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  1. kpfleger

    Vitamin D Recommendations

    Ron, that's a very old study in the world of vitamin D research (2012). Lots has come out since then. There remains disagreement about the exact optimal level. Many knowledgeable doctors & researchers quote 40-60ng/ml. Few to no people advocate 30ng/ml as better than 40ng/ml though some claim that 40 should be the upper end of the optimal range, but most of the uncertainty and debate is about where the upper end of optimal range is. As the reverse-J-shaped curve Michael R posted on the 1st or 2nd page of this thread in 2016-2017 showed, the steepness of the all-cause mortality graph is lower in the higher blood level direction than the lower level, so it makes sense there is more debate about the upper end of the optimal range. And there may be tradeoffs such as increases in some kinds of mortality vs decreases in others. But it's also important to note that there is ample evidence that low vitamin D levels worsen COVID-19 and in fact lots of evidence that vitamin D supplements directly help against this virus (more than others) and good mechanism arguments as well (including direct action against the virus particles). For a review, see my review http://agingbiotech.info/vitamindcovid19/ or its 1-pager summary: http://agingbiotech.info/vitamindcovid19facts/ So here in the year 2020 the optimal blood vitamin D (25OHD) range has probably temporarily shifted to a higher range than the previous optimal due to a higher short-term risk from COVID-19.
  2. kpfleger

    Testosterone, Luteinizing Hormone and Mortality

    So far no replies to my Feb 28 message with any compelling evidence-based reasons for those on (near)CR diets not to try to combat age-related testosterone loss by boosting it back to former personal levels. (Perhaps the timing is such that everyone quickly got distracted by the pandemic and this topic suddenly seemed less important.)
  3. kpfleger

    Testosterone, Luteinizing Hormone and Mortality

    The forums give me an error message on this way of attaching a whole file to a message, if I'm not logged in. Works fine if logged in. For those not logged in, the paper is: https://www.sciencedirect.com/science/article/pii/S1090023313004486?via%3Dihub or https://doi.org/10.1016/j.tvjl.2013.09.020 So this study showed no advantage for neutered male dogs. This quote: "In the UK, neutering was associated with increased longevity for females but not males (Michell, 1999), while neutered males outlived entire males among US military dogs (Moore et al., 2001)." shows another UK study showed the same and a US study showed an advantage (in military dogs specifically). I wonder if that's explainable based on more risky behavior, as supposed as a confounder for the human eunuchs.
  4. kpfleger

