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  1. 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
  2. Today from Science News: Another article involving the important research being conducted here at the University of Rochester: Microglia had been thought to be active all the time; not so; they are most active during sleep, especially when we are not stressed (low circulating noreprinephine) https://www.urmc.rochester.edu/news/story/5584/the-night-gardeners----immune-cells-rewire-repair-brain-while-we-sleep.aspx
  3. Dear ALL, The following fascinating article appeared in a University of Rochester publication this morning: https://www.urmc.rochester.edu/news/story/5508/not-all-sleep-is-equal-when-it-comes-to-cleaning-the-brain.aspx It describes the cleansing of the brain of debris by cerebral spinal fluid during slow wave sleep, discovered previously at UR; and notes that, during surgery, especially on older adults, it's important to use the appropriate anaesthetics, ketamine and xylazine, so that the glymphatic system should work as it usually works during deep slow wave sleep, to clear the brain. (The wrong anaesthetics can allow plaques to accumulate. Clinical examples are given. An obvious observation, not mentioned in the article (for obvious reasons): Might it be conceivably eventually a method of helping people having difficulty achieving slow wave sleep, to be take (orally take or inject ?) these two anaesthetics in (who knows what ?) quantity before bed to achieve better quality sleep? (I don't recommend experimenting with this on yourselves; but it would be fascinating if some qualified sleep researcher managed to start a clinical study of this possible method of improving sleep quality on patients at risk of Alzheimers. Probably would be VERY hard to get FDA approval). -- Saul
  4. http://www.rochester.edu/newscenter/study-suggests-how-high-blood-pressure-might-contribute-to-alzheimers-360432/
  5. All, We've talked quite a bit around here lately about the optimal BMI for longevity, most notably in this thread about the Optimal Late-Life BMI for Longevity, and this one called Will Serious CR Beat a Healthy Obesity-Avoiding Diet & Lifestyle , and this one called Relationship between BMI and Disease, Longevity, and finally this one called Body Mass Index and All-Cause Mortality. In general, it appears (to my interpretation) that it doesn't pay to be very thin when it comes to longevity, and may in fact be counterproductive, particularly as someone gets into their senior years. Being average weight or even overweight does not appear to adversely impact longevity in older folks, in fact if anything the evidence points the other way - being a heavy senior appears associated with increased longevity. But what about cognitive health? It would be pretty tragic to live an especially long time, but lose your marbles along the way. Three recent studies that came across my radar shed some light on the issue of BMI and cognitive health. The first [1] looks pretty bad for chubby folks. It found being overweight was associated with a reduction in the volume of several important brain areas. The researchers did structural MRI scans of the brains of 203 relatively young men and women (mean age 32, range 18-50). They ranged in BMI from 18.5 to 46.4. They all self-reported being healthy, and were not receiving any pharmacological treatments. They processed the MRI scans to estimate cortical thickness and surface area, both globally and on a per-region basis. Overall they didn't find a correlation between any of the global brain anatomy measures and BMI: There was no association between BMI and global measures of average cortical thickness, total surface area or average LGI [Local gyrification index - a measure of how folded the cortex is. DP]. But in two brain areas there was a difference between obese folks and people who were either thin or simply overweight: Post-hoc contrasts revealed that while lean (BMI < 25) and overweight subjects (25 ≤ BMI < 30) did not significantly differ in the thickness of the right vmPFC or left LOC (p = 0.29 and p = 0.34, respectively), obese subjects (BMI ≥ 30) had significantly thinner cortices in these clusters, compared to both lean (p < 0.0001 in both clusters) and overweight subjects (p < 0.0001 in both clusters). The ventromedial prefrontal cortex (vmPFC) is at the front of the brain, above the eyebrows and is involved in executive function and decision-making. The LOC (lateral occipital cortex) is at the back of the brain, and is involved in vision processing and object recognition. The scatter plots for the cortical thickness in those two brain areas as a function of BMI look pretty scattered to me. It seems difficult to put too much stock in their results, especially below a BMI of 30, where the plots look pretty random, at least to my eyes: My dubiousness about the result is bolstered by the fact that this cortical thinning effect