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  1. All, Testosterone (T) and other sex hormone levels have always been a topic of interest and concern to CR practitioners. Some men (like me) report dramatically reduced T levels, down to levels not typically seen in any men except the very elderly. Others seem to maintain their T at fairly normal levels for their age. So which is better? On the one hand, low testosterone has sometimes been considered a CR "badge of courage" (among men anyway) - indicating one is practicing serious CR, and a positive reflection of the body trading off fecundity for upregulation of maintenance & repair functions (similar to low IGF-1). Women live longer than men across cultures, which some attribute to differences in T level, and eunuchs have been found to live longer, by as much as 15-20 years [2]! On the other hand, low T often (but not always) has a dramatic effect on libido, and one's overall aggressive drive to succeed / accomplish things. On the health side, negative health outcomes are frequently associated with hypogonadism (low T) in men, including bone health issues [4], sarcopenia [4], cognitive decline [5], and an increased risk of cardiovascular disease. Regarding the latter, some studies (e.g. see [3] for review) have found T supplementation in hypogonadal men reduces cardiovascular disease risk, but the effect may be limited to obese men with metabolic syndrome, or may result from pharmaceutical industry bias in T supplementation trials [6]. Interestingly, this meta-analysis [6] found that in trials not sponsored by Big Pharma, CVD risk was increased among men receiving supplemental T (OR 2.06, 95% CI 1.34 to 3.17). So overall, the relationship between the low T that many serious male CR practitioners exhibit and our long-term health & longevity remains an open question. Moreover, hypogonadism in the general population is typically associated with obesity and metabolic syndrome, obviously a very different etiology than hypogonadism in CR practitioners, making the picture even more muddled... So I reacted with interest, but also some trepidation, when I saw Al Pater post this new study [1] (thanks Al!), on the association of T and other sex hormones with all-cause, cancer and cardiovascular mortality in men. So let's dive in. First off, this was not a supplementation trial - they measured the natural levels of T, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Sex Hormone Binding Globulin (SHBG), free testosterone (FT), and estradiol (E) and in 5300 men of all ages and followed them for an average of 18.5 years to see how many died, from what causes, and how their deaths were associated with these sex hormones. Here are some interesting statistics at baseline, from the free full text Table 1 (see below): As expected, T and FT was lower in older men, whereas LH, FSH, and SHBG increased. Interestingly, smokers had higher T, FT, LH, FSH, E and SHBG than non-smokers at baseline. Exercise, and particular "competitive sport" participation, was associated with increased T, FT, and lower LH. Could be reverse causality - people with high T are more aggressive and therefore more likely to be attracted to competitive sports... Overweight and obese men had dramatically lower T and FT at baseline - which will be important later. Here is the baseline data for sex hormones by demographics for anyone interested in the details (click to enlarge): Now the interesting part - the mortality results (some of which comes from the text of the supplemental material). First for cancer mortality: There was a between-quartile trend towards increased cancer mortality with higher T, but the differences was only really significant in smokers in the highest quartile of T (OR 1.53, 95%CI: 1.14 – 2.08). In non-smokers, T and FT had virtually no impact on cancer mortality. But there was a pretty strong trend towards more cancer with higher levels of LH and FSH. Keep an eye on LH in particular, it will be important later... And now, CVD mortality: Men with total testosterone levels in the highest quartile had a reduced risk of CVD mortality compared to men in the lowest quartile (HR 0.72, 95% CI: 0.53– 0.98). The same relationship held for FT. It is looking bad for us hypogonadal CRers... But this increased CVD risk with low T (and FT) was in the fully-adjusted model, which included factoring out BMI from the analysis (recall overweight/obese men had dramatically lower T and FT at baseline). In a model that adjusted for waist circumference instead of BMI, and especially in a model that adjusted for # of markers of metabolic