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  1. [Admin Note: This is a series of posts originally on another thread that started on the topic of how cold exposure can have beneficial effects for health and longevity despite increasing calorie expenditure. I debated where to move them, since they seem to fit General Health & Longevity, CR Practice, and CR Science. I finally opted for CR Science, since you'll see if you haven't been reading them already, they bear directly on CR and CR mimetics. If anyone feels strongly this was the wrong choice, I'll be happy to move the thread to another forum. --Dean] Rodney, Whenever I see someone use the word "surely", I figure the writer isn't very sure about, or doesn't have real evidence to support, what they are about to say. I'm guilty of it sometimes myself. People's appetites differ for a lot of reasons, many of them without negative health implications. Genetics is one example that can alter metabolic rate and therefore hunger (remember the ob/ob mice who ate more but didn't live shorter lives). Exercise or exposure to cold (and extra brown fat that cold exposure can create/promote) will increase calorie expenditure without detrimental effects. In fact, perhaps my favorite study of all time (except for the suffering of the animals involved) was the famous "rats with cold feet" study [1] by John Holloszy. Holloszy found that rats who lived their lives standing in a cold puddle of water ate 44% more than normally-housed rats, but nonetheless stayed thin and didn't live any shorter lives than the normally-housed rats. In fact they lived slightly longer and got less cancer. Our friend Josh Mitteldorf did a whole blog post about the hormetic benefits of cold exposure, and how it casts serious doubt (if not debunks) the popular "rate of living" theory of aging. --Dean (who composed this post while pedalling shirtless and wearing just bike shorts on his stationary bike in his 59 degF basement to maximize hormesis... ) -------- [1] J Appl Physiol (1985). 1986 Nov;61(5):1656-60. Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory". Holloszy JO, Smith EK. It has been postulated that increased energy expenditure results in shortened survival. To test this "rate-of-living theory" we examined the effect of raising energy expenditure by means of cold exposure on the longevity of rats. Male 6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water (23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5 days/wk. They were maintained on this program until age 32 mo. The cold exposure resulted in a 44% increase in food intake (P less than 0.001). Despite their greater food intake, the cold-exposed rats' body weights were significantly lower than those of control animals from age 11 to 32 mo. The average age at death of the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the controls. The cold exposure appeared to protect against neoplasia, particularly sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared with 57% for the controls. The results of this study provide no support for the concept that increased energy expenditure decreases longevity. PMID: 3781978 [PubMed - indexed for MEDLINE]
  2. An interesting article in University of Illinois Urbana-Champaign Health News It alleges to show that mice (and people) on the same diet, that exercise, have improvements in their gut microbiota, over sedentary mice (and people). Interestingly, the improvement that comes from exercise is much more pronounced in lean, vs obese, subjects. https://www.mdlinx.com/gastroenterology/top-medical-news/article/2017/12/06/7496068/?utm_source=in-house&utm_medium=message&utm_campaign=epick-gastro-dec07 Note: The article was brought to my attention by my wife, who is a Nurse Practitioner specialized in gastroenterology. (Unlike most of her colleagues, she tries to get her patients to improve their diet, with more fruits and vegetables. -- Saul
  3. All, I've been engaged in an off-forum Q&A dialog with a CR friend, and I figured some of you other crazies might appreciate reading about (and hopefully commenting on / criticizing) some of the details of my current diet & exercise regime, as well as tips & my motivation for them. If not, feel free it skip this post! I've only included my sided conversation, but I think from my answers it is pretty clear what the questions were. Feel free to ask for clarification on anything that's unclear. Regarding eating once per day. It's very hard, especially when just starting out on this regime, to eat once per day in the afternoon. It takes a lot of willpower. So I recommend, and always try myself, to wait a couple / few hours after waking before I eat, but then eat in the morning rather than waiting until afternoon, and definitely never try to grocery shop on a (very) empty stomach! For large scale chopped veggie storage, I use glass containers because I'm a bit paranoid about leeching from plastics. The glass jar I use is from Anchor Hocking. Turns out it is only 2gal. Here is a link. I believe both Target and Walmart have them as well, although I'm not sure about in-store availability. I chop my "chunky" veggies once per week, and store them in this glass jar, all mixed up, between layers of paper towels to absorb moisture and keep them fresh. I chop my "leafy green" veggies at the same time, throughly spin-dry them using salad spinner, and then store them in another containing between layers of paper towels to preserve freshness. Both go into my fridge, which I temperature control to maintain a very steady 34degF. Vegetable prep takes me just over one hour per week, but after many years I've got it down to an art/science. It used to take me about 2 hours. I find meditation and practices that cultivate mindfulness are helpful for fostering one's self-discipline. Other than that, I don't have much specific advice on that topic. I used to cook for my family when we were 4 rather than 3 . But now that it is just the three of us, and my daughter has an extremely busy schedule, my wife and daughter's eating schedule is pretty irregular. So they cook for themselves. I also found it hard to cook for them. Not because I was particularly tempted by the food I was making for them (although on occasion that too was the case), but more that I was conflicted by the opposing goals of cooking as healthy meals as possible for them, but also meals they would enjoy, and not waste by not eating. When practicing CR for a while, I've found you become extremely averse to wasting anything, but especially food. Plus I'm an ethical vegan. Both kids are (were) vegetarian, and my wife eats mostly vegetarian. But they enjoy quite a bit of dairy, which I had trouble buying/cooking for them for ethical reasons. Regarding exercise, I'll enumerate everything I do in a day, in order: [Get up at 2:45am - yes I'm kind of a early riser ] 4min - straight arm planking 2min - 100 body weight squats 10min - "10 minute abs" workout - Originally from YouTube video of that name, but after doing it several thousand times, I've got it memorized. . Video embedded at bottom. Warning - this will really hurt anyone not used to doing an ab workout, but her accent is strangely compelling... 20min - Jogging on treadmill at 4mph and 15% incline (very steep). 1.07miles, 200 kcal 120min - Stationary road bike. Modest intensity. HR around 95bpm. My Resting HR is about 45bpm. [breakfast - 1.5 hours] 10min - One mile run outdoors. Moderate pace . usually with my dog. 20min - Resistance training. 