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  1. This all started when I found an article about a method that increased the viability of sperm stem cells by culture them in a low oxygen, high glucose medium. This promoted the stem cells to use glycolysis as their energy source instead of mitochondrial oxidative phosphorylation (OXPHOS) for their energy needs. The article went on to explain that glycolysis produces a lot less ROS than OXYPHO and it prevents a lot of DNA damage. So i went on to look if this was just a specific case but it appears that Haematopoietic SCs, Embryonic SCs, pluripotent SCs, and most adult stem-cells, use glycolysis as their main way to create energy. I couldn't figure out if its because of a predominant hypoxic environment or if this is a trait of stem-cells. When stem-cells go on to differentiate, they go through a metabolic reprogramming and start using the mitonchondrion (OXPHOS). [2] CR is known to cause a shift away from Glycolysis to OXPHOS, so its not clear how this would be beneficial. Could be part of a hormesis response. Its likely that stem-cells do not go through this metabolic shift, only differentiated cells. I tried look for rapamycin and mTOR inihibition and how it effects stem-cells, and it appears some mTOR activation is beneficial in ESCs: But lower mTOR activation is better on the long-run as it prevents stem-cell exhaustion. I was thinking of doing a 1-month intake of rapamycin while on CR to further suppress mTOR activity. I don't know now if this is a good idea. We know that whatever happens here and the shift in metabolism to OXPHOS in cells during starvation will lead to a healthier life, but i can't reconcile this stuff as it appears glycolysis is a lot better to avoid DNA damage as you can see from the sperm cells that reached 40% viability from 5% when using OXPHOS. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575699/ [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095859/
  2. 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.