syndrome, the increased risk of CVD with lower T and FT dropped dramatically to the point of no longer being significant between the highest and lowest quintiles of T = (OR 0.66, 95%CI: 0.38-1.16). In other words, to first approximations, if you ignore low T and FT resulting from (or associated with) metabolic syndrome, the association between low T (and FT) and increased CVD goes away... And now, the all-important All-cause mortality: There was no significant differences in all-cause mortality across age-standardized quartiles of T (OR 1.01, 95%CI: 0.87-1.18) - to some degree higher cancer risk and lower CVD risk with higher T offset each other, so all-cause mortality was a wash with higher T. The same lack of significant mortality effect was seen for inter-quartile comparison of FT (OR 0.87, 95%CI: 0.75-1.00), but when the trend from lowest to highest quartile of FT was considered, lower FT was associated with increased all-cause mortality (p for trend < 0.02). Again, looking (somewhat) bad for hypogonadal CRers... An increased all-cause mortality was seen for men in the highest (vs. lowest) quartiles of LH and estradiol, (HR 1.32, 95% CI: 1.14 –1.53) and (HR 1.23, 95% CI: 1.06 –1.43), respectively. If you are confused by now, perhaps this graphical depiction of the major study findings for all-cause and CVD mortality (with my color highlights) will help (click to enlarge): As you can see, if we focus on all-cause mortality, higher SHBG, higher LH, and lower FT are associated with increased risk. So what the heck does all this mean?!?! Here is my take on it, basically paraphrasing the authors' discussion / speculation. Obesity, and especially metabolic syndrome, are associated with increased mortality risk, and reduced T and FT levels. It may therefore be that low T (& FT) is a marker for impaired androgen signalling in men with metabolic syndrome - i.e. their sex-hormone signalling is messed up, just like some of their other pathways (e.g. insulin signalling) are messed up by all the fat they are carrying. As a result, their LH is elevated - i.e. the "captain" is asking (via increased LH) the "engine room" (i.e. Leydig cells) to produce more T, but the Leydig cells aren't up to the task perhaps because they are gummed up with fat, so T remains low despite elevated LH calling for more. This could be similar in some respects to diabetes, in which insulin doesn't work to clear glucose because of fat so the body calls for the pancreas to produce more, and eventually the beta cells in the pancreas give up the ghost and can't make enough insulin to clear blood glucose. So what does this mean for CR practitioners? In us, T is low on purpose from the body's perspective (if I may speak teleologically) - as indicated by our low LH levels (my bloodwork shows my LH to always be near or below the low end of the RR since starting CR). In other words, rather than T being low because the body can't/won't make it (as is the case in guys with metabolic syndrome), our T is low because our body doesn't need or want it. Again it is perhaps a story similar to IGF-1 and insulin. We (hopefully) have low fasting insulin not because our beta cells are messed up and can't make it (like in late-stage diabetes resulting from metabolic syndrome), but because our bodies don't need/want much insulin - we've got enough insulin to clear the modest amount of glucose we have to process, especially since our insulin sensitivity remains high. So in short, our low T and low FT may reflect an entirely different, (hopefully) healthier state to be in than having low T and FT as a result of metabolic syndrome. But then again, that might be just wishful thinking. In particular, our low T and FT may be "intentional" on the part of our body and it may not be good for us in the long run. In other words, our bodies may be hunkering down to survive the (self-induced) famine by lowering T and FT, but in the process sacrificing "non-critical" systems like muscle mass, bone health, and cognitive function - systems that apparently benefit downstream from higher levels of testosterone. It seems it could go either way. But in any case, we're unlikely to be in as bad shape along these dimensions as men who have low T and FT as a result of metabolic syndrome. I hope this has done more to clarify than confuse. But re-reading, I'm not so sure... --Dean ---------- [1] J Clin Endocrinol Metab. 