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Dean Pomerleau

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About Dean Pomerleau

  • Birthday 11/12/1964

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  1. Dean Pomerleau

    Finnish study posted by Al Pater

    I stand corrected. You did find one. I'm pretty sure it wouldn't be wise to target a higher cholesterol based on the preponderance of evidence, but who knows. --Dean
  2. Dean Pomerleau

    Finnish study posted by Al Pater

    High cholesterol is positively correlated with longevity late in life. I think you'll have trouble finding a study where mid-life high cholesterol is associated with longer lifespan, as the subjects in this study were. But I'll admit I'm not absolutely sure of this. --Dean
  3. Thanks Karl. I agree that it's disappointing the authors haven't tried the same cocktail in mice to see if it has similar beneficial effects on the thymus and/or epigenetic age, and most importantly, to see if there are any negative side effects of long-term GH treatment that impact longevity. Here is the relevant figure on the Horvath epigenetic age (EA) measures from the Fahy paper: Treatment was conducted in months 0-12, with the 18 month data collected six months after discontinuing treatment on a subset of participants.One thing I noticed from reading the methods section of the full text was that the researchers adjusted the dosage of the elements in the cocktail per individual subject every two months during the study based on blood samples to "maximize IGF‐1 and minimize insulin." Personally I wouldn't be inclined to try to maximizing IGF-1 based on data from rodents and people. --Dean
  4. Dean Pomerleau

    Cronometer results for the FMD

    I take same 100mcg selenium tablets from NOW but only once every 4 days to supplement ~40% of the RDA per day, relying on small amounts from other foods to fill in the rest. --Dean
  5. Dean Pomerleau

    A CR Garden

    Pawpaw Update I'm happy to report my pawpaws have ripened well and they are delicious! Here is a photo of 18 pawpaws, which is about half of my harvest from the single tree that fruited this year (pictured in the top post on this page): You can see the two rows of black seeds running down the middle of the flesh. I'm saving all the seeds. I plan to sprout them over the winter do some "guerrilla planting" in the spring in the woods and open fields near my house. Below is a picture of me holding one for a sense of scale. They are each about 250g (~1/2 pound): At the bottom of the fruit near my palm you can see the divot in the flesh where the fruit was attached to the tree. I'm letting them ripen completely on the tree until they fall off under their own weight. A few of the fruit (5) are still on the tree, as you can see in the photo below. I'm using black crates suspended in the branches under the fruit clusters to catch the fruit when they fall to avoid bruising and prevent animals from taking them! I've eaten a few of the fruit that have already ripened, frozen the pulp from a few and shared a bunch with friends and family. It is about 5-to-1 people who like them vs. people who don't. In fact, my wife was about the only person who really didn't care for them due to both their taste and texture. But she doesn't like either bananas or mangos. She clearly has bad taste :-). They have the smooth custardy texture of durian, for anyone lucky enough to have tried that exotic fruit. As for taste, I'd describe it as a blend of banana and mango or better yet, banana and jackfruit. I really enjoy it. I plan to make vegan pawpaw "ice cream" soon using a combination of frozen pawpaw pulp and frozen bananas. I can't wait! --Dean
  6. Dean Pomerleau

