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  1. [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.
  2. 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
  3. The below paper is pdf-availed. Impact of Intermittent Fasting on Health and Disease Processes. Mattson MP, Longo VD, Harvie M. Ageing Res Rev. 2016 Oct 31. pii: S1568-1637(16)30251-3. doi: 10.1016/j.arr.2016.10.005. [Epub ahead of print] Review. PMID: 27810402 Abstract Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16-48hours) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer's disease Parkinson's disease and stroke. Studies of IF (e.g., 60% energy restriction on 2days per week or every other day), PF (e.g., a 5day diet providing 750-1100kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8hours or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging. Abbreviations AD, Alzheimer’s disease; ADF, alternate day fasting; ALS, amyotrophic lateral sclerosis; APP, β-amyloid precursor protein; BDNF, brain-derived neurotrophic factor; CER, continuous energy restriction; CR, caloric restriction; CREB, cyclic AMP response element-binding protein; CVD, cardiovascular disease; ERK, extracellular signal regulated kinase; FFM, fat-free mass; FGF2, fibroblast growth factor 2; FMD, fasting mimicking diet; GR, glucocorticoid receptor; GRP-78, glucose regulated protein 78; HD, , Huntington’s disease; HSP-70, heat-shock protein 70; IF, intermittent fasting; IGF-1, insulin-like growth factor 1; IL-6, interleukin 6; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MI, myocardial infarction; MR, mineralocorticoid receptor; mTOR, mammalian target of rapamycin; PGC-1a, peroxisome proliferator-activator receptor γ coactivator 1α; PD, , Parkinson’s disease; PF, periodic fasting; PMP22, peripheral myelin protein 22; SIRT1, sirtuin 1; SIRT3, sirtuin 3; TNF-α, tumor necrosis factor α; TRF, time-restricted feeding Keywords Alzheimer’s disease; blood pressure; cardiovascular disease; diabetes; insulin resistance; intermittent fasting; ketone bodies; obesity 1. Introduction The survival and reproductive success of all organisms depends upon their ability to obtain food. Accordingly, animals have evolved behavioral and physiological adaptations that enable them to survive periods of food scarcity or absence. When food is not available for extended time periods some organisms become dormant; for example, yeast enter a stationary phase, nematodes enter the dauer state, and ground squirrels and some bears hibernate (Calixto, 2015). Mammals have organs such as the liver and adipose tissue which function as energy depots that enable fasting/starvation for varying lengths of time depending upon the species. Importantly, metabolic, endocrine and nervous systems evolved in ways that enabled high levels of physical and mental performance when in the fasted state. In this article we review studies of the effects of regimens of intermittent fasting (IF) diets, which include eating patterns in which individuals go extended time periods (e.g., 16–48 hours) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. To distinguish studies of short-term frequent fasting periods from studies of less frequent but longer fasting periods we use the term periodic fasting (PF) to refer to IF with periods of fasting or “fasting mimicking diets” (FMDs) lasting from 2 to as many as 21 or more days. The term time-restricted feeding (TRF) is used to describe an eating pattern in which food intake is restricted to a time window of 8 hours or less every day. Studies of laboratory animals have elucidated the cellular and molecular mechanisms by which individuals respond to fasting in ways that can increase their overall fitness and their resistance to injury and a wide array of diseases (Longo and Mattson, 2014). Recent randomized controlled trials in human subjects have demonstrated that IF, including diets that mimic some aspects of FMDs, are achievable in humans and improve many health indicators in healthy individuals and in those with some chronic diseases. In this article we focus on studies of the effects of IF, including PF and FMD, on animals and humans. Examples of specific IF diets include: complete fasting every other day (Bruce-Keller et al., 1999 and Anson et al., 2003); 70% energy restriction every other day (Johnson et al., 2007 and Varady et al., 2015); consuming only 500-700 calories two consecutive days/week (Harvie et al., 2011); and restricting food intake to a 6–8 hour time period daily, which has also been termed ‘time restricted feeding’ (TRF) (Chaix et al., 2014). Examples of PF include a 4–5 day FMD (Brandhorst et al., 2015), 2 to 5 days of water only fasting (Raffaghello, 2008; Safdie et al., 2009), and 7 days of a FMD (Choi et al., 2016). The vast majority of IF animal studies have involved either alternate day fasting or TRF, and most randomized controlled human trials have involved either 60-75% energy restriction (500–800 kcal) on alternate days or 2 consecutive days/week. Rarely has more that one IF regimen been compared within the same study, and so it is not yet possible to make any clear conclusions as to whether one regimen is superior to another with regards to improving health and disease resistance. Although results may differ quantitatively depending on the type of IF pattern and the species studied, all of the IF regimens described in the preceding paragraph result in several fundamental metabolic changes that define a fasting period including: maintenance of blood glucose levels in the low normal range, depletion or reduction of glycogen stores, mobilization of fatty acids and generation of ketones, a reduction of circulating leptin and often elevation of adiponectin levels (Johnson et al., 2007 and Wan et al., 2010) (Fig. 1). Behavioral changes that occur during the fasting period of IF diets include increased alertness/arousal and increased mental acuity (Fond et al., 2013). As we describe in subsequent sections of this article, both the metabolic shift to ketone utilization, and adaptive responses of the brain and autonomic nervous system to food deprivation, play major roles in the fitness-promoting and disease-allaying effects of IF. Because overall calorie intake is often reduced during IF (e.g., weekly calorie intake in an individual on the ‘5:2′ diet is reduced by 25%; Harvie et al., 2011 and Harvie et al., 2013a) it is important to know if and to what extent physiological responses to IF are mediated by the overall caloric restriction (CR). In some studies of animals or human subjects, groups maintained on IF or isocaloric CR diets have been compared directly and, in those cases we will describe the similarities and differences. Otherwise, we will not review studies of CR which are much more numerous than studies of IF, and have been reviewed elsewhere recently (Speakman and Mitchell, 2011, Mercken et al., 2012 and Longo et al., 2015). It should be noted, however, that the most commonly used method for daily CR in rodent laboratory studies (limited daily feeding) is in fact a form of IF/TRF. Thus, the animals are housed singly and the average amount of food consumed each day when the animals are fed ad libitum is designated the ad libitum food intake. Animals are then randomly assigned to ad libitum control and CR groups, with the animals in the CR group being fed a designated percentage of their normal ad libitum intake (usually 60–80%; i.e., 20–40% CR). Animals on CR are typically provided their daily or, in some cases thrice weekly, food in one portion (Pugh et al., 1999). However, under these circumstances, the animals on CR often consume their entire allotment within a period of several hours of receiving the food and, accordingly, they are fasting intermittently for extended time periods of (for example, 16–20 hours when fed daily, or 36 hours or more when fed thrice weekly). The relative contributions of IF and CR to the lifespan extension and health-enhancing effects reported in studies of standard caloric restriction in these laboratory studies have not been investigated, and therefore represents a major knowledge gap in this field of research. Here we will focus on IF as the role of PF/FMDs on longevity and diseases in laboratory animals and humans. For more comprehensive recent reviews of the physiological and disease-modifying effects of fasting at the cellular and molecular levels, the reader is referred to Longo and Mattson (2014) and Longo and Panda (2016). Fig. 1. Examples of the influence of eating patterns on levels of glucose at ketones in the blood. The red arrows indicate the time of food consumption/meals during a 2 day period of time. A. This is an example of the typical eating pattern in most industrialized countries. Every day the person eats breakfast, lunch and dinner and a late evening snack. With each meal, glucose levels are elevated and then return towards baseline over a period of several hours. Ketone levels remain low, because liver glycogen stores are never depleted. B. This is an example of fasting one day, followed by a three-meal feeding day. During the fasting day, glucose levels remain in the low normal range, and ketone levels (β-hydroxybutyrate and acetoacetate) rise progressively, and then fall when the first meal is consumed on the 2nd day. C. This is an example of an eating pattern in which all food is consumed within a 6 hour time window each day. Glucose levels are elevated during and for several hours after the 6 hour period of food consumption and then remain low for the subsequent 16 hours until food is consumed the next day. Ketones are elevated during the last 6–8 hours of the 18 hour fasting period. 1.1. IF and Health Indicators in Laboratory Animals Studies of IF in animals usually compare a control group fed ad libitum with an IF group; in some cases, a daily CR group(s) is also included. Control laboratory rats and mice are also typically sedentary which, together with ad libitum feeding and an unstimulating environment, renders them rather like the stereotypical human “couch potato” (Martin et al., 2010). This is important to keep in mind when attempting to extrapolate data from IF studies in animals to humans, especially when considering the potential effects of IF amongst normal weight human subjects. The two major IF regimens that have been applied to laboratory rodents are alternate day fasting (ADF) and TRF. When maintained on an ADF diet, rats and mice exhibit lower body weights than do ad libitum fed controls, with the magnitude of the reduction in body weight ranging from 5-10% up to 25-30% depending upon the strain of animal (Goodrick et al., 1983, Anson et al., 2003 and Wan et al., 2003). Perhaps the first evidence that IF may confer widespread health benefits came from studies in which rats maintained on ADF beginning when they were young lived nearly twice as long as rats on an ad libitum diet (Goodrick et al., 1982). When ADF was initiated in middle age, the rats lived 30-40% longer than rats fed ad libitum, and this life extension could be further increased by regular exercise (Goodrick et al., 1983). ADF also results in preservation of cognitive function and sensory − motor function during aging in rodents (Singh et al., 2015). An anti-aging effect of IF appears to be evolutionarily conserved because IF increases lifespan in lower species such as nematodes (Uno et al., 2013). Multiple effects of IF on body composition and energy metabolism have been described. A reduction in levels of fat, particularly visceral fat, and retention of lean mass occurs in rats or mice maintained on ADF (Varady et al., 2007 and Gotthardt et al., 2016). The lean mass/fat mass ratio is generally greater in animals on an ADF diet compared to those on 30-40% CR diets (Gotthardt et al., 2016). In one study, mice on an ADF diet maintained body weights similar to those of mice fed ad libitum but, nevertheless, exhibit highly significant improvements in glucose