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All, Al's latest post about new CR paper contained a really interesting new study in rhesus monkeys , with potentially troubling implications for men practicing serious CR with (resulting) low testosterone. It was a study of middle-aged (~12 yo) male rhesus monkeys, making it more relevant to us than any of the rodent studies. Half the monkeys were orchidectomized ☹ to put the kibosh on their testosterone level, and the other half were subjected to mock surgery. After two months of recovery on a standard chow diet (15F / 27P / 59C) supplemented with fresh fruits & vegetables, both groups were made pudgy by shifting them for six months to a western style diet (WSD) that has a similar macronutrient profile to the diet many of us eat day-to-day (33F / 17P / 51C). Then, for 4 additional months, they calorie-restricted both groups by putting them back on the standard chow + F&V diet, but giving them only 70% of their individual baseline (pre-surgery) calorie intake (i.e. 30% CR). They intended to model in their rhesus monkeys the life history of men who undergo androgen deprivation therapy (ADT) for treatment of prostate cancer, so see if calorie-restriction could prevent the metabolic syndrome such treatment often induces in men. But while not perfect, the parallels with us CR folks are unmistakable - i.e. chronic CR resulting in the combination of reduced muscle mass and low testosterone. What they found appears to me to be pretty troubling, as I alluded to in the title and introduction. First, two months after the surgery, while still eating the standard, low-fat chow + F&V diet ad libidum, the orchidectomized (O) monkeys (OMs), but not the intact (I) monkeys (IMs) showed a decrease in lean mass. Not too surprising - lean mass drops with low testosterone. During the six-months of western-style diet (WSD), both groups gained fat. No surprise. But unlike the I monkeys, the O monkeys also lost additional lean mass and bone mass during the WSD period. Once again we see the negative effects of low-T on body composition. In short, the OMs became pretty classic examples of hypogonadal middle-aged men - pudgy, with little muscle mass and low testosterone. Now comes the interesting part - what happened as a result of 30% CR? Obviously both groups lost significant (and comparable) amount of fat mass. Both groups also lost lean mass. As a result, after the CR period both groups had returned to their relatively-lean baseline (pre-surgery) weight. But relatively to baseline, both groups had a higher percent body fat that they started with, and the O monkeys in particular had a lot less lean mass. The O monkeys also exhibited reduced bone mineral density as a result of CR, and effect not seen in the I monkeys. In short, low testosterone dropped the O monkey's lean mass and bone mass, and CR did nothing to counteract this effect - if anything it exacerbates it. But is that necessarily such a big deal? Maybe having low testosterone and reduced muscle mass after CR isn't a problem. In fact, without all that metabolically active muscle tissue, a CR practitioner could presumably eat fewer calories, and hence get more of the healthspan and lifespan benefits of CR, since "CR works by reducing Calorie intake -- period" a famous CR proponent once said. But so as to avoid getting myself into hot water yet again, I'll note that even he recognizes the importance of maintaining lean mass and bone mass via exercise while practicing CR... Obviously late-life sarcopenia and frailty is one concern some of us have about sacrificing too much muscle and bone mass to the CR gods. Unfortunately this short-term study didn't investigate the impact of these effects. But what they did find was even more germane to one of the negative side-effect that has been front and center in our discussions lately (discussed in depth here and here), namely impaired glucose tolerance (IGT). Not surprisingly, glucose tolerance (as measured by an OGTT) got worse in both I and O monkeys after eating the western diet for six months. But then, after 30% CR for four months, the I monkeys' glucose tolerance improved to the point where it was close to baseline again. In contrast, the poor, skinny, low-testosterone O monkeys, lacking much muscle mass, continued to show impaired glucose tolerance. The authors summarized their result as: CR improved these metabolic parameters [i.e. hyperinsulinemia and insulin resistance - DP] only in intact animals, whereas orchidectomized animals remained glucose-intolerant, despite a significant loss in fat mass. Put another way, CR coupled with low testosterone results in a precipitous drop in muscle mass, which led to impaired glucose tolerance. Note - the impaired metabolic health of the CR + Low-T monkeys was not a result of either differences in food intake or physical activity between the two groups - "... there was no significant group differences in these parameters under any of the dietary regimens studied." But they did observe