    Cronometer results for the FMD

    I would very seriously consider reducing or better yet, eliminating the Brazil nuts, per this post by Michael. I former ate 1/2 of a Brazil nut per day (~2.5g) and considered that too high a risk of overdoing it due to the very wide range of selenium content in Brazil nuts. From this recent review [1] : Brazil nut consumption could pose some risk if the daily Se intake from this source is much higher than the recommended amount. According to research, intake of *330mg of Se per day could be toxic not only for growth hormones and insulin-like growth factor 1 metabolism but also in the synthesis of thyroid hormones.18,19 Possible major side-effects include nail and hair loss, anorexia, diarrhea, depression, hemorrhage, liver and kidney necrosis, blindness, ataxia, and respiratory disturbances.18 There have also been instances of dermatitis and central nervous system disorders in an area with high Se content in Enshi, China.24 These signs and symptoms of Se toxicity are known as selenosis. An Se intake of 50–400mg/d is considered a safe range for adults, while 850–900mg could be allowed as minimum for Se toxicity.10 Evidently, the high Se content variation in Brazil nuts that depends on the soil of the nut tree origins increases the likelihood of Se toxicity, regardless of the quantity of nuts consumed. --Dean ------------ [1] J Altern Complement Med. 2018 Jan;24(1):3-6. doi: 10.1089/acm.2017.0159. Epub 2017 Aug 14. Commentary: Health Concerns of Brazil Nut Consumption. Mazokopakis EE(1), Liontiris MI(1). Author information: (1)Department of Internal Medicine, Naval Hospital of Crete , Chania, Greece . Brazil nuts are the fruit of the enormous tropical tree Bertholletia excelsa that are produced in and exported from the territory of the Amazon. As a natural rich source of selenium (Se), the consumption of Brazil nuts is often suggested as therapeutic among patients with autoimmune thyroid diseases. In this review, the current knowledge regarding the main health concerns of Brazil nut consumption, such as Se toxicity, Se-induced type 2 diabetes mellitus, weight gain, radioactivity, aflatoxins, and allergic reactions, is presented and discussed. DOI: 10.1089/acm.2017.0159 PMID: 28805450 [Indexed for MEDLINE]
  7. Thanks Al! Interestingly, [1] found that only muscle fiber growth (hypertrophy) was negatively affected by cold exposure. In contrast, both total muscle mass and strength increased similarly in both cold-exposed and control groups after 7 weeks of resistance training (three times per week in the control and cold-exposure groups. The one whole body measurement that differed between the groups was in % body fat, which decreased more in the cold-exposed group than the controls (1.7% vs. 1.1%) after 7 weeks of exercise. The authors speculate this difference may have been a result of extra thermogenesis in the cold-exposed group. So if you hope to develop big muscle fibers, cold exposure may not be your best bet. Although even there, the authors acknowledge the weakness of their study - namely that thrice weekly training in previously untrained individuals may not be intense enough to elucidate the benefits of post-workout cold exposure: It is possible that if the resistance training protocol were altered to exacerbate residual neuromuscular fatigue and potentially inflammation (e.g., by increasing the frequency and/or volume of training), CWI might have been beneficial for hastening recovery and maintaining training intensity, and therefore may have differentially influenced long-term adaptation. Higher frequencies and/or volumes of resistance training are more likely to be completed by more highly-trained individuals, further suggesting the applicability of the present findings to these populations may be limited. --Dean -------- [1] Cold water immersion attenuates anabolic signalling and skeletal muscle fiber hypertrophy, but not strength gain, following whole-body resistance training.Fyfe JJ, Broatch JR, Trewin AJ, Hanson ED, Argus CK, Garnham AP, Halson SL, Polman RC, Bishop DJ, Petersen AC.J Appl Physiol (1985). 2019 Sep 12. doi: 10.1152/japplphysiol.00127.2019. [Epub ahead of print]PMID: 31513450
  8. Sthira, If the authors and the press had stuck to presenting their research the way you suggest (i.e. as a small, preliminary study showing promise towards regenerating the thymus), that would have been great. But the headlines covering the research gush about "the fountain of youth" and "reversing aging". For example: Is This New 3-Drug Combo A Fountain Of Youth? (Forbes) First hint that body’s ‘biological age’ can be reversed (Nature) DRUG TRIAL REVERSES BIOLOGICAL AGING AS SUBJECTS REGAIN 2 YEARS OF YOUTH ON AVERAGE (Newsweek) And it wasn't just a case of the popular press exaggerating the significance of the study. One of the authors (Horvath) added to the hype by saying: "I'd expected to see slowing down of the clock, but not a reversal," Horvath told Nature. "That felt kind of futuristic." It appears you may have missed the first three lines of my previous post where I said: "I don't think anyone is suggesting they should have given up, or give up now. At least I'm not. Small, exploratory studies and even self-experimentation (e.g. Liz Parrish or our own "small N" foray into human CR) have their place." I'm all for more research (big and small). I just think everyone would be better off with less breathless hype. --Dean
  9. Saul, While banned by bodybuilding and sports organizations, attempting to boost IGF-1 via supplements is not that unusual among bodybuilders and professional athletes: https://nyti.ms/Wwy4mf --Dean
