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TMAO & Cardiovascular Disease
AlPater posted a topic in General Health and Longevity[Admin Note: I made this new thread as a collector for posts about the recently discovered and previously discussed apparent link between diet, micronutrients choline and carnitine, TMAO production by gut microbes that feed on these micronutrients, and elevated risk of cardiovascular disease. Four posts down is the new post (by me) on the topic. The first four posts come from a different thread. --Dean] In his post about supplements for vegetarians, Michael Rae said: For now, prudence seems to require that vegetarians err on the side of a generous and definitely supplemented intake of choline, ensuring that dietary (to the extent that it can be known) plus supplemental choline is meaningfully higher than the AI of 550 mg for men and 425 mg/day for women. Functional status is still tricky, but one obvious set of markers is the same panel used to establish signs of deficiency in Zeisel’s depletion-repletion study:iv a fivefold or more increase above normal of the muscle-damage enzyme creatine phosphokinase (CPK), or a one-and-a-half or more times normal reading of the liver enzymes aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), or lactate dehydrogenase (LD). Fatty liver, unfortunately, requires a harder-to-access MRI of fat deposits in the organ, to which your doctor is unlikely to consent. The below papers may be a reason dietary choline can be bad for us. NATURE | RESEARCH HIGHLIGHTS CARDIOVASCULAR BIOLOGY Gut microbes raise heart-attack risk Nature 531, 278 (17 March 2016) doi:10.1038/531278b Published online 16 March 2016 http://sci-hub.io/10.1038/531278b Subject terms: Microbiology Cardiovascular biology Gut microbes produce a chemical that enhances clotting in the arteries, increasing the risk of heart attack and stroke. Stanley Hazen of the Cleveland Clinic in Ohio and his colleagues treated human platelets, which form blood clots, with a compound called TMAO. This is made in the body from a waste product of gut microbes, and has been linked to heart disease. The team found that TMAO made the platelets form artery-blocking clots faster. The researchers increased blood TMAO levels in mice by feeding them a diet that was rich in choline, a TMAO precursor, and found that the animals formed clots faster than did those with lower TMAO levels. This effect was not seen in animals that lacked gut microbes or that were treated with antibiotics. When intestinal microbes from mice that produced high levels of TMAO were transplanted into mice with no gut microbes, the recipients' clotting risk increased. The results reveal a link between diet, gut microbes and heart-disease risk, the authors say. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA, Brown JM, Lusis AJ, Hazen SL. Cell. 2016 Mar 9. pii: S0092-8674(16)30113-1. doi: 10.1016/j.cell.2016.02.011. [Epub ahead of print] PMID: 26972052 http://sci-hub.io/10.1016/j.cell.2016.02.011 Abstract Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
Eating Natto for Bone, Artery & Brain Health
Dean Pomerleau posted a topic in CR PracticeDoes anyone else eat natto, the fermented soybean product which is quite popular in Japan? It is the richest food source of vitamin K2 (menaquinone-7 or MK-7) with 1 mg (1000 mcg) of K2 per 100g natto. That is about 20x higher than the next highest source, certain cheeses like Gouda. Unlike vitamin K1 which is found primarily in leafy greens, there is virtually no vitamin K2 in regular fruits and vegetables. Why should we care about vitamin K2 you ask? First and foremost because it has been shown to be protective against osteoporosis [1-2], a concern for CR practitioners. From , a study of 244 postmenopausal women supplemented with 180mcg/day of Vitamin K2 (MK-7) for three years: MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS: MK-7 supplements may help postmenopausal women to prevent bone loss. Another significant benefit of Vitamin K2 is for cardiovascular health. Vitamin K2 seems to prevent artery calcification (aka hardening of the arteries) [3-5], which happens when calcium circulating in the blood is turned into a crust in the arteries. In study  the same group of researchers from  measured arterial calcification in the same 244 postmenopausal women on 180mcg/day of K2 for three years, and found multiple markers of arterial stiffness improved with K2 supplementation, concluding: Long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness. But those were studies of direct supplementation of vitamin K2 (MK-7), rather than getting it from food. Does eating natto actually