was discovered in post-hoc analysis. In other words, the researchers were fishing for differences in brain anatomy as a function of BMI, after the main effect they were looking for (cortical changes across the whole brain varying with BMI) didn't pan out. After undoubtedly looking at many regions, these two showed up with statistically significant variations as a function of BMI. There is always the danger with this sort of post-hoc approach of finding spurious correlations if you look hard enough at enough different variables. But other studies have found variations in the vmPFC related to obesity. In fact, these authors and others have speculated that the direction of causality may be reserved for the vmPFC. Rather than obesity causing brain shrinking in the vmPFC, having a smaller vmPFC may predispose someone to gaining weight. Why? Because the vmPFC is critical for good decision-making, and the thought is that a smaller vmPFC may result in poor impulse control, and therefore overeating and weight gain. In a separate new study by the same authors [2] (popular press coverage), this time looking at white matter (axons between brain areas) rather than grey matter (neuronal cell bodies and dendrites), the authors did find a more widespread difference between the brains of obese/overweight people and thin people. This time they scanned the brains of over 500 people aged 20 to 87. Basically, when it came to white matter volume, the brains of overweight (avg BMI 27.1) or obese (avg BMI 33.5) folks looked about 10 years older than the lean (normal weight) folks (avg BMI 22.7). Here are the curves for white matter volume as a function of age: As you can see, everyone's white matter volume declines past age 40, but the overweight/obese folks appear to never reach the same peak volume as the normal weight folks and start to decline earlier than the normal weight folks as well. As a result, past middle age the overweight/obese folks' brains looked about 10 years older than the thin folks in terms of white matter volume. The impact of BMI on white matter volume appeared to be independent of exercise, income or education. Interestingly, the authors also found that "a previous diagnosis of elevated cholesterol" was associated with reduced white matter volume, independent of age and BMI. But perhaps most surprisingly, despite the reduced white matter volume in obese/overweight folks relative to lean folks, they saw no difference in cognitive scores (on the Cattell test - "used to capture fluid intelligence by measuring abstract reasoning ability") between the chubby and the lean folks: The authors say: Although previous studies have linked white matter integrity, processing speed and fluid intelligence (Kievit et al., 2016) our results suggest that BMI does not additional influence the age and brain structure relationship with cognition. In other words, despite having less white matter, the heavier folks didn't suffer any faster cognitive decline than the thin folks, at least as measured by this test of "fluid intelligence" in a snapshot of people at various ages. The authors again point to the possibility of reverse causality (less white matter → weight gain), but it seems harder to argue in this case, where the white matter shrinkage/deficit was global rather than confined to decision-making parts of the brain like they saw in [1]. Despite minor doubts about the arrow of causality, and despite a lack of cognitive deficits in the heavier folks, it seems to me like a no-brainer to prefer potentially preserving white matter by staying lean (avg BMI ~23) relative to becoming overweight (BMI >25) or obese (BMI > 30). So these two studies (weakly) suggest it's better to be lean than overweight/obese for brain health. But what about the other end of the scale? That's where study [3] comes in. In this one, a different set of researchers did PET brain imaging on 280 healthy older people (mean age 73, range 62-90) with normal cognitive function. More on demographics: Subjects were roughly average for the American population in terms of prevalence for antihypertensive use (58%) and statin use (44%), but had less diabetes mellitus type 2 (9%) and active smoking (4%).d Here was the distribution of BMIs: Body-Mass Index 26.9 (16–41) - Underweight (BMI <18.5) 2.5% (n=7) - Normal (BMI 18.5–24.9) 31.8% (n = 89) - Overweight (BMI 25–29.9) 41.4% (n = 116) - Obese (BMI >30) 24.3% (n = 68) What they did was correlate BMI with PiB retention, which is a surrogate for brain amyloid concentration, an early marker for increased risk of cognitive impairment / alzheimer disease. What they found that was being on the thin end of the BMI spectrum (i.e. < 25) was associated with an increased PiB retention, i.e. increased risk of future cognitive decline. This association was seen across the board, but was only significant in APOE4 carriers (i.e. those with a genetic tendency to develop cognitive impairment / alzheimer's