  10. Sthira, I don't think anyone is suggesting they should have given up, or give up now. At least I'm not. Small, exploratory studies and even self-experimentation (e.g. Liz Parrish or our own "small N" foray into human CR) have their place. But the kind of hype this small study has generated (whether intentionally by the researchers or not) is undeserved and potentially harmful in several ways. Better trials than this one have shown GH replacement in older people isn't very helpful and appears to have "worrisome side effects" [1][2]. Mutant mice with naturally low GH levels live longer [3] and GH replacement in these long-lived mice shorten their lifespan [4]. Even metformin is not without potential risks and downsides. As Tom pointed out, metformin treatment appears to counteract some of the beneficial effects of exercise. To quote from that study [5]: These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise. It is possible that the cocktail of GH and Metformin (+ DHEA + Vitamin D? + Zinc?) will turn out to be a magic elixer, and will counteract each other's downsides. If well-informed people want to throw the dice and try the combination, they are welcome to. But I wouldn't want to bet my life or my health on it. It would be nice to see this cocktail extend lifespan in rodents before considering it. My fear is that some people will see the media hype and start such a regime without full understanding of the potential risks and downsides, and end up harming themselves in the same way ill-informed Tesla owners over-rely on Autopilot due to the hype and end up repeatedly decapitating themselves. You seem to suggest (via your Aubrey quote) that "public enthusiasm" is good and necessary to make progress. But unwarranted hype like this also has the real potential to result in disappointment and backlash when the early promise doesn't bear up under further scrutiny. Worse it has the potential to distract attention from (and funding for) more promising approaches to slow aging and age-related disease like those being pursued by SENS researchers. For example, efforts to clear the bloodstream of 7-ketocholesterol which is a large factor in our number one killer, CVD. --Dean --------------------- [1] Best Pract Res Clin Endocrinol Metab. 2017 Feb;31(1):113-125. doi: 10.1016/j.beem.2017.02.005. Epub 2017 Feb 24. GH and ageing: Pitfalls and new insights. Bartke A(1), Darcy J(2). Author information: (1)Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA. Electronic address: abartke@siumed.edu. (2)Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA; Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois School of Medicine, Springfield, IL, USA. The interrelationships of growth hormone (GH) actions and aging are complex and incompletely understood. The very pronounced age-related decline in GH secretion together with benefits of GH therapy in individuals with congenital or adult GH deficiency (GHD) prompted interest in GH as an anti-aging agent. However, the benefits of treatment of normal elderly subjects with GH appear to be marginal and counterbalanced by worrisome side effects. In laboratory mice, genetic GH deficiency or resistance leads to a remarkable extension of longevity accompanied by signs of delayed and/or slower aging. Mechanisms believed to contribute to extended longevity of GH-related mutants [with LOW GH - DP] include improved anti-oxidant defenses, enhanced insulin sensitivity and reduced insulin levels, reduced inflammation and cell senescence, major shifts in mitochondrial function and energy metabolism, and greater stress resistance. Negative association of the somatotropic signaling and GH/insulin-like growth factor 1 (IGF-1)-dependent traits with longevity has also been shown in other mammalian species. In humans, syndromes of GH resistance or deficiency have no consistent effect on longevity, but can provide striking protection from cancer, diabetes and atherosclerosis. More subtle alterations in various steps of GH and IGF-1 signaling are associated with reduced old-age mortality, particularly in women and with improved chances of attaining extremes of lifespan. Epidemiological studies raise a possibility that the relationship of IGF-1 and perhaps also GH levels with human healthy aging and longevity may be biphasic. However, the impact of somatotropic signaling on neoplastic disease is difficult to separate from its impact on aging, and IGF-1 levels exhibit opposite associations with different chronic, age-related diseases. Copyright © 2017 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.beem.2017.02.005 PMCID: PMC5424628 PMID: 28477727 [Indexed for MEDLINE] --------------------- [2] Ann Intern Med. 2007 Jan 16;146(2):104-15. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Liu H(1), Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, Hoffman AR. Author information: (1)Stanford University, Stanford, California 94305-6019, USA. hauliu@stanford.edu Comment in Nat Clin Pract Endocrinol Metab. 2007 Jul;3(7):508-9. BACKGROUND: Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States. PURPOSE: To evaluate the safety and efficacy of GH therapy in the healthy elderly. DATA SOURCES: The authors searched MEDLINE and EMBASE databases for English-language studies published through 21 November 2005 by using such terms as growth hormone and aging. STUDY SELECTION: The authors included randomized, controlled trials that compared GH therapy with no GH therapy or GH and lifestyle interventions (exercise with or without diet) with lifestyle interventions alone. Included trials provided GH for 2 weeks or more to community-dwelling participants with a mean age of 50 years or more and a body mass index of 35 kg/m2 or less. The authors excluded studies that evaluated GH as treatment for a specific illness. DATA EXTRACTION: Two authors independently reviewed articles and abstracted data. DATA SYNTHESIS: 31 articles describing 18 unique study populations met the inclusion criteria. A total of 220 participants who received GH (107 person-years) completed their respective studies. Study participants were elderly (mean age, 69 years [SD, 6]) and overweight (mean body mass index, 28 kg/m2 [SD, 2]). Initial daily GH dose (mean, 14 microg per kg of body weight [SD, 7]) and treatment duration (mean, 27 weeks [SD, 16]) varied. In participants treated with GH compared with those not treated with GH, overall fat mass decreased (change in fat mass, -2.1 kg [95% CI, -2.8 to -1.35] and overall lean body mass increased (change in lean body mass, 2.1 kg [CI, 1.3 to 2.9]) (P < 0.001), and their weight did not change significantly (change in weight, 0.1 kg [CI, -0.7 to 0.8]; P = 0.87). Total cholesterol levels decreased (change in cholesterol, -0.29 mmol/L [-11.21 mg/dL]; P = 0.006), although not significantly after adjustment for body composition changes. Other outcomes, including bone density and other serum lipid levels, did not change. Persons treated with GH were significantly more likely to experience soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia and were somewhat more likely to experience the onset of diabetes mellitus and impaired fasting glucose. LIMITATIONS: Some important outcomes were infrequently or heterogeneously measured and could not be synthesized. Most included studies had small sample sizes. CONCLUSIONS: The literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events. On the basis of this evidence, GH cannot be recommended as an antiaging therapy. DOI: 10.7326/0003-4819-146-2-200701160-00005 PMID: 17227934 [Indexed for MEDLINE] --------------------- [3] 1. Curr Top Dev Biol. 2004;63:189-225. Life extension in the dwarf mouse. Bartke A(1), Brown-Borg H. Author information: (1)Geriatrics Research, Department of Medicine, Southern Illinois University School of Medicine, Springfield, Illinois 62794, USA. Ames dwarf mice and Snell dwarf mice lack growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH), live much longer than their normal siblings, and exhibit many symptoms of delayed aging. "Laron dwarf mice," produced by targeted disruption of the GH receptor/GH-binding protein gene (GHR-KO mice), are GH resistant and also live much longer than normal animals from the same line. Isolated GH deficiency in "little" mice is similarly associated with increased life span, provided that obesity is prevented by reducing fat content in the diet. Long-lived dwarf mice share many phenotypic characteristics with genetically normal (wild-type) animals subjected to prolonged caloric restriction (CR) but are not CR mimetics. We propose that mechanisms linking GH deficiency and GH resistance with delayed aging include reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1), reduced secretion of insulin, increased hepatic sensitivity to insulin actions, reduced plasma glucose, reduced generation of reactive oxygen species, improved antioxidant defenses, increased resistance to oxidative stress, and reduced oxidative damage. The possible role of hypothyroidism, reduced body temperature, reduced adult body size, delayed puberty, and reduced fecundity in producing the long-lived phenotype of dwarf mice remains to be evaluated. An important role of IGF-1 and insulin in the control of mammalian longevity is consistent with the well-documented actions of homologous signaling pathways in invertebrates. DOI: 10.1016/S0070-2153(04)63006-7 PMID: 15536017 [Indexed for MEDLINE] ---------------------- [4] FASEB J. 2010 Dec;24(12):5073-9. doi: 10.1096/fj.10-163253. Epub 2010 Aug 18. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. Panici JA(1), Harper JM, Miller RA, Bartke A, Spong A, Masternak MM. Author information: (1)Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, Springfield, Illinois, USA. Hypopituitary Ames dwarf mice were injected either with growth hormone (GH) or thyroxine for a 6-wk period to see whether this intervention would reverse their long life span or the resistance of their cells to lethal stresses. Ames dwarf mice survived 987 ± 24 d (median), longer than nonmutant control mice (664 ± 48), but GH-injected dwarf mice did not differ from controls (707 ± 9). Fibroblast cells from Ames dwarf mice were more resistant to cadmium than cells from nonmutant controls (LD(50) values of 9.98 ± 1.7 and 3.9 ± 0.8, respectively), but GH injections into Ames dwarf mice restored the normal level of cadmium resistance (LD(50)=5.8 ± 0.9). Similar restoration of normal resistance was observed for fibroblasts exposed to paraquat, methyl methanesulfonate, and rotenone (P<0.05 in each case for contrast of GH-treated vs. untreated dwarf mice; P<0.05 for dwarf vs. nonmutant control mice.) T4 injections into Ames dwarf mice, in contrast, did not restore normal life span. We conclude that the remarkable life-span extension of Ames dwarf mice, and the stress resistance of cells from these mice, depends on low levels of GH exposure in juvenile and very young adult mice. DOI: 10.1096/fj.10-163253 PMCID: PMC2992365 PMID: 20720157 [Indexed for MEDLINE] ---------------------- [5] Aging Cell. 2019 Feb;18(1):e12880. doi: 10.1111/acel.12880. Epub 2018 Dec 11. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Konopka AR(1)(2), Laurin JL(2), Schoenberg HM(2), Reid JJ(2), Castor WM(2), Wolff CA(2), Musci RV(2), Safairad OD(1), Linden MA(2), Biela LM(2), Bailey SM(3), Hamilton KL(2), Miller BF(2)(4). Author information: (1)Department of Kinesiology and Community Health, University of Illinois Urbana-Champaign, Urbana, Illinois. (2)Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado. (3)Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, Colorado. (4)Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. DOI: 10.1111/acel.12880 PMCID: PMC6351883 PMID: 30548390
  11. Financially motivated researchers. Relatively short-term, heterogeneous, multi-pronged intervention. Small test population. No control group. Post hoc analysis based on dubious surrogate endpoint. Yeah - real high quality... --Dean
  12. Dean Pomerleau