metabolism (reduced glucose and insulin levels) and mobilization of fatty acids (increased β-hydroxybutyrate levels) that were as great or even greater than mice on a 40% CR diet (Anson et al., 2003). Body temperature is significantly lower on fasting days compared to feeding days (Wan et al., 2003). In numerous animal and humans studies IF increases insulin sensitivity and improves glucose tolerance (Gotthardt et al., 2016). In mice hyperphagic and obese as a consequence of brain-derived neurotrophic factor (BDNF) haploinsufficiency, ADF reverses insulin resistance, and reduces levels of circulating levels of insulin and leptin (Duan et al., 2003a). IF also improves glucose regulation/insulin sensitivity in long-lived Ames Dwarf mice and growth hormone receptor mutant mice, demonstrating beneficial effects of IF in animals that maintain a low body weight during aging (Arum et al., 2014). Interestingly, and in contrast to CR, SIRT1 may not play major roles in physiological adaptations to ADF (Boutant et al., 2016). However, while the vast majority of studies of IF in rodents have demonstrated numerous improvements in health indicators and protection against various diseases (see below), there have been reports of adverse effects of IF in some rodent models. For example, one study found that rats maintained on an ADF diet for one month had improved glucose tolerance, whereas rats maintained on ADF for 8 months had impaired glucose tolerance (Cerqueira et al., 2011). The rats on IF in the latter study maintained a lower body weight than rats fed ad libitum, and the mechanism responsible for the apparent glucose intolerance despite a reduction body weight was not established. It was also reported that IF has adverse effects on glucose metabolism in hypercholesterolemic (low density lipoprotein receptor-deficient) mice (Dorighello et al., 2014), in contrast to the clear beneficial effects of ADF on lipid and glucose metabolism in wild type rodents and human subjects (Varady et al., 2009a and Varady et al., 2009b). Several changes in circulating hormones have been documented in animal studies of IF. Levels of circulating leptin and insulin are reduced, and levels of adiponectin are increased in animals on an ADF diet (Duan et al., 2003a, Varady et al., 2010 and Wan et al., 2010). Levels of corticosterone are significantly elevated in rats in response to ADF (Wan et al., 2003) but, in contrast to chronic uncontrollable stress (e.g., psychosocial stress), corticosterone does not adversely affect neurons in the brains of animals on ADF. It has been shown that chronic uncontrollable stress reduces expression of the mineralocorticoid receptor (MR), while glucocorticoid receptor (GR) levels are sustained, in hippocampal neurons which increases the vulnerability of the neurons to excitotoxic and metabolic stress (McEwen, 2007). On the other hand, IF reduces the expression of GR while sustaining MR, which would be expected to promote synaptic plasticity and neuronal stress resistance (Lee et al., 2000 and Stranahan et al., 2010). ADF has been reported to affect levels of sex hormones and gonadal function in rats, with testosterone levels increasing in males but not in females, and marked changes in gene expression in the gonads of males compared to females (Martin et al., 2009). The cardiovascular system of rats and mice responds to IF in a manner very similar to its responses to aerobic exercise training (Scheuer and Tipton, 1977). Within 1 week of initiation of ADF in rats, resting heart rate and blood pressure are significantly reduced, continue to decrease through 2 weeks, and remain reduced on both fasting and feeding days (Wan et al., 2003). However, within 1–2 weeks following return to an ad libitum diet, the heart rate of rats previously on an ADF diet returns towards pre-ADF diet levels indicating that the benefit for cardiovascular health is not sustained much beyond the IF period (Mager et al., 2004). The reduction of heart rate in response to IF is mediated by increased parasympathetic tone, namely, enhanced activity of brainstem cardiovagal cholinergic neurons (Mager et al., 2004; Wan et al., 2014). These effects of IF on heart rate are not simply the result of caloric restriction, because rats maintained on ADF are only moderately calorie-restricted (10-20%) and yet exhibit greater reductions in resting heart rate than do mice on 40% daily caloric restriction (Mager et al., 2004). Increased BDNF signaling is known to occur in response to both exercise and IF, and BDNF can reduce heart rate by increasing activity of brainstem cardiovagal neurons (Wan et al., 2014). The available data therefore suggest a scenario in which IF and exercise stimulate BDNF signaling which, in turn, results in the enhancement of activity in brainstem cholinergic neurons and a consequent reduction in resting heart rate and blood pressure, and increased heart rate variability. IF has also been shown to enhance cardiovascular stress adaptation in rat models of uncontrollable stress (Wan et al., 2003). The remarkably similar effects of exercise and IF on heart rate and blood pressure suggest that both types of intermittent bioenergetic challenge can promote optimal cardiovascular health and fitness. IF has effects on animal behavior and circadian rhythms that may have an impact on overall health and longevity. Energy metabolism is regulated in a circadian manner as indicated by circadian oscillations in all of the major energy-regulating hormones including insulin, leptin, corticosterone and adiponectin (Ramsey and Bass, 2011). Meal timing can have a major influence on circadian rhythms and IF can shift circadian aspects of behavior (e.g., activity levels). For example, when food is provided for only a few hours at a designated time each day, animals exhibit increased activity during a 1–2 hour time period preceding the time they are fed (Stephan, 2002). Effects of IF on circadian regulation of energy metabolism and behavior may occur as a result of changes in the core cell ‘clock’ molecular apparatus in peripheral tissues and/or central (hypothalamic suprachiasmatic nucleus) circadian control centers (Froy and Miskin, 2010). With regards to ADF, Froy and Miskin (2010) proposed that when food is provided or withdrawn during the daytime, the suprachiasmatic nucleus controls metabolic and behavioral rhythms, whereas when food is applied or withdrawn during the nighttime, the peripheral clock is in command. In addition to effects on the hypothalamus and periphery, there is emerging evidence that exercise and IF can affect mitochondrial physiology in neurons in the hippocampus and other brain regions by mechanisms involving increased mitochondrial biogenesis and mitochondrial stress resistance mediated by BDNF, PGC-1α (a master regulator of genes involved in mitochondrial biogenesis) and sirtuin 3 (SIRT3; a mitochondrial protein deacetylase that suppresses oxidative stress and apoptosis) (Cheng et al., 2012 and Cheng et al., 2016). The latter metabolic adaptations of neurons may contribute to the improvement in cognitive function of rodents maintained on ADF compared to those fed ad libitum (Li et al., 2013). A general conclusion that can be drawn from the available data from animal studies is that involuntary IF has been a fundamental challenge during the evolution of animals, and the brain and other organ systems therefore respond adaptively to IF in ways that improve the abilities of the individual to optimize their performance and resistance to injury and disease. 1.2. IF and Age-Related Diseases in Animal Models 1.2.1. Diabetes Put simply, IF can prevent and cure the disease in rodent models of type 2 diabetes. When sand rats are fed a high fat diet they develop insulin resistance and diabetes, which can be ameliorated by maintaining them on an 8 hour/day TRF diet (i.e., 16 hours of fasting every day) (Belkacemi et al., 2010). Similarly, when C57BL/6 mice are maintained on a high fat diet fed ad libitum they develop hyperinsulinemia, obesity and systemic inflammation, all of which are prevented by restricting food availability to 8 hours/day (Hatori et al., 2012). The latter anti-diabetic effect of TRF is not due to caloric restriction because mice provided food for only 8 hours/day consume the same amount of food as control mice fed ad libitum. Similar to leptin-deficient mice and leptin receptor mutant mice, mice with reduced BDNF levels are hyperphagic and develop insulin resistance and diabetes (Kernie et al., 2000). Daily intraperitoneal administration of BDNF to leptin receptor mutant mice, reversed obesity and diabetes (Nakagawa et al., 2003). When diabetic BDNF+/− mice are maintained on an ADF diet, their circulating levels of glucose, insulin and leptin are reduced, and glucose tolerance is normalized (Duan et al., 2003a). Interestingly, IF can ameliorate the insulin deficit and glucose intolerance in a rat model of type I diabetes by a mechanism involving preservation of pancreatic β-cells (Belkacemi et al., 2012). Although not yet established, it is likely that enhancement of cellular stress resistance by IF protects β-cells, as has been reported in studies of the effects of IF on other cell types (e.g., myocardial cells and neurons) (Mattson and Wan, 2005 and Mattson, 2015). The cellular and molecular mechanism by which IF prevents and reverses diabetes involves increased sensitivity of insulin receptor signaling such that insulin more readily stimulates glucose uptake by muscle and liver cells, and likely other cell types including neurons (Sequea et al., 2012). Changes in other signaling pathways affected by IF in one or many cell types may include: reductions of mTOR signaling; improved mitochondrial function; stimulation of mitochondrial biogenesis; and up-regulation of CREB, BDNF and autophagy pathways (Descamps et al., 2005, Cheng et al., 2012, Hatori et al., 2012, Longo and Mattson, 2014, Yuen and Sander, 2014 and Cheng et al., 2016). Inflammation of multiple organ systems occurs in diabetes (Guo, 2014), and IF can suppress inflammation (Arumugam et al., 2010) which may contribute to the anti-diabetic effects of IF. 1.2.2. Cardiovascular Disease Profound cardioprotective effects of IF have been documented in studies of rats and mice. In a model of myocardial infarction (MI; coronary artery ligation), rats that had been maintained on ADF for 3 months prior to MI, exhibited a reduced cerebral infarct size and the number of apoptotic cells in the area at risk (penumbra) was reduced by approximately 75% compared to the ad libitum control rats (Ahmet et al., 2005). Post-MI longitudinal echocardiographic analyses showed that left ventricular remodeling and infarct expansion occurred in rats on the ad libitum diet, but not in those on the ADF diet. Similar to rats, ADF protected the mouse heart against MI-induced damage (Godar et al., 2015). In contrast to wild type mice, ADF did not protect the hearts of mice with impaired autophagy (Lamp2 heterozygous mutant mice). Instead, ADF worsened myocardial damage in Lamp2-deficient mice, indicating that stimulation of autophagy mediates the cardioprotective actions of ADF (Godar et al., 2015). IF was also reported to greatly improve survival and recovery of heart function in rats when initiated beginning 2 weeks after MI induced by occlusion of the left coronary artery (Katare et al., 2009). Whereas more than 75% of the rats on the ADF diet survived during an 8-week post MI period, less than 25% of the rats on the normal ad libitum diet survived. Data regarding the mechanism of action of IF in the latter study is consistent with the involvement of hormesis/adaptive cellular stress responses in that levels of HIF-1α, BDNF and VEGF were significantly elevated in myocardial tissue of rats on IF compared to those on the control diet. When initiated in 2 month-old rats, ADF protected the heart against age-related increases in inflammation, oxidative stress and