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Dean Pomerleau

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About Dean Pomerleau

  • Birthday 11/12/1964

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  1. ALS (otherwise known as motor neuron disease or Lou Gehrig's disease) is a very scary condition of some nagging concern for CR folks, since CR pioneer Roy Walford died of complications of ALS at age 79. So this new study [1] (popular press article) linking intense exercise to increased risk of ALS caught my eye. First they looked at 125K people in the UK with ALS and 250K people without. They found that 'frequently' engaging in 'strenuous sports' (more than twice per week for 15-30min or more) was associated with an increased risk of ALS. From the full text: Movement alone [e.g. walking or other low-intensity physical activity - DP] was not significantly associated with ALS, which is consistent with our hypothesis that ALS is linked to strenuous exercise... Overall, our data are consistent with the hypothesis that risk of ALS is linked to frequent and intense leisure-time physical activity. Interestingly, being sedentary was not protective against ALS: We argued that if strenuous exercise is a risk factor for ALS, then sedentary behaviour may be protective. However, our MR study does not support this conclusion. Sedentary behaviour is not significantly related to ALS. They then looked at the exercise history of a few dozen people with ALS and found that among people with a particular genetic mutation (in gene C9ORF72) that predisposes someone to ALS, increased physical activity was associated with an earlier onset of ALS. Here is graph of ALS age of onset vs. history of high, medium or low amounts of physical activity (PA) in people with the genetic mutation: In other words, more physical activity correlated with earlier ALS onset in people with the mutation. From the discussion section: Exercise is not one homogeneous exposure; in reality different types of exercise can impact different biological pathways and even different subtypes of motor neurons. Early in the disease process ALS is known to selectively affect motor neurons supplying type IIb fast twitch muscle fibres important for high intensity anaerobic exercise [16,17]. Consistent with this, our MR study does not support a causal role for low-intensity, infrequent exercise, but does support toxicity resulting from high-intensity, frequent, leisure-time exercise. From the conclusion: The key objective for future research is to understand which individuals are at risk of developing ALS if they exercise excessively and provide appropriate lifestyle counselling. Our work goes some way towards developing this aim and in particular, we propose that C9ORF72 penetrance may be influenced by high levels of physical activity. Translating that last highlighted sentence, they are suggesting that people who have the C90RF72 mutation that predisposes them to ALS may go on to develop ALS and/or develop it earlier if they frequently engage in strenuous exercise. Since I exercise alot (albeit not very strenuously, mostly walking), I was quite interested to learn my C90RF72 status. Fortunately 23andMe has two SNPs for it - rs3849942 and rs2814707. For 23andMe customers, you can check your status for these two SNPs here and here. I was relieved to learn I'm CC for both SNPs (equivalent to GG in the SNP database), which means I have the 'normal' non-risky variant of the C90RF72 gene. --Dean ---------- [1] EBioMedicine, Volume 68, 2021, 103397, ISSN 2352-3964, https://doi.org/10.1016/j.ebiom.2021.103397. Free full text: https://www.sciencedirect.com/science/article/pii/S2352396421001900 Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes, Thomas H Julian, Nicholas Glascow, A Dylan Fisher Barry, Tobias Moll, Calum Harvey, Yann C Klimentidis, Michelle Newell, Sai Zhang, Michael P Snyder, Johnathan Cooper-Knock, Pamela J Shaw, Abstract: Background Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial. Methods First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients. Findings We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS. Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients. Interpretation Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS. Funding We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442). Keywords: Amyotrophic lateral sclerosis; Mendelian randomisation; Physical exercise; C9ORF72
  2. Dean Pomerleau

    Sci Fi Movie and Book Recommendations

    I just finished reading There is no Antimemetics Division. Simply mindbending. Has anyone else read it? It really gets you thinking about the possibility of unthinkable ideas - i.e. ones that can't be thought, or more interestingly, actively prevent themselves from being thought. The Amazon ebook is only $2.99. But you can also get a taste of it before you buy or even read the entire story for free on-line at the antimemetics subsection of the SCP (Special Containment Procedures) website. But I warn you the SCP genre is very addictive. I've now slowly begun working my way down their list of top rates stories. The genre has a very X-Files vibe to it. Or more recently, the TV series Debris, which my wife and I really enjoyed but which unfortunately was just canceled after one season. --Dean
  3. Here are the results from the YouGov poll Sibiriak linked to: What baffles me is why only 33% of people answer "not sure". It seems to me that people are far too convinced of the veracity of their own beliefs and the narratives they've been told. Epistemic humility appears to be in very short supply these days. --Dean
  4. Dean Pomerleau

    Random Lectures and talks you liked

    It's crazy that those interviews are just surfacing. I vaguely remember sitting down with him during the CR Conference in Arizona in 2016. --Dean
  5. Dean Pomerleau

    LDL: What's Optimal For Health And Longevity?