    Testosterone, Luteinizing Hormone and Mortality

    Saul, Below is the data on total T and SHBG in absolute terms and as a function of BMI from the WUSTL human CR study [1] in which both you and I participated. --Dean ------------- [1] Aging Cell. 2010 Apr;9(2):236-42. doi: 10.1111/j.1474-9726.2010.00553.x. Epub 2010 Jan 20. Long-term effects of calorie restriction on serum sex-hormone concentrations in men. Cangemi R(1), Friedmann AJ, Holloszy JO, Fontana L. Author information: (1)Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA. Calorie restriction (CR) slows aging and consistently reduces circulating sex hormones in laboratory animals. However, nothing is known regarding the long-term effects of CR with adequate nutrition on serum sex-hormone concentration in lean healthy humans. In this study, we measured body composition, and serum total testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5 +/- 13 years), who had been practicing CR with adequate nutrition for an average of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and 24 age-matched sedentary controls eating Western diets (WD). We found that both the CR and EX volunteers had significantly lower body fat than the WD volunteers (total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P = 0.0001). Serum total testosterone and the free androgen index were significantly lower, and SHBG was higher in the CR group than in the EX and WD groups (P < or = 0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both significantly lower in the CR and EX groups than in the WD group (P < or = 0.005). Serum DHEA-S concentrations were not different between the three groups. These findings demonstrate that, as in long-lived CR rodents, long-term severe CR reduces serum total and free testosterone and increases SHBG concentrations in humans, independently of adiposity. More studies are needed to understand the role of this CR-mediated reduction in sex hormones in modulating the pathogenesis of age-associated chronic diseases such as cancer and the aging process itself. DOI: 10.1111/j.1474-9726.2010.00553.x PMCID: PMC3569090 PMID: 20096034 [Indexed for MEDLINE]
  13. Dean Pomerleau