fibrosis (Castello et al., 2010). Age-related increases in myocardial cell ERK1/2 and PI3Kγ kinases, and altered STAT3 transcription factor activity, were prevented by ADF (Castello et al., 2011). Benefits of IF on cardiac function during aging appear to be highly conserved as it was reported that TRF can attenuate decline of cardiac function during aging in fruit flies (Gill et al., 2015). On the other hand, it was reported that when maintained on ADF for 6 months, rats exhibit a reduction of left ventricular diastolic compliance and evidence of diminished cardiac reserve (Ahmet et al., 2010). However, the interpretation of the latter findings is unclear because the rats on ADF weighed much less than did the rats fed ad libitum and may therefore require less cardiac output to support their requirements when living a sedentary life in laboratory cages. In humans, hypertension, low heart rate variability, insulin resistance and hyperlipidemia are associated with increased risk for cardiovascular disease and stroke (DeFronzo and Abdul-Ghani, 2011). IF reduces blood pressure (Wan et al., 2003), increases heart rate variability (Mager et al., 2004) and reduces insulin resistance (Wan et al., 2003 and Belkacemi et al., 2010) in laboratory rodents. The reduction in blood pressure may result, in part, from enhanced vascular endothelial cell-dependent vasodilation (Razzak et al., 2011). The increased heart rate variability in rats maintained on ADF may result from enhanced activity of brainstem cholinergic cardiovagal neurons (Mager et al., 2006 and Wan et al., 2014). Levels of circulating cholesterol and triglycerides are reduced in animals on ADF and TRF diets (Varady et al., 2007, Belkacemi et al., 2012 and Chaix et al., 2014). TRF protects mice against obesity and metabolic syndrome caused by consumption of atherogenic diets including a high fat + glucose diet and a high fructose diet (Chaix et al., 2014). The latter effects of TRF are associated with reductions in hepatic triglyceride content, circulating leptin and triglyceride levels, and reduced levels of proinflammatory cytokines in adipose tissue. Moreover, the physical performance of TRF mice on a rotarod test and treadmill endurance test are superior to mice fed ad libitum (Chaix et al., 2014), suggesting that IF can enhance physical fitness. The latter tests were performed during the feeding phase of the compressed (9 hour) daily feeding period suggesting that the improved motor and endurance performance was not due to the feeding state of the mice. 1.2.3. Neurological Disorders Advancing age is the major risk factor for Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke (Yankner et al., 2008). The degeneration and death of neurons that occurs in each of these disorders is believed to involve impaired mitochondrial function, oxidative damage, impaired lysosome function and dysregulation of cellular calcium homeostasis. Experimental evidence further suggests that hyperexcitability of neurons contributes to their demise in a process called excitotoxicity (Mattson, 2003). Prior to the current era of transgenic animals, experimental models of neurodegenerative disorders were based on the administration of neurotoxins that cause relatively selective degeneration of one or more populations of neurons that degenerate in the human disease. PD models include administration of the toxins MPTP, 6-hydroxydopamine and rotenone which inhibit mitochondrial complex I and cause degeneration of dopaminergic neurons. Models relevant to AD include hippocampal lesions induced by the excitotoxins (glutamate receptor agonists) kainic acid and domoic acid. The toxins 3-nitropropionic acid (3NPA) and malonate are inhibitors of succinate dehydrogenase (Complex II in the mitochondrial electron transport chain) that selectively kill striatal medium spiny neurons, the neurons most affected in Huntington’s disease (HD). In the 1990s, studies were initiated to test the general hypothesis that, because aging is the major risk factor for neurodegenerative disorders, and because IF can counteract aging processes, IF may protect neurons in animal models of the disorders (see Mattson, 2012 for review). When rats are maintained on ADF for several months prior to administration of kainic acid, their hippocampal neurons are more resistant to degeneration and learning and memory deficits were ameliorated (Bruce-Keller et al., 1999). Rats on ADF are also more resistant to 3NPA and malonate, exhibit less motor dysfunction and less degeneration of striatal neurons, suggesting a potential therapeutic application to patients with HD (Bruce-Keller et al., 1999). Mice maintained on ADF for several months are more resistant to MPTP as indicated by reduced loss of dopaminergic neurons and improved functional outcome in a PD model (Duan and Mattson, 1999). Moreover, rhesus monkeys maintained on CR for 6 months suffered less motor impairment and less striatal dopamine depletion (Maswood et al., 2004). In the latter study, levels of two neurotrophic factors known to protect dopaminergic neurons against MPTP (BDNF and glial cell line-derived neurotrophic factor) were elevated in the lesioned striatum of CR monkeys compared to those on the control diet. Several transgenic mouse models of AD have been generated that exhibit age-related accumulation of Aβ without or with Tau pathology, and associated learning and memory deficits. Such ‘AD mice’ express familial AD mutations in the β-amyloid precursor protein (APP) alone or in combination with a familial AD presenilin 1 mutation. Aβ is generated from APP by sequential enzymatic cleavages by β- and γ-secretases, and presenilin 1 is the enzymatic subunit of the γ-secretase enzyme complex (Mattson, 1997). When 3xTgAD mice (which express APP, presenilin 1 and Tau mutations) were maintained for 1 year on either 40% CR or ADF diets beginning when they were 5 months old, they did not develop the cognitive impairment exhibited by 3xTgAD mice fed ad libitum (Halagappa et al., 2007). Interestingly, whereas levels of Aβ and Tau accumulation were reduced in the brains of 3xTgAD mice on the CR diet, they were not reduced in 3xTgAD mice on the ADF diet, suggesting that IF can protect neurons against dysfunction even in the presence of Aβ and Tau pathologies. Other studies have also shown that CR can attenuate Aβ pathology in the brains of APP mutant mice (Patel et al., 2005 and Wang et al., 2005). The mechanism(s) by which IF protects against synaptic dysfunction and cognitive deficits in mouse models of AD is unknown, but may include reductions in oxidative stress, preservation of mitochondrial function and increased neurotrophic factor signaling and autophagy because: IF induces the expression of antioxidant enzymes and neurotrophic factors including BDNF and FGF2 (Arumugam et al., 2010); BDNF stimulates mitochondrial biogenesis (Cheng et al., 2012); IF up-regulates autophagy (Godar et al., 2015); neurotrophic factors and interventions that bolster mitochondrial bioenergetics (Mark et al., 1997; Caccamo et al., 2010 and Liu et al., 2013) and autophagy (Majumder et al., 2011 and Lin et al., 2013) can protect neurons in experimental models of AD. Mutations in α-synuclein cause some cases of familial PD. Several lines of transgenic mice that overexpress wild type or mutant human α-synuclein exhibit progressive accumulation of α-synuclein in neurons, motor dysfunction and death (Crabtree and Zhang, 2012). Mice expressing mutant (A53T) α-synuclein exhibit impaired autonomic regulation of heart rate characterized by elevated resting heart rate associated with accumulation of α-synuclein aggregates in the brainstem and reduced parasympathetic (cardiovagal) tone (Griffioen et al., 2013). Maintenance of the α-synuclein mutant mice on ADF reversed the autonomic deficit, whereas a high fat diet exacerbated the autonomic deficit (Griffioen et al., 2013). Consistent with the latter findings, a high fat diet hastened the onset of motor dysfunction and brainstem pathology in another line of α-synuclein mutant mice, which was associated with reduced activity of kinases known to be involved in neurotrophic factor signaling (Rotermund et al., 2014). In addition to enhancement of neurotrophic factor/BDNF signaling, IF may counteract PD-related pathogenic processes by stimulating autophagy. Indeed, inhibition of mTOR with rapamycin, which stimulates autophagy, reduced oxidative stress and synaptic damage, and improved motor function in a α-synuclein accumulation-based mouse model of PD (Bai et al., 2015). Huntingtin mutant mice exhibit progressive degeneration of striatal and cortical neurons, and also have reduced expression of BDNF in these brain regions and peripheral insulin resistance. When initiated prior to the onset of motor dysfunction in huntingtin mutant mice, ADF increases brain BDNF levels, normalizes glucose metabolism and significantly delays the onset of neurodegeneration and motor dysfunction (Duan et al., 2003b). While ADF is beneficial in animal models of AD, PD and HD, it has been reported not to be beneficial and, instead exacerbates motor dysfunction in a transgenic mouse model of amyotrophic lateral sclerosis (ALS) in which the mice overexpress a mutant form of Cu/Zn superoxide dismutase that causes familial ALS in humans (Pedersen and Mattson, 1999). One potential reason for the lack of benefit in the ALS model is that the neurons affected in ALS (lower and upper motor neurons) are unable to respond adaptively to the bioenergetics challenge of fasting. Numerous studies have shown that, when initiated prior to the ischemic insult, ADF can reduce brain damage and improve functional outcome in animal models of stroke (Yu and Mattson, 1999 and Arumugam et al., 2010). The cellular and molecular mechanisms by which IF protects brain cells against a stroke have not been fully established but involve up-regulation of expression of neurotrophic factors (BDNF and FGF2), antioxidant enzymes (heme oxygenase 1) and protein chaperones (HSP70 and GRP78) (Arumugam et al., 2010). Reduced inflammation may also mediate the beneficial effects of IF in stroke models as indicated by reduced levels of proinflammatory cytokines (TNFα, IL1-β and IL6) and suppression of the ‘inflammasome’ (Arumugam et al., 2010 and Fann et al., 2014). Indeed, IF can attenuate cerebral oxidative stress and cognitive impairment induced by lipopolysaccharide in an animal model of systemic inflammation (Vasconcelos et al., 2014 and Vasconcelos et al., 2015). Reductions in levels of leptin and increased levels of ketones may also contribute to neuroprotection by IF in stroke models (Manzanero et al., 2014). It remains to be determined whether post-stroke IF will modify functional outcome/recovery in animal models, which will be critical to know when considering whether or not IF is likely to benefit human stroke patients. IF has been reported to improve outcome in animal models of traumatic injury to the nervous system, as well as in models of peripheral neuropathy. In rat models of incomplete cervical spinal cord injury and thoracic contusion injury, ADF initiated prior to the injury and continued thereafter significantly improved functional outcome and reduced spinal cord lesion size (Plunet et al., 2010 and Jeong et al., 2011). ADF was also beneficial when initiated after thoracic contusion spinal cord injury (Jeong et al., 2011). However, in a mouse model of spinal cord injury ADF initiated after the injury did not significantly affect functional outcome or spinal cord lesion size (Streijger et al., 2011). The reason why ADF was effective in the rat models, but not in the mouse model, is unclear and merits further investigation. As with spinal cord injuries, traumatic brain injury is a major cause of disability and death, particularly in young active individuals. While IF (per se) has not been evaluated in animals models of traumatic brain injury, it was reported that CR (limited daily feeding with a 30% reduction in calorie intake) initiated 4 months prior to the injury, reduced the extent of brain damage, ameliorated cognitive deficits, and elevated BDNF levels in the affected cerebral cortex and hippocampus (Rich et al., 2010). Finally, recent studies have elucidated the potential impact of IF on peripheral nerve health and disease resistance. In a mouse model of the peripheral demyelinating neuropathic disease Charcot-Marie-tooth type 1A (Trembler mice), 5 months of ADF resulted in improved motor performance, increased myelination and decreased accumulation of PMP22 protein aggregates (Madorsky et al., 2009). Additional findings suggest that the beneficial effects of IF on peripheral nerve health and disease resistance are mediated, in part, by up-regulation of autophagy and related protein quality control mechanisms (Lee and Notterpek, 2013). 