4day split to work all body parts on successive days, but giving each enough time to recover. Little rest between sets to keep it mildly aerobic. Pretty light weights. Pull-ups, pushups, light squats, triceps extensions, curls, shrugs, etc. All the standard exercises. Using dumbbells and body weight. 4min straight arm planking 2min - 100 body weight squats 2min - Ab Slide machine. Quite a good Ab exerciser 90min - Stationary road bike again. [Time now around 10:30am - Shower & 6min inversion therapy (to decompress spine and stretch back) & 20min power nap] [Puttering around for a while, light food prep, errands etc - 1-2 hours] 10min - One mile run outdoors. With dog. ~240min - pedalling at my bike desk while reading, surfing web, posting to CR forums [Off and on throughout afternoon evening - spend time with wife and daughter, especially when they eat dinner] 30min - brisk walk with my wife (and dog) [8:00pm - bedtime. 8:15 sound asleep] So in total I run for about 40min, do resistance training / calisthenics for about 45min, walk 30-45min, and then pedal for about 7h per day. On an average day, my Fitbit tells me I log about 45K steps (or step equivalents, including bike pedal revolutions), and about 23 miles. All of it at home, by myself (except if you count the mile walk with my wife and jogging with my dog ). I don't enjoy the hassle of working out with others at a gym. I don't seem to need the motivation of having other people around to exercise with. What motivates me to such extreme exercise? Hmmm... A few ideas: I like to eat, and to stay slim. Extreme exercise let's me do both. I'm exploring the possibility of getting CR benefits while eating lots of calories, but burning them off via lots of exercise and cold exposure. It makes me feel good. I like the endorphins, opiates, whatever makes exercise feel good. With my stationary bike and bike desk, I'm able to do other things while pedaling, like composing this message! I like being different from other people. I like pushing myself to extremes, to see what's possible. Pushing the envelope of human possibliity. I think exercising one's abilities and strengths is why we are here, and what makes life meaningful and significant. My biggest strength is probably self-discipline / conscientiousness. Exercising discipline strengthens the will. As Nietzsche said in Twilight of the Idols, "From life's school of war, what does not kill me makes me stronger." He was a big proponent of hormesis before it became fashionable. I hope being very different from others, and sharing my results, will enable people (like you!) to learn from my experiences and experiments, and figure out what might work best for them. Regarding sleep. I sleep for 6.5 hours per day (8:15pm - 2:45am) + a 20min power nap. Lately I've been sleeping like a baby, without my former problem of early waking (unless you count 2:45am as early ). I hope this is helpful. --Dean
  4. Michael R

    CR and Exercise

    I wrote this survey of the literature in the early 200s; there have been a few studies examining the intersection of CR and exercise since then, but none to my knowledge have been lifespan studies, and therefore don't ultimately resolve anything. The findings from existing studies are that: 1. Exercise-induced Caloric deficit (ECD) ALONE does not extend maximum lifespan (LS) (1-10). The majority (1,3-6) of studies find that it increases average LS, but a substantial minority (2,8,9,10) haven't even found this. It improves health, but it does not slow aging. 2. CR alone increases max and average LS (2,5-10). It slows aging, and thus improves health. 2a. CR alone causes a greater increase in average LS than does an equal degree of CD from exercise alone (2,5,6); likewise, albeit less powerfully (because less rigorously), 40% CR ALONE causes a greater increase in average LS than does the large ECD (alone) typical of the AL, voluntary-exercising rat (2). Likewise for alternate-day fasting (EOD] vs voluntary exercise (7,10). The health results of slowing aging (thru' doing CR) are greater than those from exercising. 3. Within the confines of what Steve Austad once called "full-blown, weep-on-your-knees CR" (≥40% CR [the most commonly used in studies on "the effect of CR on parameter X,"]) none of the studies (2,7-10) examining the effect of adding extra CD via ECD at a given absolute caloric intake in CR found further increases max LS. (9), in fact (which was on forced exercise, unlike the voluntary exercise in the other studies), found a decrease in max LS. The above points clearly show that ECD is NOT equivalent to CD from CR. 5. CR + ECD at a given absolute caloric intake yields inconsistent results on average LS relative to that level of CR alone: 2 studies found a benefit ([2,9] — NB this latter still found a shorter max!), another reported a detriment (5), as apparently did (7); (8) found no effect. Now things get tricky! 6. What happens when you put an animal on full-blown CR, and compare it to an animal on LESS CR, but with the difference in CD "topped up" with ECD, such that the total CD is equal to "full-blown, weep-on your knees CR"? This is what (3) tested in comparing groups C and D (both at 44% CD). And, the "responsible" reading is that the two are equivalent. That is, there ARE nominal differences between the two — the CR-only group DID have longer average AND max LS than the combined-CD group — but the differences were statistically insignificant. Likewise with Holloszy's earlier work (5): when a group given full-blown CR (group E, 40% CR) is compared w/a group on mild CR (24%CR) + ECD to bring the total CD down to the same level (as assessed by BW: group D), there there are no statistically significant differences in max or average LS; yet the nominal data favor the CR-only group on both points. The most scientifically respectable conclusion to draw from this (these are AFAIK the only data on this key point) would be that "two nonsignificant differences do not create a significant one." But to see the same patter repeated twice is, to me, "suspicious" -- esp in light of all the other data clearly showing the greater LS results from CR vs ECD. The cohorts having been so small (n=30 (D) & 44 (E) in (5), & 31 © & 65 (D) in (3)), it's easy to see a significant difference being masked by sheer lack of statistical power. This, unfortunately, is the one piece of data MOST relevant to the human CR practitioner. We don't have the answer. But clearly, ECD is not fully equivalent to CR, even when the 2 are combined, under any other circumstances; my guess is that the same holds here. Implications for Human Practice I simply don't believe that anyone is doing the human equivalent of genuine "weep-on-your-knees" CR on a voluntary basis: few of us are doing CR at all, as vs. healthy weight maintenance, so my point (3) above simply falls out of it. The key findings are therefore those discussed in my points (5) and (6) above. There's obviously a bit of a tension between these 2 sets of findings, in terms of how one should govern oneself and extrapolate from current practice, unfortunately, but Holloszy's key study (1) below, and the centerpiece of my point (6) is a better-quality study, and probably should be given more weight. Thus, it does appear that, once you pass a certain minimum threshold (significantly more than healthy weight maintenance), Calories burned thru' exercise probably does add to Calories not consumed in the first place — just not as fully, and with some manner of ceiling or asymptote. At the end of the day, clearly, a person should do as intense a level of CR as s/he finds tolerable, subjectively and on a risk-management basis; any additional benefits to Calories burned to exercise (as opposed to the direct benefits of cardiovascular fitness, bone health, strength, etc) are gravy — but should not be assumed to be fully equivalent to Calories not consumed in making tradeoff decisions. Also, Holloszy's studies in particular are consistent on every point except one: does combining exercose with a given level of CR increase early mortality? (5) found yes; (3) found no. The data on the same point published by other labs are likewise inconsistent. We ought to suspend judgement on this point, IMHO. Another interesting point: (7) reports that CR animals overall ran less for the first ~3.5 mo of CR than ALers, & cites previous work (8,9) as reporting the same thing. 