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  1. University College London are running a short (15 min) online study to investigate differences in thinking abilities when on CR. This study has been preliminarily vetted by CR Society VP for Research. We are aware that there is a lot of data to support the link between CR and benefits to health, but there is currently little known about the impact of CR on cognition, particularly executive function. We are comparing the results of those on a popular intermittent fasting (IF) plan (5:2) with those who have daily CR lifestyles to see if there is a difference. Our hypothesis is that those on daily CR will with have better results for certain tests relating to executive function, when compared to those on IF. We intend to publish the results next year and we believe this will be of enormous value both to the scientific community, and to anyone who is considering their options for ways in which to improve their health. Anyone who contacts us will be sent the participant information sheet and a consent form to return before they receive a link to 5 short online tasks. All data is protected and confidential ID numbers used to further protect our participants. This study has passed rigorous ethics procedures. If you have been restricting your calorie intake for more than 4 weeks, then please contact us if you would like to know more or sign up. A prize draw of numerous Amazon vouchers is available for all who take part. ucl.fasting.cognition@gmail.com or ucjuole@ucl.ac.uk Researchers: John O’Leary , Freya Donaldson Principal Researcher: Dr Lucy Serpell
  2. All, This new study [1] (science press coverage) appears like it might be a significant breakthrough in the treatment of Alzheimer's disease. Researchers appear to have discovered a small molecule that at least in rodents is safe, crosses the blood-brain barrier, and is effective at breaking up beta amyloid plaques, thought to play an important role in the neuronal death associated with Alzheimer's disease. From the article linked above: The Korean scientists, led by YoungSoo Kim of the Brain Science Institute at the Korea Institute of Science and Technology (KIST) in Seoul, investigated the ability of EPPS [4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid] to attach to amyloid-beta clumps and convert them into simpler, smaller molecules. Through a series of experiments, they found that EPPS could break apart plaque in a living mammal. They also found the molecule could be added to drinking water yet still travel in the blood to the brain and cross the blood-brain barrier, which otherwise prevents foreign material from entering the brain. EPPS could penetrate the barrier because it is a relatively small molecule, Kim said. The scientists found that doses between 30 and 100 milligrams per kilogram of body weight per day were effective in breaking up the amyloid beta. Further tests demonstrated that EPPS appears to have no toxic effects in mice up to 2,000 mg/kg per day. From the full text, not only did mice treated with EPPS show a reduction in beta amyloid plaques in their hippocampus and other brain areas in a dose dependent manner, they also showed less cognitive impairment relative to control mice using several measures of cognitive performance. The lead author is quite optimistic about this compound's potential: "I strongly believe these drug candidates [based on EPPS] will halt the neurodegeneration and rescue patients from death," Kim said. Here's hoping human trials prove that he's right! --Dean ------ [1] Nat Commun. 2015 Dec 8;6:8997. doi: 10.1038/ncomms9997. EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques. Kim HY(1,)(2,)(3), Kim HV(1,)(2), Jo S(4), Lee CJ(4), Choi SY(1), Kim DJ(1), Kim Y(1,)(2). Full text: http://www.nature.com.sci-hub.io/ncomms/2015/151208/ncomms9997/abs/ncomms9997.html Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD. PMCID: PMC4686862 PMID: 26646366
  3. 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
  4. All, The benefits of yoga has been discussed on various threads lately, so I figured it was time to consolidate the discussions into a single master thread, particularly since there is a new study I wanted to post (see below). First we saw in this thread that yoga beats both walking and a mediterranean diet for CVD risk reduction. Then we saw in this post by Cloud that 12 weeks of yoga reduces inflammatory markers in recovering cancer patients. Now, a new study [1] (popular press story) found that 12 weeks of yoga beat out the "gold standard" memory training technique in people with mild cognitive impairment. The yoga group had lower depression scores, and improved verbal and visuospatial memory compared with memory training. While the study was small, its effects were pretty impressive, and were accompanied by changes in brain region connectivity as measured by FMRI brain scans. With all this evidence of benefit, it seems like a good idea to start practicing yoga, and consider having the next CR Conference at a yoga center like Saul suggests - maybe Sthira and Saul can teach the rest of us! --Dean ---------- [1] J Alzheimers Dis. 2016 Apr 5;52(2):673-84. doi: 10.3233/JAD-150653. Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. Eyre HA(1,)(2), Acevedo B(1), Yang H(1), Siddarth P(1), Van Dyk K(1), Ercoli L(1), Leaver AM(3), Cyr NS(1), Narr K(3), Baune BT(2), Khalsa DS(4), Lavretsky H(1). Author information: (1)Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA. (2)Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia. (3)Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, UCLA, Los Angeles, CA, USA. (4)Alzheimer's Research and Prevention Foundation, Tucson, AZ, USA. BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies. PMID: 27060939
  5. 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