raise serum MK-7 levels? Thankfully the answer is yes, according to : erum MK-7 level with the frequency of dietary natto intake were examined in 134 healthy adults (85 men and 39 women) without and with occasional (a few times per month), and frequent (a few times per week) dietary intake of regular natto including MK-7 (775 micrograms/100 g). Serum MK-7 and gamma-carboxylated osteocalcin concentrations in men with the occasional or frequent dietary intake of natto were significantly higher than those without any intake. So where to get natto? I buy my natto in frozen form at my local asian market, for about $2.50 for four styrofoam containers each of which contains about 50g of natto. Here is what the package of four look like: I eat half of a container's worth of natto per day (cost ~ $0.30/day). That 25g of natto per day provides about 250mcg of Vitamin K2 (MK-7), which is about 30% more than the dose shown to improve bone health  and reduce arterial stiffness  in postmenopausal women. What's natto like you ask? There is no getting around the fact that it looks pretty gross, and has a very slimy texture. As a result, many people can't stomach it, but I actually enjoy the taste, especially when mixed into the serving of other legumes and starches I eat. Below is a photo of natto in the styrofoam container. Pretty appetizing, huh?! The chopsticks in the photo are helpful for scale: For those of you who would be too grossed out by natto to eat it, there are supplements available. In fact I take one of these* to increase my K2 beyond what I get from natto - adding an extra 100mcg MK-7 per day for $0.09. But I'm always in favor of getting nutrients from food sources when practical. This is one of the rare cases where the natural food source is price competitive with supplement sources. So for me natto is a good choice. Does anyone else eat natto? If not, you might consider giving it a try! [Note: This post does not address Natto's brain health benefits. For discussion of that, see this post further down this thread.] --Dean *Note - I've updated my supplement regime to this vegan NOW Foods brand K2 supplement, to make sure I'm getting K2 in MK-7 form, rather than (mostly) MK-4 per my previous supplement. ---------  J Bone Miner Metab. 2014 Mar;32(2):142-50. doi: 10.1007/s00774-013-0472-7. Epub 2013 May 24. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. Koitaya N(1), Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishimi Y. Author information: (1)Department of Food Function and Labeling, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjyuku-ku, Tokyo, Japan. Menaquinone-4 (MK-4) administered at a pharmacological dosage of 45 mg/day has been used for the treatment of osteoporosis in Japan. However, it is not known whether a lower dose of MK-4 supplementation is beneficial for bone health in healthy postmenopausal women. The aim of this study was to examine the long-term effects of 1.5-mg daily supplementation of MK-4 on the various markers of bone turnover and bone mineral density (BMD). The study was performed as a randomized, double-blind, placebo-controlled trial. The participants (aged 50-65 years) were randomly assigned to one of two groups according to the MK-4 dose received: the placebo-control group (n = 24) and the 1.5-mg MK-4 group (n = 24). The baseline concentrations of undercarboxylated osteocalcin (ucOC) were high in both groups (>5.1 ng/ml). After 6 and 12 months, the serum ucOC concentrations were significantly lower in the MK-4 group than in the control group. In the control group, there was no significant change in serum pentosidine concentrations. However, in the MK-4 group, the concentration of pentosidine at 6 and 12 months was significantly lower than that at baseline. The forearm BMD was significantly lower after 12 months than at 6 months in the control group. However, there was no significant decrease in BMD in the MK-4 group during the study period. These results suggest that low-dose MK-4 supplementation for 6-12 months improved bone quality in the postmenopausal Japanese women by decreasing the serum ucOC and pentosidine concentrations, without any substantial adverse effects. PMID: 23702931 ------------  Osteoporos Int. 2013 Sep;24(9):2499-507. doi: 10.1007/s00198-013-2325-6. Epub 2013 Mar 23. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Knapen MH(1), Drummen NE, Smit E, Vermeer C, Theuwissen E. Author information: (1)VitaK, Maastricht University, Oxfordlaan 70, 6229 EV, Maastricht, The Netherlands. We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss.INTRODUCTION: Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K's role in maintenance of normal bone. In line with EFSA's opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. METHODS: Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. RESULTS: MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. CONCLUSIONS: MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation. PMID: 23525894 -----------  Acta Physiol Hung. 2010 Sep;97(3):256-66. doi: 10.1556/APhysiol.97.2010.3.2. Vitamin K and vascular calcifications. Fodor D(1), Albu A, Poantă L, Porojan M. Author information: (1)University of Medicine and Pharmacy, 2nd Internal Medicine, Clinic Iuliu Hatieganu, Cluj-Napoca, Romania. email@example.com The role of vitamin K in the synthesis of some coagulation factors is well known. The implication of vitamin K in vascular health was demonstrated in many surveys and studies conducted over the past years on the vitamin K-dependent proteins non-involved in coagulation processes. The vitamin K-dependent matrix Gla protein is a potent inhibitor of the arterial calcification, and may become a non-invasive biochemical marker for vascular calcification. Vitamin K(2) is considered to be more important for vascular system, if compared to vitamin K(1). This paper is reviewing the data from recent literature on the involvement of vitamin K and vitamin K-dependent proteins in cardiovascular health. PMID: 20843764 ----------------  Nutrients. 2015 Aug 18;7(8):6991-7011. doi: 10.3390/nu7085318. High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification. Scheiber D(1), Veulemans V(2), Horn P(3), Chatrou ML(4), Potthoff SA(5), Kelm M(6,)(7), Schurgers LJ(8), Westenfeld R(9). Author information: (1)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. firstname.lastname@example.org. (2)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. email@example.com. (3)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. firstname.lastname@example.org. (4)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. email@example.com. (5)Department of Nephrology, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. firstname.lastname@example.org. (6)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. email@example.com. (7)Cardiovascular Research Institute Duesseldorf, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. firstname.lastname@example.org. (8)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. email@example.com. (9)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. firstname.lastname@example.org. Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures. PMCID: PMC4555157 PMID: 26295257 -------------  Thromb Haemost. 2015 May;113(5):1135-44. doi: 10.1160/TH14-08-0675. Epub 2015 Feb 19. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C(1). Author information: (1)Cees Vermeer, PhD, VitaK, Maastricht University, Biopartner Center Maastricht, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands, Tel: +31 43 388 5865, Fax: +31 43 388 5889, E-mail: email@example.com. Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 µg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index βsignificantly decreased in the total group, whereas distension, compliance, distensibility, Young's Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness. PMID: 25694037 ----------  J Bone Miner Metab. 2000;18(4):216-22. Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. Tsukamoto Y(1), Ichise H, Kakuda H, Yamaguchi M. Author information: (1)Central Research Institute, Mitsukan Group Co., Ltd., Aichi, Japan. Changes in circulating vitamin K2 (menaquinone-7, MK-7) and gamma-carboxylated osteocalcin concentrations in normal individuals with the intake of fermented soybeans (natto) were investigated. Eight male volunteers were given sequentially fermented soybeans (natto) containing three different contents of MK-7 at an interval of 7 days as follows: regular natto including 775 micrograms/100 g (MK-7 x 1) or reinforced natto containing 1298 micrograms/100 g (MK-7 x 1.5) or 1765 micrograms/100 g (MK-7 x 2). Subsequently, it was found that serum MK-7 and gamma-carboxylated osteocalcin concentrations were significantly elevated following the start of dietary intake of MK-7 (1298 or 1765 micrograms/100 g). Serum undercarboxylated osteocalcin concentrations were significantly decreased by dietary MK-7 (1765 micrograms/100 g) supplementation. Moreover, the changes in serum MK-7 level with the frequency of dietary natto intake were examined in 134 healthy adults (85 men and 39 women) without and with occasional (a few times per month), and frequent (a few times per week) dietary intake of regular natto including MK-7 (775 micrograms/100 g). Serum MK-7 and gamma-carboxylated osteocalcin concentrations in men with the occasional or frequent dietary intake of natto were significantly higher than those without any intake. The present study suggests that intake of fermented soybean (natto) increases serum levels of MK-7 and gamma-carboxylated osteocalcin in normal individuals. PMID: 10874601