3.5 mo ~11.6 human years. Not too damned many of us fall into that length of CR! Semi-Digression on Mitochondria Another interesting tie-in is with de Grey's hypothesis on why CR reduces mtDNA damage and, thus, ultimately, aging.((15), and see (14) for background) It involves shuttling more NADH away from the mt to a surface membrane electron acceptor — the PMRS. de Grey's theory predicted this phenomenon, and subsequent experiments (16,17) confirmed it. Fewer electrons into the electron transport chain, fewer fumbled, less mitochondrial inner membrane damage, less passed along to mtDNA. But ALSO, less energy being produced per electron run thru' the system at peak output. Perhaps the subjective feeling of a paradoxical inability to run harder, despite the fact that one is not really breathing hard yet, is the subjective correlate of this experience? One last point. There may be another reason exercise might help slow aging, under the right circumstances — again, tying in with MiFRA. One intuitively expects that MiFRA ought to mean that exercising should speed aging due to more ROS being produced. Yet it doesn't. The reason, as de Grey points out, is that exercise doesn't actually increase the number of e- being rushed thru' each mt, because the number of mt are increased. Thus, the danger of ROS damage to mtDNA remains the SAME for each mt. And yet, this isn't quite the whole story, because an equal chance of an accident happening per car still leads to more accidents total when there are more cars on the road. De Grey agrees that this thus predicts some pro-aging effects of exercise, but that they would be minor. I've never found this to be fully convincing. Well, exercise has a mitigating effect. Apparently, "physical exercise .. modifie the fatty acid profile of the mitochondrial membranes. Total monounsaturated fatty acids decrease [and] Total polyunsaturated fatty acids in mitochondrial membranes of LIVER increase (P < 0.005) after exercise but [PUFA] in mitochondrial membranes of skeletal muscle decrease (P < 0.05)." (13) As those familiar with MiFRA will know, the former "don't count," but the latter are central, to the hypothesis. A decrease in mt membrane PUFA (which, NB, by the structure of phospholipids entails of necessity a concomitant increase in MUFA) would decrease the desaturation index of individual mt, increase their resistance to oxidation, & thus actually reduce the odds of each mt going evil on us. References 1: Holloszy JO. Longevity of exercising male rats: effect of an antioxidant supplemented diet. Mech Ageing Dev. 1998 Feb 16;100(3):211-9. PMID: 9578110 [PubMed - indexed for MEDLINE] 2: McCarter RJ, Shimokawa I, Ikeno Y, Higami Y, Hubbard GB, Yu BP, McMahan CA. Physical activity as a factor in the action of dietary restriction on aging: effects in Fischer 344 rats. Aging (Milano). 1997 Feb-Apr;9(1-2):73-9. PMID: 9177588 [PubMed - indexed for MEDLINE] 3: Holloszy JO. Mortality rate and longevity of food-restricted exercising male rats: a reevaluation. J Appl Physiol. 1997 Feb;82(2):399-403. PMID: 9049716 [PubMed - indexed for MEDLINE] 4: Holloszy JO. Exercise increases average longevity of female rats despite increased food intake and no growth retardation. J Gerontol. 1993 May;48(3):B97-100. PMID: 8482812 [PubMed - indexed for MEDLINE] 5: Holloszy JO, Schechtman KB. Interaction between exercise and food restriction: effects on longevity of male rats. J Appl Physiol. 1991 Apr;70(4):1529-35. PMID: 2055832 [PubMed - indexed for MEDLINE] 6: Holloszy JO, Smith EK, Vining M, Adams S. Effect of voluntary exercise on longevity of rats. J Appl Physiol. 1985 Sep;59(3):826-31. PMID: 4055572 [PubMed - indexed for MEDLINE] 7. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Effects of intermittent feeding upon growth, activity, and lifespan in rats allowed voluntary exercise. Exp Aging Res. 1983 Fall;9(3):203-9. PMID: 6641783; UI: 84057947 "There is also an indication that [EOD CR] was somewhat less effective in enhancing [LS] in the exercised rats, when compared to the survival of groups fed EOD in conventional cages. The mean [ls] of 124 weeks in the exercised EOD group is nearly 14 weeks shorter than that of a caged EOD group prevously observed in our laboratory. Of course, [comparing data from seperate studies is problematic]." 8. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. J Gerontol. 1983 Jan;38(1):36-45. PMID: 6848584 [PubMed - indexed for MEDLINE] Max LS data cribbed from (11): 158 vs. 145 weeks, sedentary vs. exercising CRONies. Max LS in ALers: 88 vs. 115 weeks -- ie neither AL group broke SPECIES max LS. 9. McCay CM, Maynard LA, Sperling G, and Osgood H. Nutritional requirement during the latter half of life. J Nutr. 1941;21:45-60. (Yes, THAT McCay!) result cribbed from (11). 10. Beauchenne RE, , DellwoM, Darabian P, Haley-Ziltin V, Wright DL. Biological aging and longevity in diet-restricted and exercised rats. Abstracts of Biological Effects of Dietary Restriction, an international Conference. Washington, DC:1990. Results cribbed from (11). 11. McCarter RJ. Effects of exercise and dietary restriction on energy metabolism and longevity. In Yu BP (ed). Modulation of aging processes by dietary restriction. Boca Raton, FL: CRC Press, 1994. 12. Austad, Steven. Why We Age: What Science Is Discovering About The Body's Journey Through Life. Paperback, 256 pages . April 1999: John Wiley & Sons, Inc. ISBN: 0471296465 13. Quiles JL, Huertas JR, Manas M, Battino M, Mataix J. Physical exercise affects the lipid profile of mitochondrial membranes in rats fed with virgin olive oil or sunflower oil. Br J Nutr 1999 Jan 81:1 21-4 14. The Mitochondrial Free Radical Theory of Aging Aubrey D.N.J. de Grey Landes Bioscience, 810 South Church Street Georgetown, TX, USA tel: +1 512 863 7762, fax: +1 512 863 0081 ISBN: 1-57059-564-X 15: de Grey AD. A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction. Mitochondrion. 2001 Aug;1(2):129-39. PubMed PMID: 16120273. 16: Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19908-12. Epub 2006 Dec 13. PubMed PMID: 17167053; PubMed Central PMCID: PMC1750890. 17: López-Lluch G, Rios M, Lane MA, Navas P, de Cabo R. Mouse liver plasma membrane redox system activity is altered by aging and modulated by calorie restriction. Age (Dordr). 2005 Jun;27(2):153-60. doi: 10.1007/s11357-005-2726-3. Epub 2005 Dec 10. PubMed PMID: 23598622; PubMed Central PMCID: PMC3458500.