  6. All, It's pretty much unimaginable that anyone reading this would not by now have heard about the cardiovascular benefits of dark chocolate, both in terms of preventing cardiovascular disease and even improving cardiovascular (athletic) performance. And you've probably heard the news that chocolate is good for brain health & cognition as well. Nevertheless, this new study [1], posted by Al, is noteworthy for several reasons. In it, researchers followed 530 elderly people over four years to see how their dietary habits, particularly wrt chocolate consumption, correlated with cognitive decline. The first surprising thing was the magnitude of the benefits of chocolate on cognitive health. Even after controlling for a host of potentially confounding risk factors, they found that chocolate consumption was associated with a whopping 40% reduction in likelihood of cognitive decline over the four year period. That's the good news. The not-so-good news is that this benefit was only seen in participants who eschewed caffeine. In fact, if limited to folks who consumed less than 75mg of caffeine a day (~1 cup of coffee), the cognitive protection associated with chocolate was even greater - a 50% lower risk of cognitive decline. They don't report it explicitly in the abstract (full text not available), but presumably caffeine drinkers did not see a significant cognitive benefit (nor harm!) from also consuming chocolate. This suggests the cognitive benefits of chocolate overlap and are hence redundant with (and not additive with) the beneficial effects of coffee/tea polyphenols and/or the caffeine they contain. Nevertheless, I'm going to continue consuming both cacao and caffeine products, because this is only one study, and heck, I enjoy them both ☺. --Dean --------- [1] J Alzheimers Dis. 2016 May 6. [Epub ahead of print] Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline. Moreira A, Di?genes MJ, de Mendon?a A, Lunet N, Barros H. Abstract Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease =/> 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans. KEYWORDS: Adenosine A2A receptors; Alzheimer?s disease; chocolate; cognition; prevention; theobromine PMID: 27163823
  7. Dean Pomerleau


    I was surprised to find that a search of these forums turned up very little discussion of nootropics, or so-called "smart drugs", at least as far as I could find. Obviously cognitive performance and long-term brain health is an important consideration for everyone, but especially obsessive optimizers like us ☺. So I figured I'd start a thread to inquire if anyone has experimented with nootropics, and if so, which ones (if any) did you find beneficial. To kick off the discussion, I've never experimented with any nootropics myself, except for caffeine, which honestly I don't find has much of an observable effect on me (cognitive or otherwise), but I take it anyway (as coffee/tea, and as a B12-fortified mint) for other health reasons. But today I came across a new multi-nootropic supplement from someone I trust, respect and believe to be quite intelligent - Lincoln Cannon. Lincoln is the co-founder of the Mormon Transhumanism Association, a pretty cool longevity-focused organization to which I and many other non-Mormons belong. Lincoln is also responsible for formulating the New God Argument, which I find pretty compelling (see here for related discussion and here for science/philosophy heavyweights on the topic). But I digress... Thrivous, his new company (to which I have no affiliation), has developed a nootropic supplement called Clarity. Here is the Clarity label: Has anyone any personal experience, or done any research on any of these ingredients? Here is Lincoln's research on them, plus a couple others not included in this version of Clarity. They look reasonably beneficial (and harmless) based on the controlled studies Lincoln has compiled. The price is pretty reasonable - $25 for a month's supply. I'm forever interested in self-experimentation and lifestyle optimization, so I was thinking of conducting a single-blind, crossover trial on myself to see if I notice any difference between taking Clarity vs. a placebo. But if others have had bad experiences with these nootropics, or know of research that says they may be harmful, I'll obviously steer clear. Thanks! --Dean
  8. We've known for quite some time that exercise (and CR!) can help stave off the cognitive decline that is often associated with aging. Scientists are now beginning to understand the mechanism underlying this effect. Here is a popular press description: http://www.kurzweilai.net/long-term-aerobic-exercise-prevents-age-related-brain-deterioration of a new paper [1] that helps elucidate the physiological mechanism of brain health preservation via exercise. The authors experimented with mice. They found that with age the support cells in the brain (microglia, astrocytes, etc.) are lost or become dysfunctional, reducing blood flow to neurons, increasing inflammation, etc. This age-related decline and damage was prevented in the mice that exercised (~2 miles per day on a running wheel). But exercise didn't have any positive effect in mice that were completely APOE-deficient. It is interesting that the APOE gene is involved in the beneficial cognitive benefits of exercise, since variants in this gene (i.e. APOE4) are well known to be associated with increased risk of Alzheimer's disease. Exactly what this means for people with APOE gene variants like APOE4 isn't clear, at least to me. Would exercise be somewhat of a waste of time for these people, unable to preserve cognitive health, like in the APOE-deficient mice? Or would exercise be more important for APOE4 carriers, to get the most from their relatively-impaired APOE activity on the brain? --Dean ----------- [1] PLOS Biology, October 29, 2015; DOI: 10.1371/journal.pbio.1002279 (open access) APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. Ileana Soto, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell. Abstract Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease. Author Summary Aging is frequently accompanied with frailty and cognitive decline. In recent years, increasing evidence has linked physical inactivity with the development of dementias such as Alzheimer’s disease. In fact, it is recognized that exercise combats frailty and cognitive decline in older adults, but the biological mechanisms involved are not completely known. Understanding the biological changes that trigger cognitive deterioration during aging and the mechanisms by which exercise improves health and brain function is key to ensuring the quality of life of the elderly population and to reducing risk of dementias such as Alzheimer’s disease. Here, we show that the cerebrovascular system in mice significantly deteriorates with age, and the structure and function of the blood brain barrier is progressively compromised. These age-related neurovascular changes are accompanied by neuroinflammation and deficits in common and spontaneous behaviors in mice. We found, however, that exercise from middle to older age preserves the cerebrovascular health, prevents behavioral deficits and reduces the age-related neuroinflammation in the cortex and hippocampus in aged mice. Mice deficient in Apoe, a gene associated with longevity and Alzheimer’s disease, are resistant to the beneficial effects of exercise, suggesting a possible mediating role for APOE in the maintenance and function of the neurovascular system during aging.