disease). Here are the scatter plots of data from APOE4 carriers (green) and non-carriers (blue): As you can see, once again there was a pretty wide scatter, and the blue points have only a very modest downward slope (i.e. reduced risk of cognitive decline) with increasing BMI. In short, it appears if you know you are an APOE4 carrier (or if you don't know that you aren't an APOE4 carrier) it looks like it may be a good idea to avoid being thin late in life. But once again it is hard to know if being thin causes cognitive decline in APOE4 carriers, or that being an APOE4 carrier causes weight loss later in life. When taken together, the upshot of these three studies of BMI & cognitive health seems to point to a similar conclusion as we've seen for BMI & longevity. Namely that a middle-of-the-road BMI (i.e. 23-25) in one's elder years appears associated with the maximum chance of keeping one's marbles intact with age. --Dean ------------ [1] Int J Obes (Lond). 2016 Jul;40(7):1177-82. doi: 10.1038/ijo.2016.42. Epub 2016 Mar 22. Increased body mass index is associated with specific regional alterations in brain structure. Medic N(1,)(2), Ziauddeen H(1,)(2,)(3), Ersche KD(1), Farooqi IS(2), Bullmore ET(1,)(4), Nathan PJ(1,)(5), Ronan L(1), Fletcher PC(1,)(2,)(3). Author information: (1)Department of Psychiatry, University of Cambridge, Cambridge, UK. (2)Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. (3)Cambridgeshire and Peterborough NHS Foundation Trust, University of Cambridge, Cambridge, UK. (4)Medicines Discovery and Development, GlaxoSmithKline, Clinical Unit Cambridge, Cambridge, UK. (5)School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia. Full text: http://sci-hub.cc/10.1038/ijo.2016.42 BACKGROUND: Although obesity is associated with structural changes in brain grey matter, findings have been inconsistent and the precise nature of these changes is unclear. Inconsistencies may partly be due to the use of different volumetric morphometry methods, and the inclusion of participants with comorbidities that exert independent effects on brain structure. The latter concern is particularly critical when sample sizes are modest. The purpose of the current study was to examine the relationship between cortical grey matter and body mass index (BMI), in healthy participants, excluding confounding comorbidities and using a large sample size. SUBJECTS: A total of 202 self-reported healthy volunteers were studied using surface-based morphometry, which permits the measurement of cortical thickness, surface area and cortical folding, independent of each other. RESULTS: Although increasing BMI was not associated with global cortical changes, a more precise, region-based analysis revealed significant thinning of the cortex in two areas: left lateral occipital cortex (LOC) and right ventromedial prefrontal cortex (vmPFC). An analogous region-based analysis failed to find an association between BMI and regional surface area or folding. Participants' age was also found to be negatively associated with cortical thickness of several brain regions; however, there was no overlap between the age- and BMI-related effects on cortical thinning. CONCLUSIONS: Our data suggest that the key effect of increasing BMI on cortical grey matter is a focal thinning in the left LOC and right vmPFC. Consistent implications of the latter region in reward valuation, and goal control of decision and action suggest a possible shift in these processes with increasing BMI. DOI: 10.1038/ijo.2016.42 PMCID: PMC4936515 [Available on 2017-01-01] PMID: 27089992 ------------ [2] Neurobiology of Aging (2016), Obesity associated with increased brain-age from mid-life Ronan, L., Alexander-Bloch, A.F, Wagstyl, K., Farooqi, S., Brayne, C., Tyler, L.K, Cam-CAN, Fletcher, P.C, Free full text: http://www.neurobiologyofaging.org/article/S0197-4580(16)30140-3/pdf Abstract Common mechanisms in aging and obesity are hypothesized to increase susceptibility to neurodegeneration, however direct evidence in support of this hypothesis is lacking. We therefore performed a cross-sectional analysis of MRI-based brain structure on a population-based cohort of healthy adults. Study participants were originally part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and included 527 individuals aged 20 – 87 years. Cortical reconstruction techniques were used to generate measures of whole brain cerebral white matter volume, cortical thickness and surface area. Results indicated that cerebral white matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain-age of 10 years. There were no similar BMI-related changes in cortical parameters. This study suggests that at a population level, obesity may increase the risk of neurodegeneration. Keywords obesity; white matter volume; structural MRI; population-based PMID: Not available doi: 10.1016/j.neurobiolaging.2016.07.010. ----------- [3] J Alzheimers Dis. 2016 Jun 18;53(3):1097-105. doi: 10.3233/JAD-150987. Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly. Hsu DC(1,)(2,)(3), Mormino EC(4), Schultz AP(4), Amariglio RE(4,)(2), Donovan NJ(1,)(2,)(5), Rentz DM(4,)(2,)(5), Johnson KA(4,)(6,)(2), Sperling RA(4,)(2), Marshall GA(4,)(2); Harvard Aging Brain Study. Author information: (1)Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (2)Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (3)Department of Psychiatry, Mercy Medical Group, Sacramento, CA, USA. (4)Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (5)Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (6)Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Full text: available on request BACKGROUND: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer's disease (AD) dementia. OBJECTIVE: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. METHODS: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62-90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein E ɛ4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. RESULTS: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  -0.14, p = 0.02). In the secondary analyses, APOE4 carrier status (β= -0.27, p = 0.02) and normal BMI (β= -0.25, p = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= -0.14, p = 0.04). CONCLUSIONS: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers. DOI: 10.3233/JAD-150987 PMCID: PMC4976009 PMID: 27340843
  6. All, I found this interesting. University of Pittsburgh (yeah!) researchers have found [1] (press release) that cognition tends to decline much more rapidly in elderly folks who test positive for chronic, seemingly harmless viral infections, such as cytomegalovirus, toxoplasma gondii (the virus that makes rats love cats, and humans take risks!), and various herpes simplex viruses. The lead author said: “It’s possible that these viruses, which can linger in the body long after acute infection, are triggering some neurotoxic effects.” The smart folks over at Fight Aging! observe: A good deal of evidence from past years supports the theory that CMV accelerates immune system aging, causing the immune system to devote ever more of its limited capacity to uselessly fighting CMV rather than productively carrying out its other tasks. Our immune response is incapable of clearing CMV from the body, and the virus lingers to return in force again and again regardless of the effort devoted to battle it. Chronic infections with these three viruses is surprisingly common. T. gondii infection rates are around 22% of the general population. And between 50 and 80% of people are infected with cytomegalovirus by age 40! I wonder if chronic elevation of WBC, as a sign of chronic infection, is associated with accelerated cognitive decline... I suspect it probably is. For CRers whose WBC count remains unusually high, it might be worth getting tested for chronic viral infections, including the three listed above. --Dean ------------ [1] Alzheimer Dis Assoc Disord. 2015 Dec 24. [Epub ahead of print] Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort. Nimgaonkar VL(1), Yolken RH, Wang T, Chung-Chou HC, McClain L, McDade E, Snitz BE, Ganguli M. Author information: (1)Departments of *Psychiatry ∥Medicine ¶Neurology, University of Pittsburgh School of Medicine Departments of †Human Genetics §Biostatistics #Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA ‡Department of Pediatrics, Stanley Division of Neurovirology, Johns Hopkins University School of Medicine, Baltimore, MD. BACKGROUND: Numerous cross-sectional studies have related exposure to neurotropic infectious agents with cognitive dysfunction in older adults, however, the temporal sequence is uncertain. METHODS: In a representative, well-characterized, population-based aging cohort, we determined whether the temporal trajectories of multiple cognitive domains are associated with exposure to cytomegalovirus (CMV), Herpes Simplex virus, type 1 (HSV-1), Herpes Simplex virus, type 2 (HSV-2), or Toxoplasma gondii (TOX). Complex attention, executive functions, memory, language, and visuospatial function were assessed annually for 5 years among consenting individuals. Study entry IgG antibody titers indexing exposure to each infectious agent were examined in relation to slopes of subsequent temporal cognitive decline using multiple linear regressions adjusted for potential confounders. RESULTS: The IgG levels for HSV-2 were significantly associated with baseline cognitive domain scores (N=1022 participants). Further, the IgG levels for HSV-2, TOX, and CMV, but not HSV-1 were significantly associated with greater temporal cognitive decline that varied by type of infection. CONCLUSIONS: Exposure to CMV, HSV-2, or TOX is associated with cognitive deterioration in older individuals, independent of general age-related variables. An increased understanding of the role of infectious agents in cognitive decline may lead to new methods for its prevention and treatment. PMID: 26710257