  5. I'm just throwing in this idea of opening a new forum section on physical exercise, specifically tailored for the longevity buffs. Apparently, that's an important part of any longevity strategy and even of a strict, literal regime of CR. I've been searching around but, although there is a lot of material about exercise, it is scattered and the purpose is more general fitness or bodyweight loss or increase of strenght (the latter overlaps with longevity strategies in part). There are many angles to the issue, from the proper regimen (cardio or resistance or both?) to the proper exercises, to the cautions to undertake against injuries, to the more appropriate strategies in the various age ranges, to the specific trainings against sarcopenia and osteopenia-osteoporosis, to acquiring strength to avoid injuries, to acquiring muscle mass to improve metabolism and so on. Because of the width of the topic maybe a new section would be appropriate. We can link what appears to be relevant and credible advise. We can discuss the apparent contradiction of downregulating the anabolic pathways and building up mass and strength and propose suitable strategies to overcoem the contradiction. If a new section is not possible I'm going to expand this thread.
  6. drewab

    Sleep thought of the day

    There are many factors, which act as stressors on the body, and seem to contribute to improved health outcomes. Some of these include: Exercise Fasting Cold exposure Caloric restriction Heat exposure Particular foods that exert hormetic effects (ie. cruciferous vegetables) Some of the above are not without their controversies, but it's interesting that mild sleep deprivation (a mild stressor) doesn't elicit a hormetic effect. Or perhaps it does? Has anyone else had this curious thought before and unpacked it a little?
  7. I haven't come anywhere near digesting the article fully, but it had enough interesting details about the changes in transcription brought about by endurance exercise that I thought it worth posting. It's from a study at Karolinska Institutet. The article is in the latest issue of PLOS Genetics, and is entitled (full text available at the linked article): The Impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts Here's the author's summary: Here's the abstract:
  8. Dean Pomerleau

    Metabolism, Aging, CR & Exercise

    I found this new paper %5B1%5D posted by Al Pater to the now defunct (RIP) CR mailing list to be a very interesting model of aging and how it relates to metabolism. I was particularly interested in how the authors explained the benefit (or at least, the non-harm) of exercise when it comes to lifespan, despite the fact that a naive interpretation, based on the Rate-of-Living Theory, would suggest that exercise requires more calories which will inevitably result in greater metabolic damage (e.g. via reactive oxygen species (ROS) generation), and thus faster aging. They offer a theory which compartmentalizes metabolism into several components, illustrated schematically in Fig 4: The black (outside) box represents the total metabolism of an organism, either being fed ad lib (left bar) vs. CR (middle bar). In order for the organism to grow (i.e. deposition of new biomass), it must not only sequester matter into new tissue which stores energy and therefore requires ingested calories (green box), but also active expenditure of energy to convert the food into living (muscle, fat or bone) tissue, which they call biosynthesis (blue box). With dietary restriction, the total metabolic budget is lower (middle bar shorter than left bar). With fewer calories to go around, the body decides to create less new tissue, cutting down on the green box to stay "within budget". With less tissue to create, the active cost of biosynthesis that would be required to create that tissue is also reduced (blue box) in the CR condition. That leaves more net energy available for "protection (scavaging and repair)" (yellow box) in the CR condition than in the AL condition, leading to better health maintenance and increased longevity. In the bulk of the paper, the authors develop equations to quantify these relationships, explain known (sometimes paradoxical) observations about the relationship between metabolism and longevity, and to make predictions. What it seems to boil down to is that if an organism stays small (relative to the 'normal' size for its species), it will tend to live longer. They show an interesting graph (Fig 5) to support this hypothesis, which illustrates how lifespan extension appears linearly related to the degree of body mass reduction induced by either CR or genetic manipulation of growth hormone: What I found most interesting personally was their discussion of the impact of exercise on metabolism and lifespan. Here is a quote from that section of the paper: [T]he model can be generalized to include the variation in activity level. As shown in Fig. 4, with a limited food supply, an increase in activity would further suppress growth. Thus, depending on the degree of the increase in activity, the adult mass of DR animals (MDR) will be even smaller. In Eq. (3), lifespan extension is proportional to the body mass reduction (M/MDR − 1). So, if MDR is smaller due to the increase in activity, the lifespan extension will be larger. There is no empirical data to test this prediction directly and quantitatively, because most studies did not measure the energy cost of the increased activity level. But the results from Holloszy (1997) [2] support this prediction indirectly by showing that the major determinant of lifespan extension is the body mass reduction even if activity level varies [my emphasis]. Holloszy (1997) reported the lifespan, food consumption, and body mass of four groups of male Long-Evans rats reared at different levels of food supply and exercises: ad libitum (AL)-runner, AL-sedentary, DR-runner, and DR-sedentary. The peak body mass (M and MDR) of these four groups rank in such an order: AL-sedentary (597 g) > AL-runner (420 g) > DR-runner (333 g) = DR-sedentary (330 g). Equation (3) predicts that their lifespan will be in the opposite order. The data supports this prediction: AL-sedentary (858 days) < AL-runner (973 days) < DR-runner (1058 days) = DR-sedentary (1051 days). Note, in this study, although they are both under DR, DR-runners consumed more food (13.4 g/day) than DR-sedentary group (10 g/day). So the runner and sedentary groups ended up with the same body mass (∼330 g). The interesting result is that despite the different exercise and