    Testosterone, Luteinizing Hormone and Mortality

    This is the most recently active of many CRSociety threads on testosterone (T). Some others: 1, 2, 3. There are several related but somewhat different topics: (A) Is the low-T that results from CR bad? Does boosting it reduce the benefits of CR? (B) In those not doing CR but also not obese / suffering from metabolic syndrome, is age-related decline of T bad and is boosting it back to earlier levels net long-term healthy? (C) In those doing CR is the (perhaps slower) age-related T decline bad & boosting it back to youthful CR levels (but not back to non-CR levels) net long-term healthy? I'm most interesting in the question of whether boosting T to stop age-related decline has clearcut health risks for those without metabolic syndrome / obesity, whether case B or C above, i.e. deep in CR or borderline (eg, WFPB or generally healthy obesity-avoiding lifestyle). I'm curious what everyone (especially Michael) thinks are the best arguments not to intervene to raise T to prior youthful levels (for whatever level of CR / leanness one maintains) as one ages, assuming one has records of prior levels going back some years? Is there really much trustworthy data to make any informed decision about this? Are there any studies that boost T in aging CR'ed mammals to maintain non-declining levels with age? Michael mentioned that castration lengthens the life of dogs. I haven't tried to dig up the studies. Which ones do you find most compelling? Do the castrated dogs have lower overall leanness? Any data on whether castrated, CR'ed dogs live longer than non-castrated but CR'ed dogs? More details..... It's clear there is controversy about whether low T is bad & boosting it good, both in the wider medical community for the general population and here on these forums. General population: Pro-T example: StemTalk podcast just had interviewed Abe Morgantaler, an human T expert with long Harvard credentials. The episode discusses history of the the subject from the medical community perspective, eg risk of prostate cancer, also CVD. I don't have a broad enough view to know how one-sided the presented history is, but clearly he is an advocate of T therapy. Positive evidence is discussed as well as quality of life patient anecdotes. A lot of time is spent discussing flaws in studies that caused negativity for T therapy (and some of this is generally interesting from on the issue of science errors & publishing). This interview just came across my podcast feed and isn't meant to be the best single summary of the pro-T case. Anti-T example: Michael, in one of the other threads, pointed out this article that summarizes a lot of evidence against T therapy. The author of this article is accused in the comments of the article of being biased against T therapy (opposite of the podcast interviewee above). [Note that Michael originally linked to the printable version of the article, possibly just to get to the unpaginated 1-HTML page version, but that doesn't include the comments.] The comments also point out some purported flaws in some of the studies discussed (eg differences in plaque scores in treatment vs. control groups before therapy was initiated in one study). The podcast interview above also discusses flaws in several studies---I didn't go back and try to match up the studies but I suspect many are covered in both places. I didn't try to dive into each study and its criticisms to try to decide each case myself. Michael's summary was: It should be noted that "otherwise health" here means healthy by the definition of the normal medical healthcare system that defines lack of full blown clinical disease as "healthy", but many (most?) of the studies used people who had high BMIs, ate typical diets, and thus mostly had underlying molecular accelerated aging that meant that they were already well on the road to chronic diseases and metabolic syndrome given their ages. We could dive into the studies of such people as they are and discuss the details to figure out which studies are most trustworthy and try to guess at which conclusions carry over somewhat to leaner humans---that's one direction this thread could go if anyone cares to. For CR or low-BMI healthy diet/lifestyle: The T threads here discuss many things, including whether CR lowers T, whether CR or near-CR causes the age-related rate of decline of T to be slower. [Note: Below I will just say (near)CR as a shorthand catch-all abbreviation for all of CR and other generally healthy obesity-avoiding diets, such as WFPB, Okinawans, etc. CR vs. these others is obviously different, but for the purpose of this discussion the difference between all of these and typical western diets in the important distinction.] The thing most everyone agrees on is that typical bad diets lead to obesity / metabolic syndrome (metS) and simultaneous reduction of T (in humans, and seemingly in other animals too I think). Consequently, there is naturally much epidemiological data showing correlations between low T and bad health outcomes, but this correlational data is (near-)worthless for arguing that low T in the context of (near)CR is bad. It seems to me, even randomized trials in which T is artificially lowered or raised in high-BMI subjects eating bad typical diets should be viewed with caution as to relevance for those doing (near)CR. Unsurprisingly, there is little to no data from well-done studies of (near)CR humans randomized to interventions that raise or lower T and then followed for long-term health. There just aren't enough (near)CR'ed humans in long-term studies let alone ones with this particular kind of randomized intervention. Are there good studies in rodents or other mammals that are CR'ed and then randomized to T-lowering or T-boosting interventions? My read of the existing threads on these forums and everything else I've found so far is that there is insufficient evidence to conclude that age-related low T in (near)CR is clearly bad, nor that it definitely is safe. No one really tried to discuss whether intervening to increase T (via supplements or direct use of T therapy) to correct age-related T decline would be bad for (near)CR humans. I don't see much evidence at this point to conclude it would be bad (nor that it would be safe). The best argument presented against boosting T so far seems to be the increased CVD risk, but even to the extent true in high-BMI/bad-diet individuals, how relevant is that for those doing (near)CR, whose CVD risk should be very low? What's the best argument that someone doing (near)CR would likely or possibly be doing harm to their long-term health by trying to slow or fully correct for age-related T decline by intervening to boost T? If there is insufficient evidence to conclude that low T is bad, and insufficient to conclude that boosting T back to youthful levels is bad, then it becomes at matter of intuition & guesswork played off against personal preference for how someone wants to live their life (and strength of that personal preference vs. width of the error bars on the best estimate one can come up with from the data available). Michael in one of the other threads pointed to a non-scientific episode of This American Life discussing some of the huge life changes that low vs. high T can have on a person's life (quality of life, tastes and desires, even personality). These are things reasonable people may have strong personal preferences about. I'm not having any particular low-T problems, but I see my free T levels starting to decline over time (in the context of stable diet & BMI) and personally don't have a desire to roll the dice on a changing personality---I like the one I have now thank you very much, nor roll the dice on some of the problems the patients in the Abe Morgantaler podcast episode talked about. Nor do I welcome energy level decline and I wonder whether caffeine use and variability may mask my ability to perceive a slow energy decline over time. Karl