2015 Oct 21:jc20152460. [Epub ahead of print] The association of reproductive hormone levels and all-cause, cancer and cardiovascular disease mortality in men. Agergaard Holmboe S, Vradi E, Kold Jensen T, Linneberg A, Husemoen LL, Scheike T, Skakkebæk NE, Juul A, Andersson AM. Full Text: http://press.endocrine.org/doi/pdf/10.1210/jc.2015-2460 Abstract CONTEXT: Testosterone levels (T) have been associated with mortality, but controversy exists. OBJECTIVE: To investigate associations between serum levels of total testosterone, SHBG, free testosterone, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up. DESIGN: A prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up. SETTING AND PARTICIPANTS: 5,350 randomly selected men from the general population aged 30, 40, 50, 60 or 70 years at baseline. MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular disease (CVD) mortality and cancer mortality. RESULTS: 1,533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (HR=1.32, 95%CI: 1.14 to 1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR=1.23, 95%CI: 1.06 to 1.43, HR=1.23, 95%CI: 1.06 to 1.43). No association to testosterone levels was found. Higher LH levels were associated with increased cancer mortality (HR=1.42, 95%CI: 1.10 to 1.84) independently of smoking status. Lower CVD mortality was seen for men with testosterone in the highest quartile compared to lowest (HR=0.72, 95%CI: 0.53 to 0.98). Furthermore, negative trends were seen for SHBG and free testosterone in relation to CVD mortality, however insignificant. CONCLUSION: The observed positive association of LH and LH/T, but not testosterone, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency. PMID: 26488309 ------------ [2] Curr Biol. 2012 Sep 25;22(18):R792-3. doi: 10.1016/j.cub.2012.06.036. The lifespan of Korean eunuchs. Min KJ, Lee CK, Park HN. Free Full Text: http://www.cell.com/current-biology/abstract/S0960-9822(12)00712-9 Abstract Although many studies have shown that there are trade-offs between longevity and reproduction, whether such trade-offs exist in humans has been a matter of debate [1,2] . In many species, including humans, males live shorter than females, which could be due to the action of male sex hormones. Castration, which removes the source of male sex hormones, prolongs male lifespan in many animals, but this issue has been debated in humans [3] . To examine the effects of castration on longevity, we analyzed the lifespan of historical Korean eunuchs. Korean eunuchs preserved their lineage by adopting castrated boys. We studied the genealogy records of Korean eunuchs and determined the lifespan of 81 eunuchs. The average lifespan of eunuchs was 70.0 ± 1.76 years, which was 14.4–19.1 years longer than the lifespan of non-castrated men of similar socio-economic status. Our study supports the idea that male sex hormones decrease the lifespan of men. PMID: 23017989 -------------- [3] Expert Opin Drug Saf. 2014 Oct;13(10):1327-51. doi: 10.1517/14740338.2014.950653. Epub 2014 Aug 19. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Corona G(1), Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M. Author information: (1)Azienda-Usl Bologna, Maggiore-Bellaria Hospital, Medical Department, Endocrinology Unit , Bologna , Italy. INTRODUCTION: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. AREAS COVERED: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. EXPERT OPINION: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient's metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease. PMID: 25139126 --------------- [4] Clin Endocrinol (Oxf). 2005 Sep;63(3):280-93. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Isidori AM(1), Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Author information: (1)Cattedra di Andrologia, Universita 'La Sapienza', Rome, Italy. andrea.isidori@uniroma1.it OBJECTIVES: Ageing in men is associated with a gradual decline in serum testosterone levels and a concomitant loss of muscle mass, accumulation of central adiposity, impaired mobility and increased risk of bone fractures. Whether androgen treatment might be beneficial in these subjects is still under debate. We have carried out a systematic review of randomized controlled trials (RCTs) evaluating the effects of testosterone (T) administration to middle-aged and ageing men on body composition, muscle strength, bone density, markers of bone metabolism and serum lipid profile. DATA SOURCE: A comprehensive search of all published randomized clinical trials was performed using the MEDLINE, Cochrane Library, EMBASE and Current Contents databases. REVIEW METHODS: Guided by prespecified criteria, software-assisted data abstraction and quality assessed by two independent reviewers, 29 RCTs were found to be eligible. For each investigated variable, we reported the