food levels, the same body mass led to the same lifespan (∼1050 days) in these two groups, exactly as our model predicts [my emphasis]. We postulate that if DR-runner and DR-sedentary were fed with the same level of food, then the runners will be have a smaller body mass, and therefore a longer lifespan. So the calorie-restricted running rats ate 34% more calories than the sedentary calorie-restricted rats, but as a result of their extra energy expenditure, weighed the same, and lived just as long as the sedentary CR rats. The authors point out that while burning more calories will usually generate more damaging free radicals, when calories are burned in exercise they are burned "more cleanly", and hence don't generate as many ROS's as when burned under sedentary conditions. To quote the paper again: The percentage of electron leak can also vary during exercises, where the mitochondrial respiration transits from state 4 to state 3 (Barja, 2007 and Barja, 2013). Under state 4 (resting respiration), oxygen consumption is low, proton-motive force is high, and ROS production is high (Barja, 2013 and Harper et al., 2004), whereas under state 3 (active respiration), ROS production reduces rapidly (Boveris and Chance, 1973, Boveris et al., 1972 and Loschen et al., 1971). So if exercise trains mitochondria to operate in state 3 both during exercise and (possibly) during rest as well, the net effect of exercise on free radical production may not be very significant. And if exercise also induces a hormetic effect that increases free radical scavenging (which there is quite a bit of evidence to support), the net result could be less damage from free radicals despite more calories burned as a result of exercise. This seems to contradict the oft-cited mantra among some human CR practitioners of "calories, calories, calories" - i.e. its reducing calories that matters, whether or not it leads to weight loss, and attaining a low weight as a result of extra activity/exercise won't be equivalently beneficial for longevity as a higher degree of (semi-sedentary) CR. Given that Holloszy's paper [2] is from 1997, I'm sure we hashed all this out on the old CR mailing list many years ago, and perhaps MR will point to that old thread :). But I thought it was interesting (and encouraging) given my recent disclosure that lately I've been eating more calories but exercising a lot more to maintain a very CR-like weight (BMI ~17.5). --Dean ----------------------------------------------------- [1] On the complex relationship between energy expenditure and longevity: Reconciling the contradictory empirical results with a simple theoretical model. Hou C, Amunugama K.[/size] Mech Ageing Dev. 2015 Jun 15;149:50-64. doi: 10.1016/j.mad.2015.06.003. [Epub ahead of print] PMID:26086438 http://www.sciencedirect.com/science/article/pii/S0047637415000846 http://ac.els-cdn.com/S0047637415000846/1-s2.0-S0047637415000846-main.pdf?_tid=e680437e-1d32-11e5-8323-00000aacb361&acdnat=1435454195_8ec497f0141d9e67cb89cf2909758cd4 Abstract The relationship between energy expenditure and longevity has been a central theme in aging studies. Empirical studies have yielded controversial results, which cannot be reconciled by existing theories. In this paper, we present a simple theoretical model based on first principles of energy conservation and allometric scaling laws. The model takes into considerations the energy tradeoffs between life history traits and the efficiency of the energy utilization, and offers quantitative and qualitative explanations for a set of seemingly contradictory empirical results. We show that oxidative metabolism can affect cellular damage and longevity in different ways in animals with different life histories and under different experimental conditions. Qualitative data and the linearity between energy expenditure, cellular damage, and lifespan assumed in previous studies are not sufficient to understand the complexity of the relationships. Our model provides a theoretical framework for quantitative analyses and predictions. The model is supported by a variety of empirical studies, including studies on the cellular damage profile during ontogeny; the intra- and inter-specific correlations between body mass, metabolic rate, and lifespan; and the effects on lifespan of (1) diet restriction and genetic modification of growth hormone, (2) the cold and exercise stresses, and (3) manipulations of antioxidant. -------------------- [2] J.O. Holloszy Mortality rate and longevity of food-restricted exercising male rats: a reevaluation J. Appl. Physiol., 82 (1997), pp. 399–403 Abstract Food restriction increases the maximal longevity of rats. Male rats do not increase their food intake to compensate for the increase in energy expenditure in response to exercise. However, a decrease in the availability of energy for growth and cell proliferation that induces an increase in maximal longevity in sedentary rats only results in an improvement in average survival, with no extension of maximal life span, when caused by exercise. In a previous study (J. O. Holloszy and K. B. Schechtman. J. Appl. Physiol. 70: 1529-1535, 1991), to test the possibility that exercise prevents the extension of life span by food restriction, wheel running and food restriction were combined. The food-restricted runners showed the same increase in maximal life span as food-restricted sedentary rats but had an increased mortality rate during the first one-half of their mortality curve. The purpose of the present study was to determine the pathological cause of this increased early mortality. However, in contrast to our previous results, the food-restricted wheel-running rats in this study showed no increase in early mortality, and their survival curves were virtually identical to those of sedentary animals that were food restricted so as to keep their body weights the same as those of the runners. Thus it is possible that the rats in the previous study had a health problem that had no effect on longevity except when both food restriction and exercise were superimposed on it. Possibly of interest in this regard, the rats in this study did considerably more voluntary running than those in the previous study. It is concluded that 1) moderate caloric restriction combined with exercise does not normally increase the early mortality rate in male rats, 2) exercise does not interfere with the extension of maximal life span by food restriction, and 3) the beneficial effects of food restriction and exercise on survival are not additive or synergistic.