All, As discussed in this thread, evidence suggests ALA may be beneficial for brain health in most people, while DHA/EPA may be a mixed blessing - only helpful for avoid Alzheimer's disease (but not other forms of dementia) in those with the APOE4 allele. And as discussed in this thread, fatty fish high in DHA/EPA may be detrimental for cardiovascular health if contaminated with PCBs, as was the case in several studies of Swedish fish eaters. But this new study  shared by Al Pater (thanks Al!) found in another population of fish eaters, this time from Spain, dietary DHA/EPA may in fact be beneficial for avoiding cardiovascular mortality. But dietary DHA/EPA was not significantly beneficial for all-cause mortality. For dietary Alpha Linolenic Acid (ALA) which is an omega-3 from plants (e.g. walnuts, olive oil, flax, chia seeds) the opposite was the case. Namely, dietary ALA reduced all-cause mortality, but not cardiovascular mortality risk. Putting the two together, people who met the dietary recommendations for both DHA/EPA and ALA had the lowest all-cause mortality risk - 37% lower than those who didn't meet either recommendation. Perhaps the fish from Spain have less PCBs than Swedish fish (no - I don't mean the candy :-) ). The full text of the study did not address DHA/EPA supplements - DHA/EPA intake was assessed solely from dietary sources. So it is not clear if a similar beneficial effect could be achieved through a combination of ALA from plant sources and DHA/EPA supplements as fish oil or algae oil, both of which are less likely to be contaminated with mercury or PCBs than the flesh of whole fish. --Dean ------  J Am Heart Assoc. 2016 Jan 26;5(1). pii: e002543. doi: 10.1161/JAHA.115.002543. Dietary Alpha-Linolenic Acid, Marine Omega-3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study. Sala-Vila A, Guasch-Ferré M, Hu FB, et al. http://jaha.ahajournals.org/content/5/1/e002543.long http://jaha.ahajournals.org/content/5/1/e002543.full.pdf+html Abstract BACKGROUND: Epidemiological evidence suggests a cardioprotective role of Alpha-linolenic acid (ALA), a plant-derived Omega-3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine Omega-3 fatty acids (long-chain n-3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all-cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long-chain n-3 polyunsaturated fatty acids (=/>500 mg/day). METHODS AND RESULTS: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable-adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9-y follow-up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56-0.92) for all-cause mortality and 0.95 (95% CI 0.58-1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long-chain n-3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67-1.05) for all-cause mortality, 0.61 (95% CI 0.39-0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29-0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22-1.01) for sudden cardiac death. The highest reduction in all-cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45-0.87]). CONCLUSIONS: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all-cause mortality, whereas protection from cardiac mortality is limited to fish-derived long-chain n-3 polyunsaturated fatty acids. KEYWORDS: fatty acid; nutrition; sudden cardiac death PMID: 26813890
Testosterone, Luteinizing Hormone and Mortality
Dean Pomerleau posted a topic in CR Science & TheoryAll, 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 ! 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 , sarcopenia , cognitive decline , and an increased risk of cardiovascular disease. Regarding the latter, some studies (e.g. see  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 . Interestingly, this meta-analysis  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  (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 ----------  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 ------------  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  . 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 --------------  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 ---------------  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. firstname.lastname@example.org 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 -------------  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 -------------  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