    Exercise and Mouthwash

    This new study [1] along with the popular press article about it seem crazy at first, but it actually makes sense. In a double blind, placebo-controlled, crossover trial, the researchers found that blood pressure was decreased and tissue oxygenation was increased for several hours after exercise on a treadmill. This is not surprising. But when subjects gargled with an antibacterial mouthwash 30min after exercise, these beneficial post-exercise changes to blood pressure and tissue oxygenation were eliminated. It is well known that bacterial in the mouth convert nitrate to nitrite which in turn gets converted into the vasodilator nitrous-oxide. This process seems to happen acutely after exercise with beneficial results. The authors conclude: These findings show that nitrite synthesis by oral commensal bacteria is a key mechanism to induce the vascular response to exercise over the first period of recovery thereby promoting lower blood pressure and greater muscle oxygenation. This confirms Dr. Greger's advice from this video to avoid antibacterial mouthwash and toothpaste because they can interfere with the elaborate way the body converts dietary nitrates (e.g. from beets) into cardioprotective nitrous oxide. --Dean ---------- [1] Free Radic Biol Med. 2019 Jul 29;143:252-259. doi: 10.1016/j.freeradbiomed.2019.07.035. [Epub ahead of print] Post-exercise hypotension and skeletal muscle oxygenation is regulated by nitrate-reducing activity of oral bacteria. Cutler C(1), Kiernan M(2), Willis JR(3), Gallardo-Alfaro L(4), Casas-Agustench P(1), White D(1), Hickson M(1), Gabaldon T(5), Bescos R(6). Post-exercise hypotension (PEH) is a common physiological phenomenon leading to lower blood pressure after acute exercise, but it is not fully understood how this intriguing response occurs. This study investigated whether the nitrate-reducing activity of oral bacteria is a key mechanism to trigger PEH. Following a randomized, double blind and crossover design, twenty-three healthy individuals (15 males/8 females) completed two treadmill trials at moderate intensity. After exercise, participants rinsed their mouth with antibacterial mouthwash to inhibit the activity of oral bacteria or a placebo mouthwash. Blood pressure was measured before, 1h and 2 h after exercise. The microvascular response to a reactive hyperaemia test, as well as blood and salivary samples were taken before and 2 h after exercise to analyse nitrate and nitrite concentrations and the oral microbiome. As expected, systolic blood pressure (SBP) was lower (1 h: -5.2 ± 1.0 mmHg; P < 0.001); 2 h: -3.8 ± 1.1 mmHg, P = 0.005) after exercise compared to baseline in the placebo condition. This was accompanied by an increase of circulatory nitrite 2 h after exercise (2h: 100 ± 13 nM) compared to baseline (59 ± 9 nM; P = 0.013). Additionally, an increase in the peak of the tissue oxygenation index (TOI) during the reactive hyperaemia response was observed after exercise (86.1 ± 0.6%) compared to baseline levels (84.8 ± 0.5%; P = 0.010) in the placebo condition. On the other hand, the SBP-lowering effect of exercise was attenuated by 61% at 1 h in the recovery period, and it was fully attenuated 2 h after exercise with antibacterial mouthwash. This was associated with a lack of changes in circulatory nitrite (P > 0.05), and impaired microvascular response (peak TOI baseline: 85.1 ± 3.1%; peak TOI post-exercise: 84.6 ± 3.2%; P > 0.05). Diversity of oral bacteria did not change after exercise in any treatment. These findings show that nitrite synthesis by oral commensal bacteria is a key mechanism to induce the vascular response to exercise over the first period of recovery thereby promoting lower blood pressure and greater muscle oxygenation. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.freeradbiomed.2019.07.035 PMID: 31369841
