopenia, while caloric-restricted animals showed muscle mass and strength maintenance during lifespan. An adequate amount of protein provided as a bolus, preferably in combination with exercise, is currently recommended for sarcopenic elderly and COPD patients. These recommendations are designed to promote net muscle accretion. Our results indicate that mice on a 70 E% caloric-restriction diet show habitual changes that come close to these recommendations and therefore indicate that CR should be considered as a lifestyle and not simply a diet intervention. In short, these researchers suggest that pre-meal exercise combined with lifelong CR may be especially beneficial for muscle preservation as the body ages. --Dean ------------  J Cachexia Sarcopenia Muscle. 2015 Sep;6(3):253-68. doi: 10.1002/jcsm.12024. Epub 2015 Apr 27. Behavioural changes are a major contributing factor in the reduction of sarcopenia in caloric-restricted ageing mice. van Norren K(1), Rusli F(2), van Dijk M(3), Lute C(2), Nagel J(3), Dijk FJ(3), Dwarkasing J(4), Boekschoten MV(2), Luiking Y(3), Witkamp RF(4), Müller M(2), Steegenga WT(2). BACKGROUND: In rodent models, caloric restriction (CR) with maintenance of adequate micronutrient supply has been reported to increase lifespan and to reduce age-induced muscle loss (sarcopenia) during ageing. In the present study, we further investigated effects of CR on the onset and severity of sarcopenia in ageing male C57BL/6 J mice. The aim of this study was to investigate whether CR induces changes in behaviour of the animals that could contribute to the pronounced health-promoting effects of CR in rodents. In addition, we aimed to investigate in more detail the effects of CR on the onset and severity of sarcopenia. METHODS: The mice received either an ad libitum diet (control) or a diet matching 70 E% of the control diet ©. Daily activity, body composition (dual energy X-ray absorptiometry), grip strength, insulin sensitivity, and general agility and balance were determined at different ages. Mice were killed at 4, 12, 24, and 28 months. Skeletal muscles of the hind limb were dissected, and the muscle extensor digitorum longus muscle was used for force-frequency measurements. The musculus tibialis was used for real-time quantitative PCR analysis. RESULTS: From the age of 12 months, CR animals were nearly half the weight of the control animals, which was mainly related to a lower fat mass. In the control group, the hind limb muscles showed a decline in mass at 24 or 28 months of age, which was not present in the CR group. Moreover, insulin sensitivity (oral glucose tolerance test) was higher in this group and the in vivo and ex vivo grip strength did not differ between the two groups. In the hours before food was provided, CR animals were far more active than control animals, while total daily activity was not increased. Moreover, agility test indicated that CR animals were better climbers and showed more climbing behaviours. CONCLUSIONS: Our study confirms earlier findings that in CR animals less sarcopenia is present. The mice on the CR diet, however, showed specific behavioural changes characterized by higher bursts of activity within a short time frame before consumption of a 70 E% daily meal. We hypothesize that the positive effects of CR on muscle maintenance in rodents are not merely a direct consequence of a lower energy intake but also related to a more active behaviour in a specific time frame. The burst of activity just before immediate start of eating, might lead to a highly effective use of the restricted protein sources available. PMCID: PMC4575557 PMID: 26401472 --------------  J Gerontol A Biol Sci Med Sci. 2008 Jun;63(6):556-9. Attenuation of sarcopenia by dietary restriction in rhesus monkeys. Colman RJ(1), Beasley TM, Allison DB, Weindruch R. Author information: (1)Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1220 Capitol Ct., Madison, WI 53715, USA. email@example.com Sarcopenia, the loss of muscle mass with normal aging, devastates quality of life-and related healthcare expenditures are enormous. The prevention or attenuation of sarcopenia would be an important medical advance. Dietary restriction (DR) is the only dietary intervention that consistently extends median and maximum life span, as well as health span in rodents. Evidence suggests that DR will have a similar effect in primates. Furthermore, DR opposes sarcopenia in rodents. We tested the hypothesis that DR will reduce age-related sarcopenia in a nonhuman primate. Thirty adult male rhesus monkeys, half fed a normal calorie intake and half reduced by 30% in caloric intake, were examined over 17 years for changes in dual-energy X-ray absorptiometry-estimated skeletal muscle mass. Body weight-adjusted skeletal muscle mass declined somewhat in both groups but was far more rapid in the control group. We have shown that moderate, adult-onset DR can attenuate sarcopenia in a nonhuman primate model. PMCID: PMC2812805 PMID: 18559628