  5. Don't forget that that applies only to some of the interventions these companies are working on. CR and other lifestyle habits at most slow aging relative to population average. They don't stop it. So many of the anti-aging efforts will be important to even those on the most optimal levels of CR. CR in humans probably slows aging by at most 30% (and that's probably wildly optimistic). Senolytics, partial epigenetic reprogramming, stem-cell therapies (which may work through signaling that does reprogramming), therapies to protect mitochondria from damage, persistent AGE cross-link breaking, immune system regeneration, etc. will all probably be beneficial to even those on CR.
  6. Thanks, I hadn't seen those. There were only ~26 companies mentioned (vs ~110 that I already had). There were a couple new to me so I added them to the sub-tab of my table that has companies to consider adding when I get a moment. In some ways the site I made is the answer to the site he said at the top of his part-ii post that he couldn't find anywhere. And my counts sub-sheet answers some of the money questions he lays out in his first paragraph (of part ii). I added a comment to his post but it's waiting for him to approve it.
  7. I made a website to track all aging/longevity companies, in an interactive (sortable, etc.) and quantitative way: agingbiotech.info The aging/longevity field has grown to where it's hard to follow. There are books, journals, blog, some industry reports, and a few website with forums like this one, but few structured info sources for broad context or targeted queries, particularly few focused on aging defined as the underlying molecular causes of multiple age-related diseases. The web had no comprehensive & precise list of companies with therapies or diagnostics for underlying aging in this sense. Hope this is helpful to some. For those here, it's particularly worth noting that many interventions being pursued within the aging/longevity communities (both in academic labs and companies) are focused on correcting or making up for age-accelerating factors, either genetic disorders that accelerate some aspect of aging or lifestyle factors that do so such as bad diet, lack of exercise, etc. including their downstream manifestations such as obesity. There is even a new buzz-phrase that succinctly describes a subpart of the field focused on these kinds of things: metabesity (with a conference this month in the DC area even). Interventions that are best categorized into this bucket include category buzz-phrases like CR-mimetics, exercise-mimetics, Rapalogs, etc. Metformin probably goes in this bucket. For those on a CR diet, or even just eating high micro-nutrient, obesity-avoiding, relatively healthy diet (much healthier than average Westerner), there is a question about how much such interventions will do to improve health & healthspan. The website includes companies working on such interventions, but also many working on things that should be important even to those on CR or living close to optimal long-term-health preserving lifestyles. Figuring out the exact boundary of that split is debatable and will only be answered definitively with further science so until then you have to decide which companies and which of their clinical trials are more worth paying attention to than others. But there is certainly important work being tracked. Hopefully this site is a useful way to check out the current state every now and then. Feedback welcomed (see contact link at the site). Karl
  8. Yes, I saw that he wrote an long post about it, didn't notice any discussion of FOXN1 nor of error bar methodology for small n use of methylation clocks (but I didn't read the whole thing carefully after seeing no discussion of FOXN1).
  9. There is a lot to like about Fahy's trial and a lot to dislike. The main 2 points made in this thread so far are both right: (1) It's nice to have this data in humans despite the obvious negatives of small n and uncontrolled and (2) the press regrettably but predictably over-hyped its coverage. Let's move on from those points and let me add a few other points that haven't been brought up in this thread: I'm disappointed that Fahy thought that the right order in which to do this science was human n=1 trial followed by uncontrolled human n~=10 trial without any work in mice or any other mammal. The thymus involutes in mice too. A controlled mouse trial with much larger n could have been could have been done for less than (I presume) the cost of the n~=10 human trial, and it could have included followup for a long fraction of mouse lifespan to watch for long-term negative effects (or even been a lifespan study with similar total real-time study duration, eg, start with 2-year-old naturally aged mice like the Oisin trial and follow until death roughly a year later). A big question in this work is how long will the regenerated thymus remain more effective before re-shrinking. It's possible the negative effects of GH/DHEA are not so bad if only pulsed every 5 or 10 years, but if the thymus recovery is very short-lived then that is much more worrying. Followup with scans multiple years later will be very important. (And a mouse study would have been because this could have been tested on timescales relevant to how quickly the thymus shrinks in that model organism.) Fahy is attempting to commercialize this protocol to make it available as widely as possible as quickly as possible through the company Intervene Immune. Good luck to him and his team! They observed that FOXN1 was up-regulated as one of the consequences. FOXN1 is known from other work to stimulate thymus growth. Repair Biotechnologies (disclaimer: I am an investor) is working on thymus regeneration more directly via FOXN1 upregulation (via gene therapy). If all the benefit observed in the TRIIM trial is through the intermediate of FOXN1 increase,. then other direct interventions through that can avoid the HGH/DHEA/etc. Clearly an important space to watch in coming years. A lot was made about the Horvath age-clock reversal. Morgan Levine (former Horvath lab member now Yale professor doing great work on pushing methylation clocks forward) has said that she believes that though DNA methylation clocks are useful on a population level, she thinks they are too noisy on an individual level for changes in the age they report for an individual across a time interval to be reliable. She thus believes it's not useful to have one's methylation clock age tested and then retested after an intervention. If this is right (and she's clearly an authority), then it's not clear for n~=10 how much change you would expect to get due to random chance. Presumably Horvath himself could characterize this math but I haven't seen that done and presented for comparison to these results. I didn't read the paper directly. Did it present error bars on its Horvath clock averages (and cite the data and methodology by which they were computed)? Karl