  9. All, You may have seen the recent story in the popular press about the possibility of "mysterious" causes of the obesity epidemic with titles like: Obesity is about More than Diet and Exercise: Why It’s Harder to Stay Healthier Now More Than Ever and: Not mom's weight loss: For millennials, more than diet and exercise at play Here is the sensational way the reporter in the first story describes it: According to research, a person with the same diet and exercise habits in the 80s would have a 2.3 point increase in their BMI in 2006 without changing anything at all — simply by existing 30 years in the future. That’s right — existing in our modern environment has contributed to a greater body mass among the population. Wow - that sounds bizarre, scary, and oddly comforting at the same time. Maybe it's not our lifestyle choices that are making us fat, so maybe it's not our fault. I've got to read more! ... They are reporting on a new study [1] that they (and the authors, to some degree) claim shows that over the last 30 years Americans have gotten fatter for reasons other than eating too much food and/or engaging in too little physical activity. The reporters speculate about a range of causes, including: We are more stressed and sleep less. We are exposed to more pesticides and industrial chemicals. Because of our changing diet we have less healthy gut microbiomes. We take more medications associated with weight gain than we used to, such as antidepressants. We increasingly live in climate-controlled worlds that don't require us to burn calories to maintain our body temperature. So I decided to look at the actual study to see if it is sound, and what the authors actually said. The paper [1] analyzed the NHANES data from 1971 to 2008, in which every few years researchers went to the homes of about 3000 Americans (men and women) to take measurements (e.g. height and weight) and ask them questions about their diet and lifestyle. Here is the key table from the paper showing how the various measures changed over the years (note - they are interviewing different people every few years, this isn't a longitudinal study in which they follow the same people over time): The first thing they observed is that BMI has gone up about 10% (3 units) in both men and women since the early '70s - the population has obviously gotten fatter. They also observed that self-reported calorie intake has gone up by 10-14% over that same period. So people are eating more, and getting (nearly proportionally) fatter - where is the discrepancy? The authors say that self-reported leisure time physical activity (PA) rose by 47% and 120% in men and women, respectively, over the latter part of the time period (physical activity wasn't recorded prior to 1980 in the NHANES protocol). So, the authors conclude, if people say they are only eating 10-14% more, and are exercising a ton more, their weight shouldn't have gone up by 10%, so something else besides diet and exercise must explain their weight gain. No potential flaws in this logic, no siree ... Seriously. The NHANES data was interviewing different people, using different questioning techniques and different questions over the years. In NHANES I (1971—1975) and NHANES II (1976—1980), in-person interviews were used to obtain self-reported dietary information via a 24- h dietary recall questionnaire that assessed food and beverage intake for weekdays only. In NHANES III (1988—1994), dietary information was obtained through a self-reported 24-h dietary recall using a computer-assisted, automated, interactive method for any day of the week. In NHANES 1999—2002, a multiple-pass computer-assisted dietary interview format was used to collect detailed self-reported information about all foods and beverages that were consumed the day prior to the in-person interview (weekday or weekend). In NHANES 2003—2008, 24-h self-reported dietary recalls were performed twice (3—10 days apart) using an automated multiple pass method. Right off the bat, people may have been more reluctant fudge the numbers on what / how much they ate during the face-to-face in-person interviews from 1971-1980, relative to the impersonal computer-based data collection used after 1980, which could easily have resulted in subjects underestimating calorie intake during the later years. Plus, it's well known that self-reported diet recall is a crappy source of information about what people actually eat. More importantly, the heavier people are, the more likely they are to underreport how much they eat, and overreport how much physical activity they engage in. So as people got fatter over the years, the "mystery" of why they are gaining weight when not eating that much more, while exercising a lot more, may simply be that they lie more about their eating and exercise habits as they get fatter. In fact, the authors suggest this effect as the first possible explanation for their findings: Whether self-reported dietary intake accurately reflects an individual’s true dietary intake has been questioned [34]. Indeed, doubly-labelled water studies typically show that individuals underreport their energy intake, and that the magnitude of the underreporting may be larger in people who are obese [35]. <snip> This finding is in line with those of several other studies in which individuals with obesity reported consuming similar or fewer daily calories than those who are normal weight [7,11]. While this has frequently been attributed to underreporting [19,20], several additional possible explanations must be considered... The authors then go on to speculate about a few of the 'mystery' causes of weight gain mentioned in the popular reports and listed above. This seem to me to be a clear case of the authors of the study, and especially the reporters writing about the study, downplaying the most likely explanations (i.e. under/over reporting of diet and exercise by the obese, changes in protocol skewing results) in favor of speculative explanations that appeal to people's desire to avoid personal responsibility for their weight gain, e.g. "it isn't your fault - you've gained weight because of the mysterious obesity-promoting chemicals in our food or environment these days". To be fair, the second (CNN) article linked above does acknowledge at the end the possibility that the explanation could be a mundane combination of misremembering and/or intentional underreporting. But it nonetheless stresses the significance of mysterious causes, likely to gain more eyeballs for their story. Pretty sad... Note: I'm not saying (definitively) that these other possible factors haven't contributed at all to the recent dramatic weight gain among the American population. All I'm saying is that this study provides extremely weak evidence to support such speculations, and that the mundane explanation of a positive energy balance due to eating too much and exercising too little is likely the cause of the vast majority of the observed weight gain. --Dean ---------- [1] Obes Res Clin Pract. 2015 Sep 14. pii: S1871-403X(15)00121-0. doi: 10.1016/j.orcp.2015.08.007. [Epub ahead of print] Secular differences in the association between caloric intake, macronutrient intake, and physical activity with obesity. Brown RE(1), Sharma AM(2), Ardern CI(1), Mirdamadi P(1), Mirdamadi P(1), Kuk JL(3). Full Text: http://www.obesityresearchclinicalpractice.com/article/S1871-403X(15)00121-0/pdf BACKGROUND: To determine whether the relationship between caloric intake, macronutrient intake, and physical activity with obesity has changed over time. METHODS: Dietary data from 36,377 U.S. adults from the National Health and Nutrition Survey (NHANES) between 1971 and 2008 was used. Physical activity frequency data was only available in 14,419 adults between 1988 and 2006. Generalised linear models were used to examine if the association between total caloric intake, percent dietary macronutrient intake and physical activity with body mass index (BMI) was different over time. RESULTS: Between 1971 and 2008, BMI, total caloric intake and carbohydrate intake increased 10-14%, and fat and protein intake decreased 5-9%. Between 1988 and 2006, frequency of leisure time physical activity increased 47-120%. However, for a given amount of caloric intake, macronutrient intake or leisure time physical activity, the predicted BMI was up to 2.3kg/m(2) higher in 2006 that in 1988 in the mutually adjusted model (P<0.05). CONCLUSIONS: Factors other than diet and physical activity may be contributing to the increase in BMI over time. Further research is necessary to identify these factors and to determine the mechanisms through which they affect body weight. PMID: 26383959