an interesting effect of physical activity. At the end of the western diet period (i.e. pre-CR), across the entire population of monkeys, as well as within each group, monkeys that engaged in more physical activity had a lower percent fat mass (and by implication, a higher percent lean muscle mass), and exhibited better glucose metabolism, as illustrated in these two graphs showing % body fat (left) and OGTT glucose area under the curve (right), as a function of how active each of the monkeys was, as measured by a collar-worn accelerometer (Open circles = O monkeys, solid circles = I monkeys): Unfortunately, they don't report correlation between physical activity and glucose metabolism after the CR period. But given the across-the-board drop in lean mass as a result of CR that they observed, it seems likely to me that the observed relationship would still-hold, and perhaps be exaggerated, post-CR. So how do the authors interpret their results? Here are some of the key passages from the discussion section: The present study demonstrates that skeletal muscle loss in testosterone-deficient [non-human primates] correlated with the development of [insulin resistance] and glucose intolerance during the [western style diet] and CR periods. Surprisingly, there was no significant effect of testosterone deficiency on diet-induced change in fat mass, including fat gain during the WSD period and fat loss during the CR period, suggesting that insulin resistance in [low-testosterone androgen deprivation therapy] patients is related to the loss of skeletal muscle, which is the primary anatomical site responsible for glucose disposal. In other words, according to the authors: low-T (with or without CR) → reduced muscle mass → impaired glucose tolerance. Thus, testosterone may play a protective role in male physiology, while its deficiency may increase the susceptibility of males to metabolic syndrome. While this study was really meant to model men who are hypogonadal as a results of android deprivation treatment for prostate cancer, it seems to me to have potentially important implications for CR folks1, many of whom exhibit low-T, low muscle mass, and impaired glucose tolerance. The silver lining may be the observation about physical activity. By staying active (particularly after meals), and eating enough to maintaining muscle mass and avoid getting too skinny, we may be able to mask (if not altogether prevent) the negative effects of impaired glucose tolerance associated with serious CR that many of us have observed. --Dean ------- 1And Todd A in particular. ------------  Int J Obes (Lond). 2016 Aug 18. doi: 10.1038/ijo.2016.148. [Epub ahead of print] Perpetuating effects of androgen deficiency on insulin-resistance. Cameron JL, Jain R, Rais M, White AE, Beer TM, Kievit P, Winters-Stone K, Messaoudi I, Varlamov O. Full text: http://sci-hub.cc/10.1038/ijo.2016.148 Abstract Background/Objectives: Androgen deprivation therapy (ADT) is commonly used for treatment of prostate cancer, but is associated with side effects such as sarcopenia and insulin resistance. The role of lifestyle factors such as diet and exercise on insulin sensitivity and body composition in testosterone-deficient males is poorly understood. The aim of the present study was to examine the relationships between androgen status, diet, and insulin sensitivity. Subjects/Methods: Middle-aged (11-12-yo) intact and orchidectomized male rhesus macaques were maintained for two months on a standard chow diet, and then exposed for six months to a Western-style, high-fat/calorie-dense diet (WSD) followed by four months of caloric restriction (CR). Body composition, insulin sensitivity, physical activity, serum cytokine levels, and adipose biopsies were evaluated before and after each dietary intervention. Results: Both intact and orchidectomized animals gained similar proportions of body fat, developed visceral and subcutaneous adipocyte hypertrophy, and became insulin resistant in response to the WSD. CR reduced body fat in both groups, but reversed insulin resistance only in intact animals. Orchidectomized animals displayed progressive sarcopenia, which persisted after the switch to CR. Androgen deficiency was associated with increased levels of interleukin- 6 and macrophage-derived chemokine (CCL22), both of which were elevated during CR. Physical activity levels showed a negative correlation with body fat and insulin sensitivity. Conclusion: Androgen deficiency exacerbated the negative metabolic side effects of the WSD, such that CR alone was not sufficient to improve altered insulin sensitivity, suggesting that ADT patients will require additional interventions to reverse insulin resistance and sarcopenia. Key words: androgen deprivation therapy, hypogonadal, Western-style diet, obesity, sarcopenia. Abbreviations: ADT, androgen-deprivation therapy, CR, caloric restriction; NHP, nonhuman primate; SM, skeletal muscle; SC, subcutaneous; VIS, visceral; WAT, white adipose tissue; WSD, Western-style diet. PMID: 27534842