results of pooled estimates of testosterone treatment using the random effect model of meta-analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta-regression analysis. RESULTS: Overall, 1,083 subjects were evaluated, 625 randomized to T, 427 to placebo and 31 to observation (control group). Weighted mean age was 64.5 years (range 49.9--77.6) and mean serum testosterone was 10.9 nmol/l (range 7.8--19). Testosterone treatment produced: (i) a reduction of 1.6 kg (CI: 2.5--0.6) of total body fat, corresponding to -6.2% (CI: 9.2--3.3) variation of initial body fat, (ii) an increase in fat free mass of 1.6 kg (CI: 0.6--2.6), corresponding to +2.7% (CI: 1.1--4.4) increase over baseline and (iii) no change in body weight. The effects of T on muscle strength were heterogeneous, showing a tendency towards improvement only at the leg/knee extension and handgrip of the dominant arm (pooled effect size=0.3 standard mean difference (SMD), CI: -0.0 to 0.6). Testosterone improved bone mineral density (BMD) at the lumbar spine by +3.7% (CI: 1.0--6.4%) compared to placebo, but not at the femoral neck, and produced a consistent reduction in bone resorption markers (pooled effect size = -0.6 SMD, CI: -1.0 to -0.2). Testosterone also reduced total cholesterol by 0.23 mmol/l (CI: -0.37 to -0.10), especially in men with lower baseline T concentrations, with no change in low density lipoprotein (LDL)-cholesterol. A significant reduction of high density lipoprotein (HDL)-cholesterol was found only in studies with higher mean T-values at baseline (-0.085 mmol/l, CI: -0.017 to -0.003). Sensitivity and meta-regression analysis revealed that the dose/type of T used, in particular the possibility of aromatization, explained the heterogeneity in findings observed on bone density and HDL-cholesterol among studies. CONCLUSION: The present analysis provides an estimate of the average treatment effects of testosterone therapy in middle-aged men. Our findings are sufficiently strong to justify further interventional studies focused on alternative targets of androgenic treatment carrying more stringent clinical implications, in particular the cardiovascular, metabolic and neurological systems. PMID: 16117815 ------------- [5] Mol Neurobiol. 2015 Jul 8. [Epub ahead of print] Low Testosterone Level and Risk of Alzheimer's Disease in the Elderly Men: a Systematic Review and Meta-Analysis. Lv W(1), Du N(1), Liu Y(1), Fan X(1), Wang Y(1), Jia X(2), Hou X(3), Wang B(4). Sex steroids can positively affect the brain function, and low levels of sex steroids may be associated with worse cognitive function in the elderly men. However, previous studies reported contrary findings on the relationship between testosterone level and risk of Alzheimer's disease in the elderly men. The objective of this study was to comprehensively assess the relationship between low testosterone level and Alzheimer's disease risk in the elderly men using a meta-analysis. Only prospective cohort studies assessing the influence of low testosterone level on Alzheimer's disease risk in elderly men were considered eligible. Relative risks (RRs) with 95 % confidence intervals (95 % CI) were pooled to assess the risk of Alzheimer's disease in elderly men with low testosterone level. Seven prospective cohort studies with a total of 5251 elderly men and 240 cases of Alzheimer's disease were included into the meta-analysis. There was moderate degree of heterogeneity among those included studies (I (2) = 47.2 %). Meta-analysis using random effect model showed that low plasma testosterone level was significantly associated with an increased risk of Alzheimer's disease in elderly men (random RR = 1.48, 95 % CI 1.12-1.96, P = 0.006). Sensitivity analysis by omitting one study by turns showed that there was no obvious change in the pooled risk estimates, and all pooled RRs were statistically significant. This meta-analysis supports that low plasma testosterone level is significantly associated with increased risk of Alzheimer's disease in the elderly men. Low testosterone level is a risk factor of worse cognitive function in the elderly men. PMID: 26154489 ------------- [6] BMC Med. 2013 Apr 18;11:108. doi: 10.1186/1741-7015-11-108. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. Xu L(1), Freeman G, Cowling BJ, Schooling CM. Author information: (1)School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China. Comment in Evid Based Med. 2014 Feb;19(1):32-3. BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy. PMID: 23597181
