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[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.

Does 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 [2], 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 [5] the same group of researchers from [2] 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 [6]: 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 [2] and reduce arterial stiffness [5] 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. --------- [1] 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 ------------ [2] 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 ----------- [3] 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. dfodor@umfcluj.ro 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 ---------------- [4] 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. daniel.scheiber@med.uni-duesseldorf.de. (2)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. verena.veulemanns@med.uni-duesseldorf.de. (3)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. patrick.horn@med.uni-duesseldorf.de. (4)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. m.chatrou@maastrichtuniversity.nl. (5)Department of Nephrology, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. sebastian.potthoff@med.uni-duesseldorf.de. (6)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. malte.kelm@med.uni-duesseldorf.de. (7)Cardiovascular Research Institute Duesseldorf, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany. malte.kelm@med.uni-duesseldorf.de. (8)Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands. l.schurgers@maastrichtuniversity.nl. (9)Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany. ralf.westenfeld@med.uni-duesseldorf.de. 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 ------------- [5] 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: c.vermeer@vitak.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 ---------- [6] 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 [1] 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 ------ [1] 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

[Admin Note: Over on the LDL particle size thread, Todd asked the question of why eggs are bad. Seems like a question that deserves its own thread, given the recent supposed exoneration of dietary cholesterol. So here it is.] The important difference between consumption of dietary cholesterol, which has a negligible influence on heart disease risk, and cholesterol produced endogenously in the body (which can be a marker of risk, depending on a complete profile).... So why exactly is it that eggs are so damn bad? http://www.whfoods.com/genpage.php?tname=foodspice&dbid=92

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

All, We had a pretty long thread not too long ago about Total Cholesterol and Heart Attack Risk but as far as I can tell we haven't talked much about the relative value of a standard lipid panel vs. some of the newer tests for various LDL particle sizes, densities etc. I bring it up for two reasons: One is personal. A family member in their early 50s is an APOE4 carrier (single allele) and not surprisingly, has borderline high cholesterol (210 mg/dL total, 120 LDL, 55 HDL). They are otherwise thin, active, healthy with good fasting blood glucose. So it seems they are one of those borderline cases for statins, and I'm wondering whether getting their LDL particle sizes tested might provide some additional useful diagnostic information for making that decision. I would lean against starting statins in their case (due to possible side effects see below), but I'm wondering if the discovery that they have many (or very few) small dense LDL particles might tip the scales one way or the other. The second reason I bring it up is because I just listened to a long (1:20:00) but very interesting interview by Dr. Rhonda Patrick with Dr. Ronald Krauss, who appears to be a pioneer in research into cholesterol and CVD, the effects of diet on CVD risk, statin side effects, particle size testing etc. I found it really educational to learn more about the mechanics of atherosclerosis, e.g. the details of how inflammation is involved and why we might have evolved to work that way. How small LDL particles have the part of their surface structure occluded just where the liver's LDL-receptor tries to attach to them, making the small particles harder to clear from the bloodstream, making them stick around in the bloodstream for longer to get oxidized / glycated and to infiltrate the arterial walls. Lots of good stuff I didn't know before. But a couple caveats. I'm not an expert on the details of how atherosclerosis works, or anything about particle sizes, so while I found it interesting, I can't vouch for the validity of Dr. Krauss's perspective or the information he shared. And I will note that Dr. Krauss co-authored with Dr. Patty Siri-Tarino and several others a pretty poor and misleading meta-analysis which appeared to call into question the link between saturated fat and heart disease. Their meta-analysis has been roundly criticized briefly by Michael in this thread and more thoroughly by PlantPositive here. He also mentioned he's been sponsored by the dairy industry, and has a patent and receives royalties on a new cutting edge LDL particle measurement test called Cardio IQ® Lipoprotein Fractionation, Ion Mobility which is now available from Quest. So all that is to meant to suggest that one should take what