  10. All, Sthira, in a recent post to the exercise thread ,which I wantonly edited (my bad, sorry Sthira...) in order to create this new thread on animal cruelty, mentioned how beneficial dance is for health & longevity, complementing my daughter, who is a dancer. In vindication Sthira's assessment, this new study [1] (press release, popular press article) found that engaging in social dancing, particularly rigorous social dancing (enough to make one "out of breath and sweaty"), reduced cardiovascular mortality risk by 50% relative to people who didn't dance. Dancing was about twice as beneficial for CVD mortality as walking, even after controlling for a pretty extensive set of potential confounders, including age, sex, socioeconomic status, smoking, alcohol, BMI, chronic illness, psychosocial distress, and total physical activity amount. Discussing the study, one of the authors said: "We should not underestimate the playful social interaction aspects of dancing which, when coupled with some more intense movement, can be a very powerful stress relief and heart health promoting pastime... The Bee Gees said it best - you should be dancing," Maybe we should have a dance party one evening at the CR Conference.☺ --Dean ---------- [1] American Journal of Preventive Medicine Available online 1 March 2016, DOI: http://dx.doi.org/10.1016/j.amepre.2016.01.004 Dancing Participation and Cardiovascular Disease Mortality: A Pooled Analysis of 11 Population-Based British Cohorts Dafna Merom, PhD, Ding Ding, PhD, Emmanuel Stamatakis, PhD Free full text: http://www.ajpmonline.org/article/S0749-3797(16)00030-1/pdf Abstract Introduction Little is known about whether cardiovascular benefits vary by activity type. Dance is a multidimensional physical activity of psychosocial nature. The study aimed to examine the association between dancing and cardiovascular disease mortality. Methods A cohort study pooled 11 independent population surveys in the United Kingdom from 1995 to 2007, analyzed in 2014. Participants were 48,390 adults aged ≥40 years who were free of cardiovascular disease at baseline and consented to be linked to the National Death Registry. Respondents reported participation in light- or moderate-intensity dancing and walking in the past 4 weeks. Physical activity amount was calculated based on frequency, duration, and intensity of participation in various types of exercise. The main outcome was cardiovascular disease mortality based on ICD-9 codes 390−459 or ICD-10 codes I01−I99. Results During 444,045 person-years, 1,714 deaths caused by cardiovascular disease were documented. Moderate-intensity, but not light-intensity, dancing and walking were both inversely associated with cardiovascular disease mortality. In Cox regression models, the hazard ratios for cardiovascular disease mortality, adjusted for age, sex, SES, smoking, alcohol, BMI, chronic illness, psychosocial distress, and total physical activity amount, were 0.54 (95% CI=0.34, 0.87) for moderate-intensity dancing and 0.75 (95% CI=0.62, 0.90) for moderate-intensity walking. Conclusions Moderate-intensity dancing was associated with a reduced risk for cardiovascular disease mortality to a greater extent than walking. The association between dance and cardiovascular disease mortality may be explained by high-intensity bouts during dancing, lifelong adherence, or psychosocial benefits.
  11. We've known for quite some time that exercise (and CR!) can help stave off the cognitive decline that is often associated with aging. Scientists are now beginning to understand the mechanism underlying this effect. Here is a popular press description: http://www.kurzweilai.net/long-term-aerobic-exercise-prevents-age-related-brain-deterioration of a new paper [1] that helps elucidate the physiological mechanism of brain health preservation via exercise. The authors experimented with mice. They found that with age the support cells in the brain (microglia, astrocytes, etc.) are lost or become dysfunctional, reducing blood flow to neurons, increasing inflammation, etc. This age-related decline and damage was prevented in the mice that exercised (~2 miles per day on a running wheel). But exercise didn't have any positive effect in mice that were completely APOE-deficient. It is interesting that the APOE gene is involved in the beneficial cognitive benefits of exercise, since variants in this gene (i.e. APOE4) are well known to be associated with increased risk of Alzheimer's disease. Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain? --Dean ----------- [1] PLOS Biology, October 29, 2015; DOI: 10.1371/journal.pbio.1002279 (open access) APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. Ileana Soto, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell. Abstract Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. Author Summary Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.
  12. In his weekly post of new CR Science studies, James Cain (thanks James!) posted [1], another in the series of papers about results from the CALERIE study of six months of CR in modestly overweight humans. In this analysis they divided 24 people into three groups of 8 people each and followed them for six months: control diet (control group) 25% Calorie Restriction (CR group) 12.5% CR + enough exercise to equal a 25% calorie deficit (CREX group). Both intervention groups lost about the same amount of bodyweight (~11%). They took subcutaneous fat cell biopsies from the three groups at baseline and at six months, and subjected them to gene expression analysis. Here are the major highlights from the full text: Despite comparable transcriptional and clinical response in energy metabolism, we showed that CR vastly outweighed CREX in the total number of differentially regulated genes (88 vs 39) and pathways (28 vs 6). This suggests that calorie restriction is probably eliciting molecular changes beyond adaptations to energy deficit per se. <snip> CR induced a ... 2.1-fold (p < .05) increase in the mRNA expression of ... CGI-85 [a regulator of epigenetic histone modification - DP], ...whereas CREX and Control were without effect. <snip> [W]e observed a distinct effect of CR on downregulating the chemokine signaling-related pathways. [From this description of the chemokine signalling pathways: "chemokines are a critical component of basal leukocyte trafficking essential for immune system architecture and development, and immune surveillance." - DP] <snip> Together, our data suggest that CR regulates the overall transcriptional function, and this does not appear to be a primary response to energy deficit per se but rather a distinct effect of calorie restriction. Genomic effects may also be the key regulator of the aging process. Pioneering work from the laboratories of Weindruch and Spindler showed that most differential gene expression induced by aging in rodents was at least partly or completely reversed by calorie restriction (42,43). The Spindler group further showed that shifting mice from long-term calorie restricted to control diet reversed 90% of the transcriptional changes induced by calorie restriction and returned the animals to an aging rate similar to the controls (44), implicating a causal relationship between calorie restriction, gene expression, and aging. <snip> Available literature to date largely agrees that calorie restriction and exercise training overlap in a wide range of health benefits from weight loss to protection against some age-related diseases (55). Extension of maximal life span, however, remains as a unique feature of calorie restriction that so far cannot be replicated by any form of exercise training (56,57). <snip> Finally, given the enormous challenge (and an almost impossible task) of maintaining drastic lifestyle changes such as life-long calorie restriction, identifying specific molecular targets will be critical for the development of calorie restriction mimetics (59). Its pretty annoying that authors feel obligated to dismiss the possibility of people practicing long-term CR as being "almost impossible". Luigi Fontana wasn't an author on this one (thankfully), and perhaps if he had been the paper wouldn't have ended on such a low note. But despite this disempowering