1.2.4. Cancer Recently a series of studies in animal models have shown that periodic fasting (PF) lasting 2 or more days can be as effective as chemotherapy in delaying the progression of a wide range of cancers but, more importantly, can protect normal cells from the toxic effects of chemotherapy drugs while sensitizing cancer cells to the treatment (Raffaghello et al., 2008, Lee et al., 2012, Safdie et al., 2009 and Dorff et al., 2016; Lee and Longo, 2011). A severely restricted diet that mimics PF started at middle age was effective in causing a major reduction in tumor incidence, in addition to delaying tumor onset and reducing the number of sites with tumor-like lesions, suggesting a reduction in metastatic cancers (Brandhorst et al., 2015). The role of PF and FMDs in cancer prevention and treatment has been discussed in more detail elsewhere (Longo and Mattson, 2014 and Longo and Panda, 2016). Here we will focus on IF and cancer. IF has been studied in murine cancer models, although mostly in cancer prevention. Siegel et al. studied the effects of ADF on the survival of 3-4 month-old tumor-free and tumor-bearing Fisher rats. 50% of the ADF rats survived to day 10 compared to 12.5% survival in the control diet group (Siegel et al., 1988). In addition, this study included both a tumor prevention and a tumor treatment component since the ADF was initiated one week before rats were inoculated intraperitoneally with ascites tumor cells, making it difficult to understand the mechanisms responsible for its effects. In another study, p53+/− mice with an accelerated cancer death phenotype, undergoing one day per week fasting survived significantly, albeit modestly, longer than mice on an ad libitum diet (Berrigan et al., 2002). The one day per week IF diet resulted in only an 8% reduction in IGF-1 levels, which may explain in part its limited efficacy. Considering the recent development of relatively high calorie FMDs tested in both mice and humans (Brandhorst et al., 2015), and the ability of the combination of PF or FMDs with chemotherapy to have very strong effects including cancer-free survival in multiple murine cancer models, it will be important to directly compare PF or FMDs, with IF diets with shorter periods of fasting such as ADF, the 5:2 diet and TRF. Future studies on IF and cancer treatment should consider the potential toxicity of its combination with chemotherapy, particularly during the feeding days, which may cause an increase in the proliferation of various cell types and promote the generation of secondary tumors. In addition, it will be important to determine whether IF diets affect the metabolism of chemotherapeutic agents, as this could influence the impact of the drug treatment on the cancer cells. 1.2.5. IF in Humans 1.3. Weight loss and maintenance amongst overweight and obese subjects The majority of studies of IF in humans have considered whether IF can be a potential strategy to reduce weight and correct adverse metabolic parameters amongst obese and overweight subjects. This is important since the problems of long term adherence to continuous energy restriction (CER) for weight management are well known (Anastasiou et al., 2015). Johnson et al. undertook the first trial of IF for weight loss amongst 10 obese subjects with asthma which tested alternate days of an 85% energy restricted low carbohydrate diet regimen. This study reported beneficial reductions in serum cholesterol and triglycerides, markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts) and inflammation (serum tumor necrosis factor-α) (Johnson et al., 2007). Circulating ketone levels were also elevated on the fasting days (Johnson et al., 2007) (Fig. 1). This study was the first to show the feasibility of IF amongst obese subjects, however, the lack of a CER comparison group means that we cannot distinguish if the benefits were as a result of the overall energy restriction and weight loss or a specific effect of the IF regimen. The most studied IF regimen has been alternate days of 70% CR, a modified form of ADF. Most studies of ADF summarized in recent reviews show benefits in terms of reductions in weight (-3 to − 7%), body fat (3- 5.5 kg), total serum cholesterol(-10 to − 21%) and triglycerides (- 14 to − 42) (Tinsley & La Bounty, 2015), as well as improvements in glucose homeostasis (Seimon et al., 2015). However the lack of a CER comparator in most of these studies means again, we cannot determine if these effects are a function of the overall energy restriction/weight loss or a specific effect of the IF regimen. To date only a few published randomized controlled trials (RCTs) have assessed whether IF may be equivalent or superior to an isocaloric CER for managing weight and metabolic risk amongst overweight or obese subjects (Table 1). These trials have tested various IF regimens; 2 consecutive days of a 55–70% CR every week (Harvie et al., 2011 and Harvie et al., 2013a; Fig. 2), 4 days of 50% CR each week (Ash et al., 2003), an alternating pattern of 3–7 days of 70%, 60%, 45% and 10% calorie restriction per week (Hill et al., 1989a), and alternating days of a 70% CR and ad libitum eating (Varady et al., 2011). These studies have been relatively small and all reported equivalent weight loss between IF and CER. The only study to show a difference was by Harvie et al., 2013. In this study there was no significant difference in weight loss between the groups, but there was a greater loss of body fat with two different low carbohydrate IF regimens compared with CER over 4 months (Harvie et al., 2013a). The two IF regimens allowed two consecutive days/week of either a low carbohydrate, low energy IF diet (70% CR, 600 kcal, 40 g carbohydrate/d) or a less restrictive low carbohydrate IF which allowed ad libitum protein and monounsaturated fatty acids (55% CR, 1000 kcal, 40 g carbohydrate/d), both with 5 days of a healthy Mediterranean type diet (45% energy from low glycemic load carbohydrates 30% fat; 15% monounstaturated fatty acids, 8% polyunsaturated fatty acids and 7% saturate fatty acids). They were compared to an isocaloric 25% CER Mediterranean type diet. The differences in overall carbohydrate intake between the diet groups were modest (41% and 37% of energy for the two IF diets compared to 47% of energy for CER, which is unlikely to account for any differences in adherence and reductions in adiposity between the diets (Sacks et al., 2009). Fig. 2. Patterns of energy intake in subject on either the ‘5:2′ intermittent energy restriction (IER) diet or continuous (daily) energy restriction (CER). Based on Harvie et al., 2011. Drop out from the selected studies was between 0 and 40%, and similar between the IF and CER groups. Studies which reported adherence to the IF days show a good level of compliance, with 65 − 75% of potential IF days achieved during the trial period. (Harvie et al., 2011 and Harvie et al., 2013a). Importantly, IF does not appear to lead to compensatory over-consumption on the non-dieting days in any of the trials. The two Manchester trials reported a ‘carry over effect’ of reduced energy intake by 23–32% on non-restricted days. Thus on these days the energy restriction was similar to the planned 25% restriction in women taking CER (Harvie et al., 2011 and Harvie et al., 2013a). The greater loss of fat with the two-day low carbohydrate IF diet compared to CER in our 2013 study appears to be linked to good adherence to the restricted days and the spontaneous restriction of energy intake on non-restricted days (Fig. 3). Fig. 3. Examples of effects of intermittent fasting on different organ systems. Abbreviations;: 3OHB, 3-hydroxybutyrate; CRP, C-reactive protein; IGF-1, insulin-like growth factor 1; IL-6, interleukin 6; TNFα, tumor necrosis factor α. Weight loss diets aim to maximize loss of body fat and minimize loss of fat-free mass (FFM) to maintain physical function and attenuate declines in resting energy expenditure and to help prevent weight gain. Proponents of IF diets claim they may preserve FFM, and allowed our Palaeolithic hunter gatherer ancestors to survive spells of food shortage. There are, however, few data to support this assertion as the modest sized IF trials which have been undertaken are unlikely to be powered sufficiently to demonstrate changes in FFM (Heymsfield et al., 2014). Weight loss trials amongst overweight and obese subjects suggest losses of FFM with IF and CER are equivalent and are dependent on the overall protein content of the IF and CER diet, rather than the pattern of energy restriction, which is well established for CER diets (Soenen et al., 2013). Our first IF trial reported an equivalent loss of weight as FFM with IF and CER (both 20%) when both diets provided 0.9 g protein/kg body weight (Harvie et al., 2011). Our 2013 trial reported equal losses of FFM (both 30% of weight lost) with a standard protein (1.0 g protein/kg body weight) IF compared to a standard protein CER (1.0 g protein/kg body weight), but a greater preservation of FFM (20% of weight loss) with a higher protein IF (1.2 g protein/kg weight) (p < 0.05) (Harvie et al., 2013b). Studies of ADF have reported the proportion of weight lost as FFM to be as low as 10% in obese women (Varady et al., 2009a and Varady et al., 2009b) and as high as 30% amongst non-obese subjects (Varady et al., 2013) (Heilbronn et al., 2005b). Subsequent studies have shown that exercise helps to retain FFM amongst subjects undergoing IF (Hill et al., 1989b and Bhutani et al., 2013) which is well documented with CER (Weinheimer et al., 2010). Indeed, a study of young adult men who performed resistance training demonstrated that eight weeks of TRF (8 hour feeding period every day) resulted in loss of fat mass, with retention of lean mass and improved muscle endurance (Moro et al., 2016 and Tinsley et al., 2016). The latter findings are consistent with results of TRF in mice (Chaix et al., 2014) and show that at least some IF diets do not adversely affect, and can even enhance, physical performance. While the equivalent or sometimes superior effects of IF versus CER in the aforementioned studies is of interest, these studies have been short term (≤ 6 months). The true test of a successful weight loss diet is its ability to maintain weight loss long term. Estimates of successful weight loss maintenance with CER (defined as >10% weight loss maintained at ≥12 months), vary between 20% and 50% (Anastasiou et al., 2015 and Wing and Phelan, 2005), which depends on the level of ongoing support. In a recent study, obese subjects were randomized to either zero calorie ADF or daily CER (400 calories/day below baseline intake) for 2 months, followed by 6 months of unsupervised follow-up (Cattenacci et al., 2016). During the 2-month diet intervention period, both groups exhibited weight and fat mass loss; however, at the 6 month post-diet follow-up, changes from baseline in lean mass and fat mass were more favorable in the subjects in the ADF group. However, the latter study is the only published data on weight loss maintenance with IF which is a major gap in the evidence base. There are no data on the potential for IF regimes to prevent weight gain amongst normal weight subjects. Strategies to prevent weight gain in normal weight subjects are important for public health, since adult weight gain is a major public health problem linked to risk of many non-communicable diseases including cancer, diabetes, CVD and dementia (Sun et al., 2009). Reports of sustained hunger with IF (Heilbronn et al., 2005b and Wegman et al., 2014), and difficulties maintaining daily living activities during restricted days of IF (Wegman et al., 2014) in non-obese subjects suggests a more limited compliance and potential efficacy with these specific regimens in the non-obese. However, other patterns of IF, e.g. 1 day/week of CR, may be better tolerated and need to be studied in non-obese subjects. Finally, in addition to controlled studies of IF in human subjects, there have been several studies of health indicators in subjects who fast from dawn until dusk during the month of Ramadan (Mazidi et al., 2015). Overall, it appears that many subjects lose weight during Ramadan and exhibit improvements in some health indicators. However, such studies are generally not well controlled because the time period during which the individuals fast each day varies considerably (9–20 hours) depending upon the day length in the region of the world where the subjects reside. 