Dr. Krauss says in this interview with a pretty grain of salt. I'd be curious to hear what anyone with more knowledge in the area has to say about particle size testing, as well as the information Dr. Krauss shares both about the etiology of atherosclerosis and the significance of "small dense" LDL particle count vs the standard LDL measure on a lipid panel, particularly for people with borderline risk of CVD. To his credit, Dr. Krauss acknowledges that particle testing isn't for everyone. People at either extreme (i.e. very low or very high LDL cholesterol) probably don't need it - for obvious and opposite reasons. It's only in the borderline cases, like my family member, where it might be helpful. He also said the standard heart attack risk calculators, which don't take into account anything about particle size, do a pretty good job, and particle size and counts doesn't add very much to their accuracy / predictive power. But he sticks by idea that mechanistically, it's the small dense LDL particles that matter most for CVD risk. He also talks about how statins do work, but don't work as well as you might think because they upregulate the liver's LDL-receptor, which is pretty ineffective at clearly the most atherogenic particles - the small dense ones. He talks about statin side effects (muscle pain / weakness, but especially increased risk of diabetes, particularly in women). He is very much in favor of diet and lifestyle interventions to manage CVD risk, but as a researcher and clinician, he says there is trouble both proving the benefits of diet/lifestyle on CVD risk in clinical trials, and convincing his patients to adopt diet and lifestyle modifications, due both to compliance issues, and also in terms of getting the funding to do the research to make a convincing case. He says it's much easier to both get funding for, and to conduct, research on statins and other pharmacological interventions, because there is money to be made, and compliance is much less of an issue. Whether or not Dr. Krauss is blowing smoke about the value of particle size testing, it seemed to my (admittedly relatively naive) ears that Rhonda had a good set of questions and Dr. Krauss had clear and well thought out set of answers. For anyone interested in the topic, check out the show notes below and give it a watch/listen and let us know what you think. --Dean Begin Show Notes ============== Dr. Ronald Krauss on LDL Cholesterol, Particle Size, Heart Disease & Atherogenic Dyslipidemia In this podcast, I interview my friend and colleague Dr. Ronald Krauss. Ronald Krauss, M.D. is the director of atherosclerosis research at Children’s Hospital Oakland Research Institute, Adjunct Professor at UCSF and UC Berkeley. Dr. Krauss is really one of the pioneering scientists that changed the way we all think about cholesterol and saturated fat. The work of Dr. Krauss has demonstrated that smaller, denser LDL particles, which he pioneered a test for, known as the "Ion Mobility" test, has special significance when it comes to determining risk of heart disease. Regrettably, this test is not yet universally employed in a clinical setting in the manner in which total LDL cholesterol is, however. This test is called Cardio IQ® Lipoprotein Fractionation, Ion Mobility and is offered by quest diagnostics. Dr. Krauss is responsible for having played a part in the actual guidelines used by the American Heart Association in his role as chairman of the Nutrition Committee. Additionally, Dr. Krauss has also served on both the Committee on Dietary Recommended Intakes for Macronutrients and the Committee on Biomarkers of Chronic Disease of the Institute of Medicine of the National Academy of Sciences. In this podcast, Ron and I discuss what HDL and LDL cholesterol are, what they do in the body and how they play a role in heart disease. We talk about what small, dense LDL particles are, how they form, what effect eating saturated fat versus refined carbohydrates have on LDL particle size and heart disease risk and more generally what the main risk factors for heart disease are. Ron also talks about the good, bad and the ugly of LDL-lowering drugs known as statins and much more. In this conversation, Ron and I discuss... Changes in the availability of funding for good nutritional research."It's a fact that NIH, which is the major funder of biomedical research in the world, has basically pulled the plug on clinical research support as a general area of emphasis. The infrastructure for doing good nutritional studies, in particular, has relied on a mechanism that is now being withdrawn." - Dr. Ronald M Krauss The important difference between consumption of dietary cholesterol, which has a negligible influence on heart disease risk, and cholesterol produced endogenously in the body (which can be a marker of risk, depending on a complete profile). The good, bad and the ugly of LDL-lowering drugs known as statins and much more. What differentiates fructose from fruit versus fructose as an added sugar, namely: speed of absorption, presence or absence of other beneficial compounds (fiber, micronutrients, polyphenols, etc.), and differences in dose. How LDL (low-density lipoprotein), and particularly the ApoB protein inside of LDL, is needed to transport cholesterol, triglycerides, and fatty acids throughout the bloodstream in order to deliver them to other tissues in the body that may need them. What small, dense LDL particles are, how they