    We've always wondered why my wife's cholesterol is on the high side despite her pretty good diet and exercise routines. Unfortunately she is a carrier of one copy of the e4 allele of the apo gene (I. E. Apoe4), which has been shown to elevate LDL and total cholesterol in numerous studies, as can be seen in this graph from [1]. As you can see, the e2 allele reduced total cholesterol by 15-20 mg/dL and the e4 allele raises it by around 5-10 mg/dl. According to the authors, no other common genetic variation impacts cholesterol as much (genes that cause familial hypercholesterolimia are rare in the general population). --Dean --- [1] Davignon J. Apolipoprotein E polymorphism and atherosclerosis. In: Born GVR, Schwartz CJ, eds. New Horizons in Coronary Heart Disease. London, England: Current Science; 1993:5.1-5.21.
  6. Dean Pomerleau

    LDL: What's Optimal For Health And Longevity?

    For anyone following along at home and perhaps thinking about trying amla for high cholesterol, I've switched my wife to this amla supplement: https://www.amazon.com/dp/B07XZB9DJ2/ Since it utilizes the same TRI-low formulation of amla extract from the same company whose supplement was used in the study I referenced above. --Dean
  7. Dean Pomerleau

    LDL: What's Optimal For Health And Longevity?

    Good catch Mike!. No they aren't equivalent. I looked at the paper's supplemental material and it said: The crude extract was purified and standardized to contain about 35% polyphenols, 8% triterpenoids and 10% amla oil. The HealthyHey product you linked to doesn't appear to be available in the US. But I found this extract, which has 45% tannins (the major class of polyphenols in amla), so it looks to be about equivalent to the concentration used in the above study. It claims a 15:1 extraction ratio, and that each 1000mg daily serving is equivalent to about 8000mg of amla powder. I odred it and will report back in a couple months if it worked to lower my wife's cholesterol. --Dean
  8. Dean Pomerleau

    LDL: What's Optimal For Health And Longevity?

    My wife has modestly high cholesterol (TC 213 mg/dl, LDL 126 mg/dL, HDL 71mg/dL) despite having a pretty reasonable diet (pesco-vegetarian, lots of fruits and veggies). IMO, it's not quite high enough to warrant statins. Dr. Greger recently talked about Amla for cholesterol lowering, based on several studies, including this double blind, placebo controlled study [1] of 98 people with high cholesterol. It found 1000mg of dried amla power per day for 12 weeks resulted in a drop in total cholesterol from 231 to 177 mg/dL and a drop in LDL from 140 to 111 mg/dL. I actually already add amla powder to my spice mix for its antioxidant content already so I consider it safe and generally healthy. Has anyone here considered or tried amla specifically for cholesterol reduction? I think we're going to try it for my wife and see if it drops her cholesterol after a few months. --Dean ------------ [1] BMC Complement Altern Med. 2019 Jan 22;19(1):27. doi: 10.1186/s12906-019-2430-y. A randomized, double blind, placebo controlled, multicenter clinical trial to assess the efficacy and safety of Emblica officinalis extract in patients with dyslipidemia. Upadya H(1), Prabhu S(2), Prasad A(3), Subramanian D(4), Gupta S(5), Goel A(6). BACKGROUND: Dyslipidemia is one of the most frequently implicated risk factors for development of atherosclerosis. This study evaluated the efficacy of amla (Emblica officinalis) extract (composed of polyphenols, triterpenoids, oils etc. as found in the fresh wild amla fruit) in patients with dyslipidemia. METHODS: A total of 98 dyslipidemic patients were enrolled and divided into amla and placebo groups. Amla extract (500 mg) or a matching placebo capsule was administered twice daily for 12 weeks to the respective group of patients. The patients were followed up for 12 weeks and efficacy of study medication was assessed by analyzing lipid profile. Other parameters evaluated were apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1), Coenzyme Q10 (CoQ10), high-sensitive C-reactive protein (hsCRP), fasting blood sugar (FBS), homocysteine and thyroid stimulating hormone (TSH). RESULTS: In 12 weeks, the major lipids such as total cholesterol (TC) (p = 0.0003), triglyceride (TG) (p = 0.0003), low density lipoprotein cholesterol (LDL-C) (p = 0.0064) and very low density lipoprotein cholesterol (VLDL-C) (p = 0.0001) were significantly lower in amla group as compared to placebo group. Additionally, a 39% reduction in atherogenic index of the plasma (AIP) (p = 0.0177) was also noted in amla group. The ratio of Apo B to Apo A1 was reduced more (p = 0.0866) in the amla group as compared to the placebo. There was no significant change in CoQ10 level of amla (p = 0.2942) or placebo groups (p = 0.6744). Although there was a general trend of FBS reduction, the numbers of participants who may be classified as pre-diabetes and diabetes groups (FBS > 100 mg/dl) in the amla group were only 8. These results show that the amla extract used in the study is potentially a hypoglycaemic as well. However, this needs reconfirmation in a larger study. CONCLUSIONS: The Amla extract has shown significant potential in reducing TC and TG levels as well as lipid ratios, AIP and apoB/apo A-I in dyslipidemic persons and thus has scope to treat general as well as diabetic dyslipidemia. A single agent to reduce cholesterol as well as TG is rare. Cholesterol reduction is achieved without concomitant reduction of Co Q10, in contrast to what is observed with statins. TRIAL REGISTRATION: Registered with Clinical Trials Registry- India at www.ctri.nic.in (Registration number: CTRI/2015/04/005682 ) on 8 April 2015 (retrospectively registered). DOI: 10.1186/s12906-019-2430-y PMCID: PMC6341673 PMID: 30670010 [Indexed for MEDLINE]
  9. Dean Pomerleau

    Mailing List?