1.4. IF and Age-Related Diseases in Humans 1.4.1. Type 2 diabetes There are minimal data on the effects of IF versus CER on glucose homeostasis amongst overweight/obese individuals with type 2 diabetes. Ash et al. (2003) reported that a four day IF led to comparable reductions in percentage body fat and reductions in HbA1c to an isocaloric CER. Mean (SD) reduction for the overall group was 1.0 (8.4)%, although this small study may have been underpowered to show significant differences (Ash et al., 2003). Williams et al. (1998) assessed the effect of enhancing a standard 25% CER diet with periods of IF, (75% ER either 5 days/week every 5 weeks or 1 day/week for 15 weeks). Predictably, additional periods of ER increased weight loss. The 5 days/week every 5 weeks intervention resulted in the greatest normalization of HbA1c, independent of weight loss suggesting a potential specific insulin-sensitizing effect of this pattern of IF added to CER (Williams et al., 1998). The two studies of a 2 days/week IF mentioned previously have reported greater reductions in insulin resistance versus CER amongst overweight and obese non-diabetic subjects (Harvie et al., 2011 and Harvie et al., 2013a). In the first study the subjects on the IF diet exhibited a 25% greater reduction in insulin resistance compared to the CER group when measured on the morning after five normal feeding days, with a further 25% reduction in insulin resistance compared with CER on the morning after the two energy restricted days. These differences in insulin sensitivity occurred despite comparable reductions in body fat between the groups (Harvie et al., 2011 and Harvie et al., 2013a). Our follow up study reported greater reductions of insulin resistance with the 2 days/week low carbohydrate IF compared to CER, which this time was associated with a greater loss of fat with the IF regimen (Harvie et al., 2011 and Harvie et al., 2013a). Three studies have assessed the effects of 2-3 weeks of an IF with alternating 20–24 hour periods of a total fast interspersed with 24–28 hour periods of hyperphagia (175-200% of normal intake) and were designed to ensure there was no overall energy deficit or weight loss. Results have been variable between the studies. Halberg et al. reported improvements in insulin-mediated whole body glucose uptake and insulin-induced inhibition of adipose tissue lipolysis when measured after two normal feeding days, (Halberg et al., 2005), whereas Soeters et al. failed to replicate these findings (Soeters et al., 2009). Heilbronn assessed 3 weeks of ADF (24 hour total fast and 24 hour ad lib feeding) amongst 16 normal and overweight men and women (Heilbronn et al., 2005a). Glucose uptake during a test meal (peripheral insulin sensitivity) was assessed on the morning after a fasting day, i.e. after a 36 hour fast; interestingly, insulin sensitivity was increased in men but decreased in women. The latter observation may be a benign observation linked to greater fluxes of free fatty acids amongst fasting women (Hedrington and Davis, 2015), and likely to be a normal physiological adaptation to fasting rather than a cause for concern (Gormsen et al., 2008). Thus, IF has been reported to have variable effects on peripheral and hepatic insulin sensitivity which may be different in obese and normal weight subjects and may be gender-specific. Further studies are required using more robust measures of insulin sensitivity e.g. insulin clamp or other techniques. 1.4.2. Cardiovascular disease Varady et al. performed several different studies to evaluate the effects of modified ADF on cardiovascular risk factors in overweight and obese subjects. In one study, ADF for 2 months resulted in decreases in resting heart rate, and circulating levels of glucose, insulin and homocysteine, all of which are favorable with regards to the risk of cardiovascular disease (Klempel et al., 2012). In another study, 2 months of ADF reduced fat mass, total cholesterol, LDL cholesterol and triglyceride concentrations (Varady et al., 2015). However, there have been few studies that have evaluated the relative effects of IF and CER on cardiovascular risk markers. The randomized comparisons of IF and CER have reported equivalent reductions in blood pressure (Hill et al., 1989a, Harvie et al., 2011 and Harvie et al., 2013a) and triglycerides (Hill et al., 1989a), (Ash et al., 2003). (Harvie et al., 2011 and Harvie et al., 2013a), and increased LDL particle size (Varady et al., 2011). Whilst Hill et al. reported a greater reduction in serum cholesterol with IF (14%) versus CER (6%) (Hill et al., 1989a). 1.5. IF and cancer There are no data on the effects of IF on cancer rates in humans. Weight control is likely to reduce the incident risk of thirteen cancers which have been linked to obesity (Renehan et al., 2008), although the role of weight management after diagnosis on the outcome of obesity related cancers is not known (WCRF, 2014 and Goodwin et al., 2015). Surrogate evidence that IF may reduce cancer risk can be derived from its effects on a number of cancer risk biomarkers such as insulin, cytokines, and the inflammation-related molecules leptin and adiponectin, which are thought to mediate the effects of adiposity and excessive energy intake on the development and growth of cancers in humans (Hursting et al., 2012 and Wei et al., 2016). The effect of IF on total and bioavailable insulin-like growth factor 1 (IGF-1) in human studies has been variable. This reflects the fact that, in contradistinction to animal studies, circulating levels of total IGF-1 and bioactive IGF-1 (determined by measuring IGF-binding proteins 1, 2 and 3) are poor markers of the effects of energy restriction and weight loss in humans (Byers and Sedjo, 2011), and do not relate well to IGF-1 bioactivity at the tissue level (Ramadhin et al., 2014). We reported no change in total circulating IGF-1 alongside weight loss with IF or CER in either of our studies (Harvie et al., 2011 and Harvie et al., 2013a). IF and CER both increased IGF binding protein 1 (26% and 28%) and IGFBP-2 (22% and 36%), but did not change serum bioavailable IGF-1 (ultrafiltered) when measured after feeding days. There is a further acute 17% increase in IGF binding protein 2 on the morning after the two restricted days of a 70% ER, but no measurable change in total or serum bioavailable IGF-1 (ultrafiltered) (Harvie et al., 2011). Reductions in IGF-1 (-15%) have been reported in normal and overweight subjects who had followed an IF diet which involved 5 days per month of a low protein, low energy diet (∼ 0.25 g protein/kg weight, 34–54% of normal energy intake) interspersed with normal intake for the remaining 25 days of the month. These reductions were observed after 5 days of normal eating after three months alongside modest reductions in body weight (-2%) (Brandhorst et al., 2015). The aforementioned effects of IF in relation to insulin resistance and diabetes risk (see references in the section on diabetes above) may therefore have an important role in protecting against obesity-related cancers (Goodwin et al., 2015). Adipose tissue exhibits increased leptin and decreased adiponectin production with increasing adiposity, which is thought to have a role in cancer development and progression via effects on insulin sensitivity, inflammation, and direct effects on cell proliferation and apoptosis (Hursting et al., 2012). Adiponectin levels only increase in overweight humans following CER when there are large reductions in body and visceral fat ( > 10%) (Klempel and Varady, 2011). Some studies of IF have reported increases in adiponectin with more modest weight loss. i.e. a 30% increase in plasma adiponectin on both restricted and feeding days, alongside modest reductions in weight (-4%) and body fat (-11%) (Bhutani et al., 2010). We reported a tendency for a greater increase in adiponectin with IF than CER despite a comparable reductions in weight and adiposity (p = 0.08) (Harvie et al., 2011). These observations are interesting; however our follow up IF study reported no change in adiponectin levels with either IF or CER. (Harvie et al., 2013a). IF brings about large and comparable reductions in leptin as CER (both 40%) and the leptin: adiponectin ratio (Harvie et al., 2011 and Harvie et al., 2013a). Weight loss with CER reduces circulating levels of C reactive protein (CRP) by 2-3% for every 1% weight loss, whereas TNF-α and IL-6 are reduced by around 1-2% per 1% weight loss ( Byers and Sedjo, 2011). Reductions of inflammatory markers with IF are comparable to CER for a given weight loss (Harvie et al., 2011). Thus, although limited, the available biomarker data suggest that IF leads to comparable changes in most cancer risk biomarkers to CER, with the possible exceptions of insulin resistance and adiponectin which require further study using robust methodologies. 2. Conclusions and Future Directions Numerous physiological indicators of health are improved in laboratory rats and mice maintained on IF diets including alternate day fasting and time-restricted feeding. Among such responses to IF are: reduced levels of insulin and leptin which parallel increases in insulin and leptin sensitivity; reduced body fat; elevated ketone levels; reduced resting heart rate and blood pressure, and increased heart rate variability (resulting from increased parasympathetic tone); reduced inflammation; increased resistance of the brain and heart to stress (e.g., reduced tissue damage and improved functional outcome in models of stroke and myocardial infarction); and resistance to diabetes. IF can delay onset and slow the progression of neuronal dysfunction and degeneration in animal models of Alzheimer’s, Parkinson’s and Huntington’s diseases. Emerging findings are revealing cellular and molecular mechanisms by which IF increases the resistance of cells, tissues and organs to stress and common diseases associated with aging and sedentary, overindulgent lifestyles. The results of human studies in which various health indicators are measured at baseline and after periods of IF of 2–6 months or more, suggest that IF can protect against the metabolic syndrome and associated disorders including diabetes and cardiovascular disease. Recent small trials of IF in patients with cancer (Safdie et al., 2009) or multiple sclerosis (Choi et al., 2016) have generated promising results that provide a strong rationale for moving forward with larger clinical trials in patients with a range of chronic age- and obesity-related disorders.