  2. Low testosterone (hypogonadism), besides potentially reducing quality of life (a commonly held notion the validity of which many of us male CR folks would contend...), has been thought to be potentially associated with increased mortality, particularly from cardiovascular disease, at least among the general (non-CR) population. Here again is a situation where we hope that our low testosterone (as frequently but not universally experienced by CR men) has different health/longevity implications than hypogonadism in the general population, where it is frequently associated with obesity and other indicators of ill-health. Well, this study posted by Al Pater (thanks Al!) from the Framingham Heart Study may help ease those doubts and concerns. It found that even in a general population of 254 elderly men (avg age 75), neither low testosterone nor absolute level or change in other sex hormones were associated with increased mortality at either 5 or 10 year follow-up, once other confounding factors were statistically factored out. The confounders they corrected for were age, body mass index, smoking, total cholesterol, high-density lipoprotein cholesterol, type 2 diabetes, systolic blood pressure, and antihypertensive medication - all of which seem reasonable to factor out. To quote from the discussion of the free full text: Leveraging the unique data set and design of the community-based FHS, the present study is the first to investigate longitudinal trajectory patterns of serial sex steroid and gonadotropins measurements and their associations with 5-year and 10-year risk of incident clinical CVD and all-cause mortality. We observed no consistent association of sex steroids, gonadotropins, and their trajectories with incident clinical CVD or all-cause mortality risk in 254 elderly men in the community. In other words, it appears that if you are a healthy elderly man (i.e. without the confounders listed above, which hopefully most CR folks do/will avoid), having low testosterone is not associated with an increased risk of cardiovascular disease or overall mortality. So we've got that goin' for us... --Dean ----------- [1] Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study. Haring R, Teng Z, Xanthakis V, Coviello A, Sullivan L, Bhasin S, Murabito JM, Wallaschofski H, Vasan RS. Clin Endocrinol (Oxf). 2013 Apr;78(4):629-34. doi: 10.1111/cen.12013. PMID: 22901104 Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161203/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161203/pdf/nihms622794.pdf Abstract BACKGROUND: Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date. METHODS: We prospectively evaluated 254 elderly men (mean age, 75·5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5- and 10-year follow-up. RESULTS: We observed no association between baseline concentrations of sex steroids, gonadotrophins and their trajectories with incident clinical CVD over 5- and 10-year follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5 years (hazard ratio per quartile increment, 0·74; 95% confidence interval, 0·56-0·98), correction for multiple statistical testing (P < 0·005) rendered this association statistically nonsignificant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotrophins or their trajectories and mortality. CONCLUSION: Investigating longitudinal trajectory patterns of serial sex steroid and gonadotrophin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men from the community.
  3. All, Al's latest post about new CR paper contained a really interesting new study in rhesus monkeys [1], 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. ------------ [1] 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
  4. I came across this gem - a cross sectional/correlational study on being a father and T levels. The reason I think it's important is that Tanzanian hunter gatherers are known to eat 100-150g of fibre daily, something many of us here do. In addition they have a low BMI and low energy intake. http://rspb.royalsocietypublishing.org/content/276/1655/347 I'm typing this from my phone so my response has to be limited, but here were some points I picked up on: -their T in general is far lower than Americans - 150 pmol vs Americans being 250-400pmol (I'm not familiar with this unit and google didn't help) -caring for offspring closely lowered AM T by 30% and PM T by 50% (same trend not seen in America) -more closely caring for children lowered T more, while distance parenting didn't -fidelity lowered T -T didn't vary by age in these groups, suggesting you can maintain some T as you age Maybe this is why some CR practitioners like Paul McGlothin are able to maintain youthful T levels. Thoughts?