form, what effect eating saturated fat versus refined carbohydrates have on LDL particle size and heart disease risk and more generally what the main risk factors for heart disease are. The functional difference between large, buoyant LDL particles and small, dense LDL particles and introduces us to the traits of what he terms "atherogenic dyslipidemia." These traits consist of: High levels of small, dense LDL cholesterol. Low levels of HDL cholesterol. High levels of triglyceride-rich lipoproteins (very-low-density lipoproteins or "VLDL") and their remnants. How small, dense LDL particles increase the risk of atherosclerosis. There is only one ApoB protein per LDL particle, which is what enables ApoB to be a surrogate blood biomarker for LDL particle number. How access to the ApoB protein can become obscured due to conformation changes in the small, dense LDL particles. As the size of the particle decreases, this conformation change reduces the ability for the particle to bind to the LDL receptor and be recycled by the liver. How VLDL particles, the precursor to LDL, demonstrate an interaction with LPS (also known as endotoxin, a component of bacterial cell membranes), and how it's possible that some of the negative associations with this particle size may be a result of their simply being in the blood stream longer: this gives them a greater opportunity to undergo inflammatory transformations.This part is especially exciting to me because it may be an interesting link by which gut health (where much of the bacteria and immune cells in the body are located) and the importance of controlling inflammation to cardiovascular health. How saturated fat appears to increase the larger, more buoyant LDL particles, which do not have the same robust correlation to heart disease risk that the smaller, more dense particles do. Dr. Krauss also takes the stance that consumption of saturated fat does not have as strong of a link to heart disease risk as previously suggested by others, and may be less relevant except in the case of what he termed "hyper-responders." These "hyper-responders" have gene polymorphisms that cause them to respond differently to saturated fat. How increased carbohydrate consumption, especially simple sugars may have been an unintended consequence of the push for low-fat diets, and how this increased traits associated with atherogenic dyslipidemia: namely, a shift from the larger, more buoyant LDL particles to the smaller, more dense LDL particles. Broadly, the differences between the various types of lipoprotein particles, including very-low-density lipoproteins (VLDL), and high-density lipoprotein (HDL) and what their roles are in the body. This really is one of the better science-based podcasts I've posted to date. It's often a bit nuanced, but hopefully with the help of some of the annotations in the video you will find it as enriching as I have. Dr. Krauss is a real pioneer in the field and drops huge amounts of knowledge, so go check it out now! ============== End Show Notes

All, Like Michael, I've got a huge backlog of posts I want to get to, and unlike Michael, I'm actually planning to get to them all. So I'm going to try to keep this one short. We'll see how that works out... OK - I admit brewing olive oil is a strange idea, and really a misnomer. The title is an allusion to a similar thread about chocolate/cacao - So Why Don't We Brew Our Chocolate? Brewing chocolate, instead of eating it, is a practice I've engaged in since that thread began in November, in order to get the health-promoting phytonutrients in cacao without the calories, refined sugar, saturated fat or heavy metals (e.g. cadmium) that chocolate products generally contain. Now, in researching this recent post for the cold exposure thread about the ability of extra virgin olive oil (EVOO) and olive leaf extract (OLE) to promote beneficial thermogenesis and the browning of white fat, I realized the same argument about brewing vs. eating can and perhaps should be made for olive polyphenols that I made for cacao polyphenols in the brewing chocolate thread. As we all know by now, EVOO may be one of the keys to the health benefits of a Mediterranean diet, although it's merits relative to nuts & seeds is a perennial topic of debate on these forums. I personally come down on the side of nuts & seeds. But one thing I believe everyone can agree on, is that, while the MUFA in EVOO is relatively harmless compared to other forms of fat, the real reason EVOO is considered healthy are all the polyphenols it contains. In fact, I'd go so far as to say Michael (and other extremely health conscious individuals) wouldn't touch refined olive oil (without the polyphenols but with the MUFA) with a 10-foot pole - the polyphenols are that critical to EVOO's benefits. So if it's all about the polyphenols, why can't we get them without all the fat and calories of EVOO? It seems to me that we can, and in a form not much different in degree of refinement than EVOO. How you ask? Sure, we could eat olives. In fact store-bought olives have about 400mg/kg total polyphenols [1], higher than the minimum level Michael insists on for his high-quality, high-polyphenol EVOO (350 mg/kg). So if you aren't worried about the salt, store-bought olives might be a better option for getting your olive polyphenols, since kg-for-kg, calorie-for-calorie, and certainly dollar-for-dollar, they are a much better source of polyphenols. But before