  4. All, I'm not sure if many people around here still do dairy, especially high fat dairy. But if you do, you might want to think again, and not just for the sake of the animals, but for the sake of your heart. This new study [1] analyzed the data from over 200K people in the Health Care Professionals and Nurses Health Studies followed for 20-30 years. The good news? Dairy fat intake was associated with a slightly lower cardiovascular disease risk than other forms of animal fat. The bad news? Replacing 5% of energy from PUFA for 5% more dairy fat resulted in a 24% increase in your risk of cardiovascular disease. Replacing dairy with whole grains was even better (28% lower risk of CVD). Here is a graph showing the estimated impact of substituting various other foods in place of dairy fat on risk of cardiovascular disease overall (A), as well as broken down by coronary heart disease (B) vs. stroke (C ): The authors summarize as follows: To our knowledge, this is the first large-scale prospective study to examine dairy fat intake and its replacement with other types of fat in relation to CVD risk... These results support current recommendations to replace animal fats, including dairy fat, with vegetable sources of fats and polyunsaturated fat (both n–6 and n–3) in the prevention of CVD. Sorry to be the bearer of bad news, cheese lovers. Whom I kidding, no I'm not... --Dean ------------ [1] Am J Clin Nutr. 2016 Aug 24. pii: ajcn134460. [Epub ahead of print] Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults. Chen M(1), Li Y(2), Sun Q(3), Pan A(4), Manson JE(5), Rexrode KM(5), Willett WC(6), Rimm EB(6), Hu FB(7). Full text: http://sci-hub.cc/10.3945/ajcn.116.134460 BACKGROUND: Few prospective studies have examined dairy fat in relation to cardiovascular disease (CVD). OBJECTIVE: We aimed to evaluate the association between dairy fat and incident CVD in US adults. DESIGN: We followed 43,652 men in the Health Professionals Follow-Up Study (1986-2010), 87,907 women in the Nurses' Health Study (1980-2012), and 90,675 women in the Nurses' Health Study II (1991-2011). Dairy fat and other fat intakes were assessed every 4 y with the use of validated food-frequency questionnaires. RESULTS: During 5,158,337 person-years of follow-up, we documented 14,815 incident CVD cases including 8974 coronary heart disease cases (nonfatal myocardial infarction or fatal coronary disease) and 5841 stroke cases. In multivariate analyses, compared with an equivalent amount of energy from carbohydrates (excluding fruit and vegetables), dairy fat intake was not significantly related to risk of total CVD (for a 5% increase in energy from dairy fat, the RR was 1.02; 95% CI: 0.98, 1.05), coronary heart disease (RR: 1.03; 95% CI: 0.98, 1.09), or stroke (RR: 0.99; 95% CI: 0.93, 1.05) (P > 0.05 for all). In models in which we estimated the effects of exchanging different fat sources, the replacement of 5% of energy intake from dairy fat with equivalent energy intake from polyunsaturated fatty acid (PUFA) or vegetable fat was associated with 24% (RR: 0.76; 95% CI: 0.71, 0.81) and 10% (RR: 0.90; 95% CI: 0.87, 0.93) lower risk of CVD, respectively, whereas the 5% energy intake substitution of other animal fat with dairy fat was associated with 6% increased CVD risk (RR: 1.06; 95% CI: 1.02, 1.09). CONCLUSIONS: The replacement of animal fats, including dairy fat, with vegetable sources of fats and PUFAs may reduce risk of CVD. Whether the food matrix may modify the effect of dairy fat on health outcomes warrants further investigation. © 2016 American Society for Nutrition. DOI: 10.3945/ajcn.116.134460 PMID: 27557656
  5. All, As I've elaborated on elsewhere, I'm rather obsessive about dental hygiene. This is in part because I want to avoid cavities, but also out of a vague awareness of studies linking teeth & gum problems with heart attack risk, likely mediated by systemic inflammation induced by chronic oral infections. So I was happy to see my recall of the linkage between poor dental health and cardiovascular disease supported by this new study [2], as well as this review [1] of many previous studies, both of which were shared by Al Pater (thanks Al!). From the review [1]: [N]ew onset as well as prevalent periodontitis is associated with increased coronary heart disease risk,7 and there is a graded association between tooth loss and stroke, cardiovascular death, and all-cause mortality in patients with stable coronary artery disease.8 From the case-control study [2]: There was an increased risk for [heart attack] among those with [periodontal disease] (OR = 1.49; 95% CI 1.21-1.83), which remained significant (OR =1.28; 95% CI 1.03-1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes, years of education and marital status). So we should all be taking good care of our teeth and gums if we want to avoid cardiovascular disease. --Dean ----------------- [1] Circulation. 2016 Jan 13. pii: CIRCULATIONAHA.115.020869. [Epub ahead of print] Increasing Evidence for an Association Between Periodontitis and Cardiovascular Disease. Stewart R, West M. http://circ.ahajournals.org.sci-hub.io/content/early/2016/01/13/CIRCULATIONAHA.115.020869.abstract Abstract Periodontitis is a chronic inflammatory disease caused by bacterial colonisation, which results in destruction of the tissues between the tooth surface and gingiva, loss of connective tissue attachment, erosion of alveolar bone and tooth loss.1 Periodontitis is common and increases with age. In a US survey about half of adults aged over 30 years have some periodontitis and almost 10% have severe disease.2 Evidence for an association between periodontitis and atherosclerotic vascular disease, including stroke, myocardial infarction, peripheral vascular disease, abdominal aortic aneurysm, coronary heart disease and cardiovascular death, comes from more than 50 prospective cohort and case control studies undertaken during the last 25 years.3-6 More recent analyses from large cohort studies suggest new onset as well as prevalent periodontitis is associated with increased coronary heart disease risk,7 and there is a graded association between tooth loss and stroke, cardiovascular death, and all-cause mortality in patients with stable coronary artery disease.8 If causal, these associations would be of great importance because of the potential that preventing or treating periodontal disease could reduce the risk of major adverse cardiovascular events. KEYWORDS: Editorial; cardiovascular disease risk factors; periodontitis; teeth PMID: 26762522 --------------- [2] Circulation. 2016 Jan 13. pii: CIRCULATIONAHA.115.020324. [Epub ahead of print] Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study. Rydén L, Buhlin K, Ekstrand E, de Faire U, Gustafsson A, Holmer J, Kjellström B, Lindahl B, Norhammar A, Nygren Å, Näsman P, Rathnayake N, Svenungsson E, Klinge B. Abstract BACKGROUND: -The relationship between periodontitis (PD) and cardiovascular disease (CVD) is debated. PD is common in patients with CVD. It has been postulated that PD could be causally related to the risk for CVD, a hypothesis tested in PAROKRANK. METHODS AND RESULTS: -805 patients (age <75 years) with a first MI and 805 age (mean 62±8), gender (male 81%) and area matched controls without MI underwent standardized dental examination including panoramic x-ray. The periodontal status was defined as healthy (=/>80% remaining bone) or as mild-moderate (79-66%) or severe PD (<66%). Great efforts were made to collect information on possibly related confounders (~100 variables). Statistical comparisons included Student's pair-wise t-test and Mc Nemar's test in 2x2 contingency tables. Contingency tables exceeding 2x2 with ranked alternatives were tested by Wilcoxon signed rank test. Odds Ratios (95% CI) were calculated by conditional logistic regression. PD was more common (43%) in patients than in controls (33%; p<0.001). There was an increased risk for MI among those with PD (OR = 1.49; 95% CI 1.21-1.83), which remained significant (OR =1.28; 95% CI 1.03-1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes, years of education and marital status). CONCLUSIONS: -In this large case-control study of PD, verified by radiographic bone loss and with a careful consideration of potential confounders, the risk of a first MI was significantly increased in patients with PD even after adjustment for confounding factors. These findings strengthen the possibility of an independent relationship between PD and MI. KEYWORDS: cardiovascular disease risk factors; myocardial infarction; panoramic dental radiography (OPG); periodontitis PMID: 26762521
  6. All, Dr. Greger has another interesting video out today (embedded below) on the benefits of vinegar (diluted acetic acid). Adding a tablespoon or so of vinegar to meals reduces the post-meal spikes in glucose, insulin and triglycerides. I've included his references (with links to the Pubmed abstracts) at the bottom. The fact that I add a little more than a tablespoon of (cider) vinegar to my salad dressing may explain in part how my glucose remains below 125 mg/dl despite eating so many calories in a single big meal per day. --Dean Dr. Greger Vinegar Video References: J B Kohn. Is vinegar an effective treatment for glycemic control or weight loss? J Acad Nutr Diet. 2015 Jul;115(7):1188. P Mitrou, E Petsiou, E Papakonstantinou, E Maratou, V Lambadiari, P Dimitriadis, F Spanoudi, S A Raptis, G Dimitriadis. Vinegar Consumption Increases Insulin-Stimulated Glucose Uptake by the Forearm Muscle in Humans with Type 2 Diabetes. J Diabetes Res. 2015;2015:175204. T Kondo, M Kishi, T Fushimi, S Ugajin, T Kaga. Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects. Biosci Biotechnol Biochem. 2009 Aug;73(8):1837-43. J H O'Keefe, N M Gheewala, J O O'Keefe. Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health. J Am Coll Cardiol. 2008 Jan 22;51(3):249-55. C S Johnston, A J Buller. Vinegar and peanut products as complementary foods to reduce postprandial glycemia. J Am Diet Assoc. 2005 Dec;105(12):1939-42. K Ebihara, A Nakajima. Effect of acetic acid and vinegar on blood glucose and insulin responses to orally administered sucrose and starch. May 1988. C J Panetta, Y C Jonk, A C Shapiro. Prospective randomized clinical trial evaluating the impact of vinegar on lipids in non-diabetics. World J. Cardiovas. Dis. 3, 191-196. 2013. J L Chiasson, R G Josse, R Gomis, M Hanefeld, A Karasik, M Laakso; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002 Jun 15;359(9323):2072-7. M Naissides, J C Mamo, A P James, S Pal. The effect of acute red wine polyphenol consumption on postprandial lipaemia in postmenopausal women. Atherosclerosis. 2004 Dec;177(2):401-8. M Hanefeld, J L Chiasson, C Koehler, E Henkel, F Schaper, T Temelkova-Kurktschiev. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke. 2004 May;35(5):1073-8. Epub 2004 Apr 8. J L Chiasson, R G Josse, R Gomis, M Hanefeld, A Karasik, M Laakso; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003 Jul 23;290(4):486-94. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001 Feb 12;161(3):397-405. A M Opperman, C S Venter, W Oosthuizen, R L Thompson, H H Vorster. Meta-analysis of the health effects of using the glycaemic index in meal-planning. Br J Nutr. 2004 Sep;92(3):367-81. "Z Beheshti, Y H Chan, H S Nia, F Hajihosseini, R Nazari, M Shaabani, M T S Omran. Influence of apple cider vinegar on blood lipids. Life Science Journal 2012;9(4). T C Wascher, I Schmoelzer, A Wiegratz, M Stuehlinger, D Mueller-Wieland, J Kotzka, M Enderle. Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance. Eur J Clin Invest. 2005 Sep;35(9):551-7. G Livesey, R Taylor, H Livesey, S Liu. Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies. Am J Clin Nutr. 2013 Mar;97(3):584-96. J I Mann, L Te Morenga. Diet and diabetes revisited, yet again. Am J Clin Nutr. 2013 Mar;97(3):453-4. J Fan, Y Song, Y Wang, R Hui, W Zhang. Dietary glycemic index, glycemic load, and risk of coronary heart disease, stroke, and stroke mortality: a systematic review with meta-analysis. PLoS One. 2012;7(12):e52182. S H Holt, J C Miller, P Petocz. An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods. Am J Clin Nutr. 1997 Nov;66(5):1264-76. E A Gale. Lessons from the glitazones: a story of drug development. Lancet. 2001 Jun 9;357(9271):1870-5.