and dismissive ending, it was one of the most interesting papers I've seen coming out of the CALERIE study, suggesting that CR in humans (whether induced by straight calorie reduction or CR + exercise) does have some pretty fundamental effects on gene expression in fat cells. In addition, it found that CR-alone has a more profound and widespread impact on gene expression than more modest CR "topped off" with extra exercise (the CREX group), at least in the relatively short term (6 months) in this (relatively overweight) cohort. In particular, they found that CR (but not CR+EX) downregulates certain aspects of chemokine pathways related to immune system function (good or bad, who knows, but our immune systems seem pretty competent...), and changes the expression of genes involved in epigenetic regulation (master genes regulating expression of other genes) - which is increasingly thought to be important in the aging process. These results complement and extend similar findings in skeletal muscle cells from this same cohort [2] and some of us long-term CR practitioners [3]. Interestingly, from [2], it seems that CR-alone and CR+Exercise had much more similar effects on muscle cell gene expression as compared to this study of gene expression in fat cells, where the effects of CR-alone differed markedly from CR+exercise. --Dean ------------ [1] J Gerontol A Biol Sci Med Sci. 2015 Oct 20. pii: glv194. [Epub ahead of print] Six-month Calorie Restriction in Overweight Individuals Elicits Transcriptomic Response in Subcutaneous Adipose Tissue That is Distinct From Effects of Energy Deficit. Lam YY1, Ghosh S2, Civitarese AE3, Ravussin E4. Abstract Calorie restriction confers health benefits distinct from energy deficit by exercise. We characterized the adipose-transcriptome to investigate the molecular basis of the differential phenotypic responses. Abdominal subcutaneous fat was collected from 24 overweight participants randomized in three groups (N = 8/group): weight maintenance (control), 25% energy deficit by calorie restriction alone (CR), and 25% energy deficit by calorie restriction with structured exercise (CREX). Within each group, gene expression was compared between 6 months and baseline with cutoffs at nominal p ≤ .01 and absolute fold-change ≥ 1.5. Gene-set enrichment analysis (false discovery rate < 5%) was used to identify significantly regulated biological pathways. CR and CREX elicited similar overall clinical response to energy deficit and a comparable reduction in gene transcription specific to oxidative phosphorylation and proteasome function. CR vastly outweighed CREX in the number of differentially regulated genes (88 vs 39) and pathways (28 vs 6). CR specifically downregulated the chemokine signaling-related pathways. Among the CR-regulated genes, 27 functioned as transcription/translation regulators (eg, mRNA processing or transcription/translation initiation), whereas CREX regulated only one gene in this category. Our data suggest that CR has a broader effect on the transcriptome compared with CREX which may mediate its specific impact on delaying primary aging. PMID: 26486851 ----------- [2] PLoS Med. 2007 Mar;4(3):e76. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. Civitarese AE(1), Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E; CALERIE Pennington Team. BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y), overweight (body mass index, 27.8 +/- 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% +/- 5% in the CR group (p = 0.005) and 21% +/- 4% in the CREX group (p < 0.004), with no change in the control group (2% +/- 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (-0.56 +/- 0.11 arbitrary units, p = 0.003) and CREX (-0.45 +/- 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. CONCLUSIONS: The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults. PMID: 17341128 -------------- [3] Aging Cell. 2013 Aug;12(4):645-51. doi: 10.1111/acel.12088. Epub 2013 Jun 5. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Mercken EM(1), Crosby SD, Lamming DW, JeBailey L, Krzysik-Walker S, Villareal DT, Capri M, Franceschi C, Zhang Y, Becker K, Sabatini DM, de Cabo R, Fontana L. Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans. PMID: 23601134
  13. I have a BMI ~20 at 5'10" / 140lbs. My body fat percentage is possibly as low as 8%? As far as I can tell with rough tracking on cronometer, my current caloric intake is around 1900-2100kcal -- Right now, I exercise for around 30-45m 3-4x a week, although, I would like to increase this as the weather improves, which will likely require more calories. I like the idea of practicing mild caloric restriction and protein / methionine restriction. However, I would also like to gain some muscle mass, or at least maintain a high level of lean mass. I'm not particularly active, so I wouldn't want to drop activity lower. Is there a way to balance these competing goals of mild CR / protein restriction vs gaining muscle mass / strength & staying physically active (perhaps eating lower protein / calories most days, and higher calories / protein on exercise days?) What sort of protein intake (grams) / caloric intake does the average CR practitioner consume? Gaining muscle mass seems to require eating at a caloric surplus with a high quantity of protein and it seems like eating fewer calories would drop body fat even lower, where I don't have too much to burn there. If I have a low body fat percentage at a 2,000kcal intake, am I already practicing caloric restriction for my activity level?
  14. Lose 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 [2]. 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 [1] 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 ------------ [1] 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 -------------- [2] 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. rcolman@primate.wisc.edu 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
  15. Here is another study posted by Al Pater that particularly interested me, both because it focused on inflammation (now understood to be an important contributor to all of the major chronic diseases of aging) and because it focused on CR vs. exercise vs. both. It compared the effects of one-year of a calorie restricted diet, aerobic exercise (without calorie restriction) or both exercise and calorie restriction on biomarkers of inflammation in overweight/obese postmenopausal women. The results can be summarized as follows: The diet-only group and the diet+exercise group lost close to the same amount of weight (8.5% vs 10.5%, respectively). The exercise-only group lost much less on average (2.5%), although there were some women in the exercise-only group who lost > 5% (see below). "There were no significant differences between the diet and diet+exercise groups or between the exercise[-only] and control groups, in any inflammatory biomarker." Virtually everyone* in the study who lost >5% of body weight saw a significant reduction in hr-CRP, an important marker of inflammation, independent of whether they lost weight via diet-alone, exercise-alone, or diet+exercise. So by my reading, it looks like its either the weight/fat loss or possibly the energy deficit, rather than simply eating fewer calories, that determines the benefits, at least when it comes to biomarkers of inflammation in this population. In particular, the women who lost nearly 10% of their bodyweight saw a dramatic (and equivalent) improvement in biomarkers of inflammation whether they achieved this weight loss via a large calorie deficit, or via a more modest calorie deficit "topped off" with exercise. --Dean * Except for two outliers with very high hr-CRP who were excluded ------------------------ [1] Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wang CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A. Cancer Res. 2012 May 1;72(9):2314-26. doi: 10.1158/0008-5472.CAN-11-3092. PMID:22549948 Free PMC Article http://cancerres.aacrjournals.org/content/72/9/2314.long http://cancerres.aacrjournals.org/content/72/9/2314.full.pdf+html Abtract Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P < 0.001) in the diet and 0.87 mg/L (0.51-1.23, P < 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P < 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 × 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 × 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction.
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