you go out and raid the antipasto bar at your local supermarket, one other potential shortcoming of olives is the fact that olives appears to maintain the same (or better) total polyphenol content as EVOO, the curing process used to debitter olives shifts which polyphenols are present. In particular, curing reduces the (bitter tasting) polyphenol oleuropein which is high in fresh olives (and high-quality EVOO), and replace it with two other derivative polyphenols, hydroxytyrosol and tyrosol. I'm not totally sure if this polyphenol shift is a step down or a step up, but it certain is a change, and most of the evidence for benefits of EVOO seem to point to the oleuropein (see below). So eating olives isn't the equivalent of eating EVOO, in terms of polyphenols (or salt or fat, obviously). So is there a better alternative to EVOO and olives that can provide the same (or higher) total polyphenol content, and in the same ratio as demonstrably healthy high-quality EVOO? Unfortunately, raw, uncured olives don't seem to be available, at least not on the biggest store in the world (Amazon). Anyone ever eaten them fresh off the tree? I bet they taste really bad. But there may be a better alternative, in the form of olive leaves and olive leaf tea. Now would be a good time for anyone who hasn't read it to check out my recent post to the cold exposure thread about how olive polyphenols turn white fat cells to brown/beige, increasing thermogenesis, insulin sensitivity, SIRT1 and AMPK as additional nice side effects. In short, olive polyphenols cured what ailed these white fat cells. But what really caught my attention about that study (PMID 27303302), was the method they used to obtain the olive polyphenols. They took fresh picked olive leaves, dried them, soaked them in hot (80 °C) water for 24 hours, strained out the leaf solids, and then concentrated the resulting liquid by removing much of the water. to create Olive Leaf Extract (OLE). In short, they made a tea from olive leaves, which they and others call Olive Leaf Extract (OLE). How do the polyphenols concentration and ratio in OLE compare with high-quality EVOO? The details are in that post, so I won't repeat them here. But to summarize, unlike cured olives, but like EVOO, Oleuropein was the most abundant polyphenol in OLE, along with (apparently) all the other major polyphenols in EVOO. So how much polyphenols are there in OLE? The authors of that study found their olive leaf tea concentrate (OLE) contained 40mg of total phenolics per gram. That equates to 40,000mg/kg (40g/kg) of polyphenols, or about two orders of magnitude higher concentration of polyphenols in the OLE than in Michael's top-notch olive oils or in cured olives themselves. So OLE, at least the way these researchers prepared it, is pretty potent stuff - a little goes a long way! So what about benefits of OLE vs. EVOO? As I discussed in detail in the cold exposure post above, OLE appears to boost BAT activity both in vitro and in vivo, just like EVOO. It looks like the polyphenol oleuropein, rich in EVOO and especially rich in OLE, is where the cardioprotective and neuroprotective effects come from [3]. LEF has a good review article with references to all the benefits of OLE and oleuropein, including improvements in blood pressure, arterial health, brain health, diabetes risk, cancer risk, and arthritis. But you might be saying - I like to eat whole foods, and olive leaf extract doesn't seem to qualify. Obviously EVOO, even of highest quality, isn't a whole food either. In fact, EVOO and OLE are quite similar, except the former has a lot more fat. And clearly green tea, coffee, or cocoa powder aren't whole foods either, but people around here generally consider them quite healthy. You may be saying by now "OK Dean, you've piqued my interest. How can I get my hands on some of this OLE stuff?" Not surprisingly, LEF and other nutraceutical vendors sells it in capsule form. For $0.36, one LEF OLE capsule contains 80mg of oleuropein among other polyphenols, the equivalent amount in about 200ml of the very highest quality EVOO, according to this table. That amount of high-quality EVOO will cost you about $8, and 1800 calories. Seems like a pretty good bargain to me... For those of you (like me) who'd rather not get your nutrition from pills if you can help it, you can buy dried olive leaves inexpensively in whole or powder form, for making tea. One benefit of being so busy posting about other topics, is that this post about OLE was delayed for a few days since I made the post over on the cold exposure thread which brought OLE to my attention. That gave me time to put my money where my mouth is, by ordering, receiving and testing out the Frontier organic whole olive leaf powder linked to above. All I can say is that if oleuropein is what makes EVOO and OLE bitter (and healthy), this stuff has a lot of oleuropein! Eating even a tiny pinch straight is not pleasant - to put it mildly. Fortunately as we saw above, it doesn't take much. I'm now adding just a pinch per day of olive leaf powder to my coffee/tea/cacao concoction, which has enough flavors in it that I don't even notice the OLE's unpleasant taste. Plus by cold brewing it overnight, warm brewing it briefly in the morning, and filtering the heck out of it, I'm eliminating any nastiness left in the solids. The powder I purchased are supposed to be from organic olive leaves, but who knows... Just like with cadmium from the