  7. All, There seems to be growing evidence that systemic inflammation is involved in many diseases of aging, including cardiovascular disease, diabetes and cognitive impairment / Alzheimer's disease. This new study [1] speaks to the latter. It found the rate of cognitive decline in people suffering from mild cognitive impairment or early-stage Alzheimer's disease was 6x higher in those people who also suffered from periodontal disease, likely as a result of the systemic inflammatory effects of the subjects' infected gums. So take care of those teeth and gums! --Dean ---------- [1] PLoS One. 2016 Mar 10;11(3):e0151081. doi: 10.1371/journal.pone.0151081. eCollection 2016. Periodontitis and Cognitive Decline in Alzheimer's Disease. Ide M(1), Harris M(2), Stevens A(3), Sussams R(2,)(3), Hopkins V(3), Culliford D(4), Fuller J(5), Ibbett P(5), Raybould R(6), Thomas R(6), Puenter U(5), Teeling J(5), Perry VH(5), Holmes C(2,)(3). Author information: (1)Dental Institute, Kings College London, Guy's Hospital, London, United Kingdom. (2)University of Southampton, Faculty of Medicine, Clinical Experimental Science, Southampton, United Kingdom. (3)Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom. (4)University of Southampton, Faculty of Health Sciences, NIHR CLAHRC Wessex Methodological Hub, Southampton, United Kingdom. (5)University of Southampton, Faculty of Natural and Environmental Science, Centre for Biological Sciences, Southampton, United Kingdom. (6)Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786266/ Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation. PMCID: PMC4786266 PMID: 26963387
  8. Sthira, you'll love this one [1] posted by Al Pater (thanks Al!) to the CR email list. It compared various group lifestyle interventions, including yoga, walking, Mediterranean diet and group smoking cessation classes for their effect over the following 10 years on risk of cardiovascular disease. It found: [Y]oga was associated with the largest 10-year cardiovascular disease risk reductions (maximum absolute reduction 16.7% for the highest-risk individuals). Walking generally ranked second (max 11.4%), followed by Mediterranean diet (max 9.2%), and group therapy for smoking (max 1.6%). Of course, the effectiveness of a treatment is dependent on subject compliance and treatment efficacy. That's why smoking cessation treatments were almost completely ineffective - almost nobody quits for very long. The authors acknowledge this, saying: We have presented a rank order of strategies that do not include taking any pills or medication. As such, non-adherence with lifestyle change and other health behaviors, including pill-taking, is of concern and may dilute intervention effects. Our calculations are based on intention to-treat rates from the clinical trials, which incorporate non-adherence. For a current smoker, successfully quitting smoking is the most effective lifestyle change. Smoking cessation is, however, difficult to achieve and group therapy for stopping smoking has only a small probability of success. From an intention-to-treat perspective, if yoga is as effective as reported in currently published meta-analyses, then yoga could be considered among the strongest lifestyle interventions for reducing CVD risk. Too bad they didn't include a dance intervention group. Based on the benefits of dance discussed here, I bet it might have done best of all! --Dean ---------- [1] Comparative Effectiveness of Personalized Lifestyle Management Strategies for Cardiovascular Disease Risk Reduction. Chu P, Pandya A, Salomon JA, Goldie SJ, Hunink MG. J Am Heart Assoc. 2016 Mar 29;5(3). pii: e002737. doi: 10.1161/JAHA.115.002737. PMID: 27025969 Free Article http://jaha.ahajournals.org/content/5/3/e002737.full http://jaha.ahajournals.org/content/5/3/e002737.full.pdf+html Abstract BACKGROUND: Evidence shows that healthy diet, exercise, smoking interventions, and stress reduction reduce cardiovascular disease risk. We aimed to compare the effectiveness of these lifestyle interventions for individual risk profiles and determine their rank order in reducing 10-year cardiovascular disease risk. METHODS AND RESULTS: We computed risks using the American College of Cardiology/American Heart Association Pooled Cohort Equations for a variety of individual profiles. Using published literature on risk factor reductions through diverse lifestyle interventions-group therapy for stopping smoking, Mediterranean diet, aerobic exercise (walking), and yoga-we calculated the risk reduction through each of these interventions to determine the strategy associated with the maximum benefit for each profile. Sensitivity analyses were conducted to test the robustness of the results. In the base-case analysis, yoga was associated with the largest 10-year cardiovascular disease risk reductions (maximum absolute reduction 16.7% for the highest-risk individuals). Walking generally ranked second (max 11.4%), followed by Mediterranean diet (max 9.2%), and group therapy for smoking (max 1.6%). If the individual was a current smoker and successfully quit smoking (ie, achieved complete smoking cessation), then stopping smoking yielded the largest reduction. Probabilistic and 1-way sensitivity analysis confirmed the demonstrated trend. CONCLUSIONS: This study reports the comparative effectiveness of several forms of lifestyle modifications and found smoking cessation and yoga to be the most effective forms of cardiovascular disease prevention. Future research should focus on patient adherence to personalized therapies, cost-effectiveness of these strategies, and the potential for enhanced benefit when interventions are performed simultaneously rather than as single measures. KEYWORDS: cardiovascular risk reduction; comparative effectiveness; lifestyle modification
  9. All, Sthira, in a recent post to the exercise thread ,which I wantonly edited (my bad, sorry Sthira...) in order to create this new thread on animal cruelty, mentioned how beneficial dance is for health & longevity, complementing my daughter, who is a dancer. In vindication Sthira's assessment, this new study [1] (press release, popular press article) found that engaging in social dancing, particularly rigorous social dancing (enough to make one "out of breath and sweaty"), reduced cardiovascular mortality risk by 50% relative to people who didn't dance. Dancing was about twice as beneficial for CVD mortality as walking, even after controlling for a pretty extensive set of potential confounders, including age, sex, socioeconomic status, smoking, alcohol, BMI, chronic illness, psychosocial distress, and total physical activity amount. Discussing the study, one of the authors said: "We should not underestimate the playful social interaction aspects of dancing which, when coupled with some more intense movement, can be a very powerful stress relief and heart health promoting pastime... The Bee Gees said it best - you should be dancing," Maybe we should have a dance party one evening at the CR Conference.☺ --Dean ---------- [1] American Journal of Preventive Medicine Available online 1 March 2016, DOI: http://dx.doi.org/10.1016/j.amepre.2016.01.004 Dancing Participation and Cardiovascular Disease Mortality: A Pooled Analysis of 11 Population-Based British Cohorts Dafna Merom, PhD, Ding Ding, PhD, Emmanuel Stamatakis, PhD Free full text: http://www.ajpmonline.org/article/S0749-3797(16)00030-1/pdf Abstract Introduction Little is known about whether cardiovascular benefits vary by activity type. Dance is a multidimensional physical activity of psychosocial nature. The study aimed to examine the association between dancing and cardiovascular disease mortality. Methods A cohort study pooled 11 independent population surveys in the United Kingdom from 1995 to 2007, analyzed in 2014. Participants were 48,390 adults aged ≥40 years who were free of cardiovascular disease at baseline and consented to be linked to the National Death Registry. Respondents reported participation in light- or moderate-intensity dancing and walking in the past 4 weeks. Physical activity amount was calculated based on frequency, duration, and intensity of participation in various types of exercise. The main outcome was cardiovascular disease mortality based on ICD-9 codes 390−459 or ICD-10 codes I01−I99. Results During 444,045 person-years, 1,714 deaths caused by cardiovascular disease were documented. Moderate-intensity, but not light-intensity, dancing and walking were both inversely associated with cardiovascular disease mortality. In Cox regression models, the hazard ratios for cardiovascular disease mortality, adjusted for age, sex, SES, smoking, alcohol, BMI, chronic illness, psychosocial distress, and total physical activity amount, were 0.54 (95% CI=0.34, 0.87) for moderate-intensity dancing and 0.75 (95% CI=0.62, 0.90) for moderate-intensity walking. Conclusions Moderate-intensity dancing was associated with a reduced risk for cardiovascular disease mortality to a greater extent than walking. The association between dance and cardiovascular disease mortality may be explained by high-intensity bouts during dancing, lifelong adherence, or psychosocial benefits.