  5. Here is a crazy study [1] that Al came across (thanks Al!) that appears legit. It found that men who suffered from moderate "male pattern baldness" had an 83% higher risk of developing fatal prostate cancer then men with a full head of hair. It seems that male pattern baldness, otherwise know as androgenic alopecia, results from exposure of hair follicles to the hormone dihydrotestosterone (DHT) which is synthesized from testosterone. So the authors suggest that male pattern baldness is a proxy for higher long-term testosterone exposure, which seems to be associated with elevated risk of fatal prostate cancer. So practicing CR, which appears to reduce total and free testosterone in men, may not (only?) extend our lives, but may help us keep our hair and avoid dying from prostate cancer. :-) --Dean ------------ [1] Am J Epidemiol. 2016 Feb 1;183(3):210-7. doi: 10.1093/aje/kwv190. Epub 2016 Jan 12. Male Pattern Baldness in Relation to Prostate Cancer-Specific Mortality: A Prospective Analysis in the NHANES I Epidemiologic Follow-up Study. Zhou CK, Levine PH, Cleary SD, Hoffman HJ, Graubard BI, Cook MB. http://sci-hub.io/10.1093/aje/kwv190 Abstract We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer–specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971–1974), we included 4,316 men who were 25–74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables used to calculate sample weights. During follow-up (median, 21 years), 3,284 deaths occurred; prostate cancer was the underlying cause of 107. In multivariable models, compared with no balding, any baldness was associated with a 56% higher risk of fatal prostate cancer (hazard ratio = 1.56; 95% confidence interval: 1.02, 2.37), and moderate balding specifically was associated with an 83% higher risk (hazard ratio = 1.83; 95% confidence interval: 1.15, 2.92). Conversely, patterned hair loss was not statistically significantly associated with all-cause mortality. Our analysis suggests that patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms. PMID: 26764224
  6. drewab

    Is CR for me?

    Hi All, I'm trying to decide if CR is really a good fit for me. Without revealing too much, here is what I can say. I've been following a WFPB for nearly 5 years. By default a plant-based diet (vegan) diet is a form of CR, but not quite all the way to what many people here practice. I seem to oscillate right of the cusp of authentic CR. Many biomarkers are close, but may sway back and forth. Here is some of my info: -31, male, BMI = 20.7, (always between 20-21) -5"11, 143-150 pounds, depending on time of year, fitness, etc. -Low body temperature (usually 35.8ish) -BP fluctuates between being super good, and just good (i.e.. 100/60 up to 120/80). This seems to tell me I'm right on the cusp of CR. -I exercise a decent amount. Covering 15000-20000 footsteps daily, along with weight training 2x weekly, daily meditation and yoga. -Extremely low or immeasurable markers of inflammation (PSA, CRP, homocysteine, low-ish WBC) -Cortisol sometimes creeps up, sometimes not -I recently had my IGF-1 tested and was really surprised it came back at 280! But I may have messed up the test results by binging on some dates the night before. -The reason for WFPB/CR is that I was experiencing some major health crisis at the time, which had been ongoing for a long, long time. Here is a sample of what I ate yesterday, for about 2500 calories: (anything less for calories, and my weight has been dropping) a. Oats, chia, cocoa, spinach/chard/kale, banana, cherries b. Lentils, spring mix, banana, 1/2 avocado c. Barley, bell pepper, onion, green beans, broccoli, cauliflower, blackberries, 1/2 avocado My biggest conundrum is the issue of testosterone. I had it tested pre-WFPB and it came back at 9 (range 10-28 and my weight at that time was about 175 pounds). Since then it's been all over the place. It's been as low as 2 and as high as 15, and I've had it tested maybe 6 times. My concern is that if I really get serious about CR, I will decimate my already 'iffy' levels of testosterone. Now, I'm married, have kids, and don't need to be chasing around anyone, but it seems like I might not be the best fit for CR. Or maybe I'm right in the range of CR/not CR'd given that my T levels and some other tests have varied so much. Thoughts? Am I a good candidate for CR?
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