soil in cacao, lead in tea leaves etc. In summary, if you are interested in the benefits of the highest quality olive oil, without the financial or calorie burden, you might seriously consider olive leaf extract or olive leaf tea as alternatives. I'm curious, has anyone else tried olive leaf products, and if so (or even if not), what do you think? --Dean --------- [1] J Agric Food Chem. 2004 Feb 11;52(3):479-84. Effect of cultivar and processing method on the contents of polyphenols in table olives. Romero C(1), Brenes M, Yousfi K, García P, García A, Garrido A. Author information: (1)Food Biotechnology Department, Instituto de la Grasa (CSIC), Avenida Padre García Tejero 4, Seville, Spain. Full text: http://sci-hub.cc/10.1021/jf030525l Polyphenols were determined by HPLC in the juice and oil of packed table olives. The phenolic compositions of the two phases were very different, hydroxytyrosol and tyrosol being the main polyphenols in olive juice and tyrosol acetate, hydroxtyrosol acetate, hydroxytyrosol, tyrosol, and lignans (1-acetoxypinoresinol and pinoresinol) in oil. The type of processing had a marked influence on the concentration of polyphenols in olive juice and little on the content in oil. The analyses carried out on 48 samples showed that turning color olives in brine had the highest concentration in polyphenols ( approximately 1200 mg/kg), whereas oxidized olives had the lowest ( approximately 200 mg/kg). Among olive cultivars, Manzanilla had a higher concentration than Hojiblanca and Gordal. The type of olive presentation also influenced the concentration of polyphenols in olives, decreasing in the order plain > pitted > stuffed. The results obtained in this work indicate that table olives can be considered a good source of phenolic antioxidants, although their concentration depends on olive cultivar and processing method. PMID: 14759136 ----------- [2] J Agric Food Chem. 2012 Jul 25;60(29):7081-95. doi: 10.1021/jf3017699. Epub 2012 Jul 11. Factors influencing phenolic compounds in table olives (Olea europaea). Charoenprasert S(1), Mitchell A. Author information: (1)Department of Food Science and Technology, University of California, One Shields Avenue, Davis, California 95616, United States. The Mediterranean diet appears to be associated with a reduced risk of several chronic diseases including cancer and cardiovascular and Alzheimer's diseases. Olive products (mainly olive oil and table olives) are important components of the Mediterranean diet. Olives contain a range of phenolic compounds; these natural antioxidants may contribute to the prevention of these chronic conditions. Consequently, the consumption of table olives and olive oil continues to increase worldwide by health-conscious consumers. There are numerous factors that can affect the phenolics in table olives including the cultivar, degree of ripening, and, importantly, the methods used for curing and processing table olives. The predominant phenolic compound found in fresh olive is the bitter secoiridoid oleuropein. Table olive processing decreases levels of oleuropein with concomitant increases in the hydrolysis products hydroxytyrosol and tyrosol. Many of the health benefits reported for olives are thought to be associated with the levels of hydroxytyrosol. Herein the pre- and post-harvest factors influencing the phenolics in olives, debittering methods, and health benefits of phenolics in table olives are reviewed. PMID: 22720792 --------- [3] Saudi Pharm J. 2010 Jul;18(3):111-21. doi: 10.1016/j.jsps.2010.05.005. Epub 2010 May 31. Cardioprotective and neuroprotective roles of oleuropein in olive. Omar SH(1). Author information: (1)College of Pharmacy, Qassim University, P.O. Box 31922, Buraidah-51418, Saudi Arabia. Traditional diets of people living in the Mediterranean basin are, among other components, very rich in extra-virgin olive oil, the most typical source of visible fat. Olive is a priceless source of monounsaturated and di-unsaturated fatty acids, polyphenolic antioxidants and vitamins. Oleuropein is the main glycoside in olives and is responsible for the bitter taste of immature and unprocessed olives. Chemically, oleuropein is the ester of elenolic acid and 3,4-dihydroxyphenyl ethanol, which possesses beneficial effects on human health, such as antioxidant, antiatherogenic, anti-cancer, anti-inflammatory and antimicrobial properties. The phenolic fraction extracted from the leaves of the olive tree, which contains significant amounts of oleuropein, prevents lipoprotein oxidation. In addition, oleuropein has shown cardioprotective effect against acute adriamycin cardiotoxicity and an anti-ischemic and hypolipidemic activities. Recently, oleuropein has shown neuroprotection by forming a non-covalent complex with the Aβ peptide, which is a key hallmark of several degenerative diseases like Alzheimer and Parkinson. Thus, a large mass of research has been accumulating in the area of olive oil, in the attempt to provide evidence for the health benefits of olive oil consumption and to scientifically support the widespread adoption of traditional Mediterranean diet as a model of healthy eating. These results provide a molecular basis for some of the benefits potentially coming from oleuropein consumption and pave the way to further studies on the possible pharmacological use of oleuropein to prevent or to slow down the cardiovascular and neurodegenerative diseases. PMCID: PMC3730992 PMID: 23964170