  10. 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
  11. 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
  12. [Another one for the "Non-CR Health forum"...] Recently there has been much hype in the popular press, including a Time Magazine story, with this provocative cover: that claim we've been wrong about saturated fat (like butter) all along. These stories have been based on meta-analyses like this one [1], that purport to find no association between saturated fat and chronic diseases, even cardiovascular disease. One of my favorite nutrition bloggers, PlantPositive, did a thorough debunking of the Time story and the people & studies it uses as sources. Among other faults of these previous meta-analyses outlined in PlantPositive's post, some of the biggest problems include: Over correction by factoring out serum cholesterol in the analysis - which is elevated by saturate fat intake and so shouldn't be controlled for. Failing to factor out the low cholesterol of saturated fat eaters who take statins to control their cholesterol. Failing to account for the health effects of what people choose to eat instead when they don't eat saturated fat-rich foods. As I recall (but an unable to verify due to the archives being down... ), we talked about all these studies and their shortcomings on the CR email list before. But now, we have something even better than critical analysis of flawed studies. We have a new prospective cohort study [2] of some of the best data available on diet, lifestyle and health from the Health Professionals and Nurses Health Studies. It appears to do a much better job, particularly with respect to the third confounder - food substitution effects. Here is popular press coverage of the new study. The Harvard researchers have followed these two cohorts of 42K men and 84K women for over 30 years, assessing their diet, lifestyle and health repeatedly during that time. This study looked at their fat consumption habits, and in particular changes in those habits over time and how those changes relate to coronary heart disease (CHD). In a nutshell, they found that: Replacing 5% of energy intake from saturated fats with equivalent energy intake from PUFAs, monounsaturated fatty acids, or carbohydrates from whole grains was associated with a 25%, 15%, and 9% lower risk of CHD, respectively (PUFAs, HR: 0.75, 95% CI: 0.67 to 0.84; p < 0.0001; monounsaturated fatty acids, HR: 0.85, 95% CI: 0.74 to 0.97; p = 0.02; carbohydrates from whole grains, HR: 0.91, 95% CI: 0.85 to 0.98; p = 0.01). Replacing saturated fats with carbohydrates from refined starches/added sugars was not significantly associated with CHD risk (p > 0.10). Here is a graphical depiction of these results: As you can see, trans fat is toxic relative to any other foods, including saturate fat - no surprise. More interestingly, it is about a wash to substitute saturated fat with refined carbohydrates when it comes to heart disease risk. But substituting any of the following for saturated fat results in significantly reduced CHD risk - MUFA, PUFA and whole grain carbohydrates. PUFAs appear particularly protective. Unfortunately the study did not address other healthy carbohydrate sources besides whole grains, like fruits, vegetables or legumes (which I willing to bet would do at least as well as whole grains at reducing CHD risk relative to saturated fat). They also didn't discriminate between the health effects of different types of saturated fats, some of which might not be as bad as others (i.e. those found in plants vs. animal sources). One concern is that when people clean up their diet by eliminating saturated fat, they might also undertake other health promoting lifestyle changes, making it appear that reducing saturated fat was beneficial when it actually was the other changes that made the difference. The authors addressed this potential problem by controlling for a host of other factors in their analysis, including: The multivariable model was adjusted for total energy intake, the energy contribution from protein, cholesterol intake, alcohol intake, smoking status, body mass index, physical activity, use of vitamins and aspirin, family history of myocardial infarction and diabetes, and presence of baseline hypercholesterolemia and hypertension. These results confirm what I think most people have believed all along - that saturated fat is detrimental to heart health, but probably no more so than what people will normally eat instead, crappy carbs. This explains those previous studies that found lower saturated fat intake was often not associated with lower risk of heart disease - people who ate less saturated fat were eating more refined carbs instead, and so weren't any better off. But when you replace saturated fat-rich foods with healthy fats or healthy carbs, you reduce your risk of heart disease dramatically. --Dean --------------- [1] BMJ. 2015 Aug 11;351:h3978. doi: 10.1136/bmj.h3978. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. de Souza RJ(1), Mente A(2), Maroleanu A(3), Cozma AI(4), Ha V(5), Kishibe T(6), Uleryk E(7), Budylowski P(8), Schünemann H(9), Beyene J(10), Anand SS(11). OBJECTIVE: To systematically review associations between intake of saturated fat and trans unsaturated fat and all cause mortality, cardiovascular disease (CVD) and associated mortality, coronary heart disease (CHD) and associated mortality, ischemic stroke, and type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Registry of Controlled Trials, Evidence-Based Medicine Reviews, and CINAHL from inception to 1 May 2015, supplemented by bibliographies of retrieved articles and previous reviews. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational studies reporting associations of saturated fat and/or trans unsaturated fat (total, industrially manufactured, or from ruminant animals) with all cause mortality, CHD/CVD mortality, total CHD, ischemic stroke, or type 2 diabetes. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed study risks of bias. Multivariable relative risks were pooled. Heterogeneity was assessed and quantified. Potential publication bias was assessed and subgroup analyses were undertaken. The GRADE approach was used to evaluate quality of evidence and certainty of conclusions. RESULTS: For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90 501-339 090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12 942-230 135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was "very low." The certainty of associations of trans fat with CHD outcomes was "moderate" and "very low" to "low" for other associations. CONCLUSIONS: Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats. © de Souza et al 2015. PMCID: PMC4532752 PMID: 26268692 ------------ [2] J Am Coll Cardiol. 2015 Oct 6;66(14):1538-48. doi: 10.1016/j.jacc.2015.07.055. Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study. Li Y(1), Hruby A(1), Bernstein AM(2), Ley SH(1), Wang DD(1), Chiuve SE(3), Sampson L(1), Rexrode KM(4), Rimm EB(5), Willett WC(5), Hu FB(6). BACKGROUND: The associations between dietary saturated fats and the risk of coronary heart disease (CHD) remain controversial, but few studies have compared saturated with unsaturated fats and sources of carbohydrates in relation to CHD risk. OBJECTIVES: This study sought to investigate associations of saturated fats compared with unsaturated fats and different sources of carbohydrates in relation to CHD risk. METHODS: We followed 84,628 women (Nurses' Health Study, 1980 to 2010), and 42,908 men (Health Professionals Follow-up Study, 1986 to 2010) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by a semiquantitative food frequency questionnaire every 4 years. RESULTS: During 24 to 30 years of follow-up, we documented 7,667 incident cases of CHD. Higher intakes of polyunsaturated fatty acids (PUFAs) and carbohydrates from whole grains were significantly associated with a lower risk of CHD comparing the highest with lowest quintile for PUFAs (hazard ratio : 0.80, 95% confidence interval [CI]: 0.73 to 0.88; p trend <0.0001) and for carbohydrates from whole grains (HR: 0.90, 95% CI: 0.83 to 0.98; p trend = 0.003). In contrast, carbohydrates from refined starches/added sugars were positively associated with a risk of CHD (HR: 1.10, 95% CI: 1.00 to 1.21; p trend = 0.04). Replacing 5% of energy intake from saturated fats with equivalent energy intake from PUFAs, monounsaturated fatty acids, or carbohydrates from whole grains was associated with a 25%, 15%, and 9% lower risk of CHD, respectively (PUFAs, HR: 0.75, 95% CI: 0.67 to 0.84; p < 0.0001; monounsaturated fatty acids, HR: 0.85, 95% CI: 0.74 to 0.97; p = 0.02; carbohydrates from whole grains, HR: 0.91, 95% CI: 0.85 to 0.98; p = 0.01). Replacing saturated fats with carbohydrates from refined starches/added sugars was not significantly associated with CHD risk (p > 0.10). CONCLUSIONS: Our findings indicate that unsaturated fats, especially PUFAs, and/or high-quality carbohydrates can be used to replace saturated fats to reduce CHD risk. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. PMCID: PMC4593072 [Available on 2016-10-06] PMID: 26429077
  13. In my exploration of nutrigenomics, I came across this interesting recent study [1] that looked at the interaction between a particular gene polymorphism (rs4977574 - available on 23andMe) and cardiovascular disease (CVD), as mediated by consumption of either vegetables or wine. The researchers followed 24,000 people for 15 years, during which time about 3000 of them developed cardiovascular disease. So it was a pretty big cohort, with lots of people experiencing the outcome in question - cardiovascular disease. Across the entire population, eating more veggies and drinking more wine resulted in less CVD - not too surprising given previous research on the health benefits of these foods. Things got more interesting when the researchers looked at polymorphisms of SNP rs4977574. Having one or two of the risk alleles (G worse than A) for this SNP on chromosome 9 has been previously shown to be associated with an increased risk of CVD [2]. For example, study [3] found for every G allele one carries, one has about a 13% increased risk of CVD. Study [2] was similar - in the 20-25% of the population that carry two G alleles for this SNP, risk of CVD was increased 30-40% relative to people with AA for rs4977574. This new study [1] found something very similar - for each additional G allele at rs4977574, people were 16% more likely to develop CVD. And these polymorphisms are quite common, ~30% of the study population were AA for rs4977574, 50% were AG, and 20% were GG. But things got really interesting when they looked at how vegetable and wine consumption influenced with the link between this polymorphism and CVD. For people with two 'normal' alleles for rs4977574 (AA), increasing vegetable intake was associated with lower CVD, just like in the population as a whole - no surprise. But for people with either one or two G's for rs4977574, higher vegetable intake didn't help! In other words, compared with high consumers of vegetables who carried two A's for rs4977574 (the reference group), people with AG for rs4977574 were 20-30% more likely to develop CVD, and people with GG for rs4977574 were 40-50% more likely to develop CVD, regardless of how many vegetables they ate! The opposite was true for wine. Wine didn't help reduce risk of CVD in AA carriers for rs4977574, but it did reduce risk in AG and GG carriers, by ~30% and ~40% respectively! In fact, drinking wine appeared to nearly entirely counteract the baseline increased risk of CVD in AG and GG carriers, relative to AA carriers. Here is the relevant table of results from the paper for those interested in the precise details: In summary, this study suggests that if you have one or (especially) two G alleles for rs4977574, you are at higher risk for cardiovascular disease, and that consuming wine, but not vegetables, can help lower your risk. FYI, 23andMe shows I've got one G allele for rs4977574 - which is a bummer since I love veggies and don't drink alcohol. :( Of course its only one study, and one gene locus, so the results should be taken with a grain of salt. I don't plan to eat fewer veggies or take up drinking as a result of this study, particularly since alcoholism runs in my family. I figure my good cholesterol numbers and healthy diet/lifestyle make it unlikely I'll die of CVD anyway. But it seems like another interesting example how genes and diet/lifestyle can interact to influence health in significant and sometimes surprising ways. --Dean ------------------------------------------- [1] BMC Med Genet. 2014 Dec 31;15(1):1220. [Epub ahead of print] The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study. Hindy G, Ericson U, Hamrefors V, Drake I, Wirfält E, Melander O, Orho-Melander M. Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331503/pdf/12881_2014_Article_138.pdf AbstractBackgroundChromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers.MethodsMultivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmö Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow-up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan® Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline.ResultsEach rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10¿1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91¿0.996]), wine intake (HR, 0.91 [CI: 0.86¿0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86¿0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction¿=¿0.043), and to non- and low consumers of wine (Pinteraction¿=¿0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction¿=¿0.015 and 0.049, respectively).ConclusionsOur results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD. PMID: 25551366 --------------------- [2] Science. 2007 Jun 8;316(5830):1488-91. Epub 2007 May 3. A common allele on chromosome 9 associated with coronary heart disease. McPherson R1, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC. Author information AbstractCoronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD. PMID: 17478681 --------------------------------- [3] J Intern Med. 2013 Sep;274(3):233-40. doi: 10.1111/joim.12063. Epub 2013 Mar 25. Chromosome 9p21 genetic variation explains 13% of cardiovascular disease incidence but does not improve risk prediction. Gränsbo K1, Almgren P, Sjögren M, Smith JG, Engström G, Hedblad B, Melander O. Author information AbstractOBJECTIVES:To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors. DESIGN, SETTING AND PARTICIPANTS:rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models. RESULTS:In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11-1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy. CONCLUSION:The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.
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