  14. Cold Exposure Boosts Anti-inflammatory Treg Cells and may Inhibit mTOR Chronic inflammation is increasingly recognized as a significant contributor to metabolic dysfuction, diseases such as diabetes and CVD, as well as the aging process itself - hence the recently coined term inflammaging. This new paper [1] found that in both mice and humans, cold exposure (2h spent just above individually-determined shivering threshold) triggers an increase in the number of Treg cells circulating in the bloodstream. Treg cells are immune system T-cells that play a beneficial regulatory role by suppressing the chronic inflammatory state thought to contribute to aging and disease. Interestingly, people with higher circulating leptin levels (the "I'm stuffed" signaling hormone) showed less of a boost in Treg Cells following cold exposure. This is in line with the evolutionary hypothesis that CE + CR (and hence low leptin) work synergistically to improve health and longevity. I also found this sentence from the discussion section interesting: The increased BORCS6 mRNA abundance in human CD4+ T cells exposed to short-term cold is in line with a concept in which physiological levels of beta3-adrenergic stimulation can exert mTORC1-inhibiting activity, thereby directly supporting the induction of human FOXP3+ Tregs. Both CR and potential longevity boosters like rapamycin are known to work at least in part by suppressing mTOR activity, particularly the mTORC1 complex. This was the first I'd heard that adrenergic stimulation (via e.g. cold exposure) can also tamp down mTORC1 activity. --Dean ----------- [1] Mol Metab. 2019 Aug 5. pii: S2212-8778(19)30554-X. doi: 10.1016/j.molmet.2019.08.002. [Epub ahead of print] Short-term cold exposure supports human Treg induction in vivo. Becker M(1), Serr I(1), Salb VK(1), Ott VB(2), Mengel L(3), Blüher M(4), Weigmann B(5), Hauner H(6), Tschöp MH(7), Daniel C(8). OBJECTIVE: Obesity and type-2 diabetes (T2D) are metabolic diseases that represent a critical health problem worldwide. Metabolic disease is differentially associated with fat distribution, while visceral white adipose tissue (VAT) is particularly prone to obesity-associated inflammation. Next to their canonical function of immune suppression, regulatory T cells (Tregs) are key in controlling adipose tissue homeostasis. Towards understanding the molecular underpinnings of metabolic disease, we focus on how environmental-metabolic stimuli impinge on the functional interplay between Tregs and adipose tissue. Here, cold exposure or beta3-adrenergic signaling are a promising tool to increase energy expenditure by activating brown adipose tissue, as well as by reducing local inflammation within fat depots by supporting immunosuppressive Tregs. However, in humans, the underlying mechanisms that enable the environmental-immune crosstalk in the periphery and in the respective tissue remain currently unknown. METHODS: We used combinatorial approaches of next generation humanized mouse models and in vitro and in vivo experiments together with beta3-adrenergic stimulation to dissect the underlying mechanisms of human Treg induction exposed to environmental stimuli such as cold. To test the translational relevance of our findings, we analyzed samples from the FREECE study in which human subjects were exposed to individualized cooling protocols. Samples were analyzed ex vivo and after in vitro Treg induction using qRT-PCR, immunofluorescence, as well as with multicolor flow cytometry and cell sorting. RESULTS: In vivo application of the beta3-adrenergic receptor agonist mirabegron in humanized mice induced thermogenesis and improved the Treg induction capacity of naïve T cells isolated from these animals. Using samples from the human FREECE study, we demonstrate that a short-term cold stimulus supports human Treg induction in vitro and in vivo. Mechanistically, we identify BORCS6 encoding the Ragulator-interacting protein C17orf59 to be significantly induced in human CD4+ T cells upon short-term cold exposure. Strong mTOR signaling is known to limit successful Treg induction and thus likely by interfering with mTOR activation at lysosomal surfaces, C17orf59 improves the Treg induction capacity of human naïve T cells upon cold exposure. CONCLUSIONS: These novel insights into the molecular underpinnings of human Treg induction suggest an important role of Tregs in linking environmental stimuli with adipose tissue function and metabolic diseases. Moreover, these discoveries shed new light on potential approaches towards tailored anti-inflammatory concepts that support human adipose tissue homeostasis by enabling Tregs. Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved. DOI: 10.1016/j.molmet.2019.08.002 PMID: 31427184
  15. You are right Ron. What I mean is eating sufficiently few net calories (food - (baseline metabolism + exercise expenditure)) to maintain a relatively low BMI and (hopefully) trigger the health/longevity-promoting CR response. --Dean
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