    No CR email list still exists, except as a mirror of the posts Al Pater makes to his two threads on these forums. --Dean
  10. I'm a skeptic about brain interface technology being useful for healthy people anytime soon. But this is pretty impressive - 90 characters per minute typing by imagining handwriting characters using a sensor array imbedded in the motor cortex of a quadrapalegic person. https://www.npr.org/sections/health-shots/2021/05/12/996141182/paralyzed-man-communicates-by-imagining-handwriting?ft=nprml&f=1001 --Dean
  11. Dean Pomerleau

    Organ Donation

    You are right the liver regenerates and the kidney doesn't. Risk of death and serious complications is a lot higher with liver in the first six months after donating, but longer term being down a kidney poses its own unique risks. These risks are mostly mitigated for people who donate via the National Kidney Registry though. The NKR promises all its donors that they will go to the top of the list to receive a living donor kidney should their remaining kidney ever stop functioning properly. There is no equivalent backstop for liver donors. Liver donors also loose their gallbladder in the transplant process, which you know has its own associated risks. Plus the liver doesn't completely regenerate - you can't donate your liver again once you've recovered from liver donation since the blood vessels supplying the donated portion of your liver don't grow back. Maybe, as long as you disclose her upcoming surgery. Again here is a place where kidney donation has an advantage, at least through the NKR. The NKR automatically offers all its donors $1M in life and disability insurance for one year to cover just such a risk, although as far as I know, nobody has every had to cash it in among the ~4000 NKR-facilitated donations. I like that attitude. Just don't let Tom hear you expressing it :-). Speaking of Tom, I wonder what has happened to him. He hasn't posted in ~5 months. I tried emailing him a couple weeks ago and haven't heard back. I hope he's ok. That would technically be a swap or a loop. Chains, swaps and loops aren't done often in livers (unlike kidneys where they are done all the time). But I've heard UPMC in Pittsburgh has recently started doing liver chains and loops. That might be a possibility for you since you live in Pennsylvania. Optimally your liver would be a match for someone whose incompatible donor matches your wife's cousin. You would then basically swap donors between the two incompatible pairs. Good luck, and let us know what you and your wife decide! --Dean
  12. Dean Pomerleau

    Organ Donation

    Gordo, It's a very personal decision, but solid organ donation is an awesome way to help someone in need. Great of your wife to be considering it. It is one of the only ways an average person can be almost guaranteed to save someone's life. One correction: While the mortality risk for liver donors is indeed estimated to be about 1 in 300, that is substantially more risky than kidney donation, which has an estimated mortality rate of less than 1 in 10,000. --Dean
  13. Dean Pomerleau

    Random Lectures and talks you liked

    The history of the universe is amazing. --Dean
  14. Yes, that is a fair summary of my hypothesis. I'm somewhat skeptical of the "and gaining muscle" portion of the above statement. Gaining muscle (like gaining fat) requires calories in excess of that required to remain weight-stable at a given activity level, which may be enough to undermine the CR effect. Or put another way, eating enough to stay buff may be enough to kick your body out of the "CR mode" even if you are weight stable. I'm doubtful, but I'm also not sure, since there really isn't a good way to turn rodents into bodybuilders (although some have tried) to test the hypothesis that it is possible to sustain significant extra muscle and still enjoy the health and longevity benefits of CR. I personally consider it a safter bet to burn off calories via cold exposure and exercise that doesn't result in significant increase in muscle mass, remaining thin (BMI ~19). Specifically, my exercise routine consists mostly of walking, running and resistance training with relatively low weight and high reps. Note that I am specifically not referring to lower body temperature of CR, but exposure to cold per se, and especially cold exposure (CE) in combination with (net) CR. For the full answer, there is conveniently an entire thread devoted to the topic of why CE is good for you and the evidence supporting it. Unfortunately it is over 500 pages long. As a quick intro, this post is a good place to get a summary of the many benefits of CE. These two posts discuss the potential evolutionary explanation and biochemical mechanism for synergy between CR and CE if case you are really interested in a deep dive. Happy reading! --Dean
  15. Dean Pomerleau

    Puzzling over approach and calorie paramaters

    Hi Starlitght, Welcome to the CR Forums! Gordo may have overstated things a bit, but he is generally on-point when it comes to what at least some of us old-timers think about hardcore CR these days. The thread he pointed to is a good one, but if you really want to get into the weeds about whether strict CR is worth it relative to a more normal, healthy, obesity-avoiding diet, I recommend this one: Then you can judge the evidence for yourself and make an informed choice. --Dean
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