  10. TomBAvoider, Michael Rae's post that started this thread provided a pretty long list of links that look pretty scientifically respectable. That post by itself seems to disagree with any claim that this is all hype hype hype. I come at this with default skepticism about the therapeutic effects and view those as just bonus if they do exist. To me this is the long-awaited successor to the Zeo headband, the first sleep measuring device that actually had EEG. This and its Philips competitor (which seems to require regularly replacing something consumable and thus seems less desirable to me) are the first sleep things that can potentially do a reasonable job at sleep phase classification. After a big analysis of all the best sleep things on the market a couple years ago, including taking 2 of the same model of one of the best devices and measuring them against each other) I concluded that movement + pulse and the other things one gets easily from wrist-based on under-mattress type sensors are just not going to be able to classify sleep phases accurately. I default assume that this will be more accurate than the Oura ring, any watch, or any ballistocardiography device. I think this is a reasonable default position until data says otherwise (rather than requiring data to prove this). Even if it's not perfect and classifying deep vs. shallow vs REM perfectly, the EEG should mean it is better at hitting sleep vs wake than the other categories of device. Why is good passive recoding of sleep important without therapeutic effect? Because there are dozens of known ways to influence sleep quality (blue-light blocking glasses, get bright light during the day, don't eat late, keep bedroom dark, keep bedroom cool, just go to bed earlier, etc.---just Google sleep hygiene, or if more time read Why We Sleep by Walker). A tool to measure how you are doing and track that over the years as you age and sleep quality naturally gets worse with age is useful to help dose doing all of these things. Karl
  11. Dreem2 headband is now on sale for $500. This appears to be the summary list of changes from Dreem 1.
  12. This is surprising: the study did report results at finer-grained breakpoints (8 sleep ranges instead of 3), but it was not a U-shaped curve with mortality. The lowest and highest sleeping groups survived much better than the 2nd lowest and 2nd highest, and not that much worse than the groups in the middle ranges (with confidence intervals that don't go way into bad territory so it doesn't look like just randomness due to low n). The differences between adjacent groups may not have been statistically significant, but when graphed the overall 8-group bar-chart still represents a striking departure from what you would expect for a U-shaped dose-response (see attached bar chart, fig 1 of the paper). In numbers, those sleeping >7.5hr (n=15) had 89% survival (95% CI 81-91%) vs those sleeping 7-7.5hr (n=31) having 58% (45-71%). The 81-91% range for >7.5hr doesn't seem that much worse than the 85-94% CI for the pooled 5-6.5hr group. If this were some weird quirk due to the low n, I would expect a bigger CI that ranged down further into bad survival %s. I didn't see any discussion of this turning down of the ends of the U curve in glancing very briefly through the later parts of the paper. But this doesn't match any of the other sleep research I've ever heard about. It seems so odd, it's hard for me to take this paper as a reason to think that >6.5hr is the point at which more starts to become bad, as suggested by their pooled 3-group analysis (and the figure 2 that Ron posted above). So until I see some study that replicated this, I'm still going to go with 7.5hr of actual sleep measured by a tracking device as the rough amount where more sleep may start to become a negative, as suggested by the hunter gatherer research reported in the Walker book and the studies described by Parsley. My own sleep averages around 6.5hrs (measured w/ Emfit QS under mattress + Garmin Fr235 at wrist). Karl
  13. Ron, thank you for the https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010336/#!po=1.21951 study. This is the best direct answer yet to the question I posed in the 1st post. As Michael said, it will be some time before we have lots of studies using actual sleep measurement and long-term health followup because we didn't have measurement a long time ago and what measurement we had (sleep studies) were very sleep disruptive. We obviously didn't have FitBits and Apple Watches in the 1970s, but even if whatever wrist actigraphs we did have were systematically different than what people use now, it is clearly a strict improvement on self-reported time-in-bed, and the study demonstrates exactly what I hypothesized in the 1st post: It's notable that getting too little sleep is much worse than getting too much, based on the pasted graph. It seems odd that the highest breakpoint they used was 6.5hrs. Given the other science suggesting 7-7.5hr as optimal (the studies Kirk Parsley described in the linked podcast above) or 6-7.5hr as optimal (some of the modern hunter-gatherer studies described in Matthew Walker's book I recommended above), it seems strange they wouldn't separate the above 6.5hr group with a breakpoint at ~7.5hr. I haven't had a chance to read the paper yet, but will look at this when I do. Maybe there weren't enough subjects in the above 7.5hr range. But if there were, one hopes their outcomes don't drag down those in the 6.5-7.5hr range. Tangentially, I note that Dreem's website homepage says the Dreem2 is available now, but when you click through to the order page, it still says not available yet and has a place to register your email to be notified when that changes. Karl
  14. FYI, 2nd generations of the Dreem and Philips sleep enhancing headbands announced/shown at CES this week: https://www.usatoday.com/story/tech/columnist/2019/01/08/sleep-tech-ces-2019/2505688002/ ...along with a new 3rd sleep enhancing headband called Urgonight from another French startup, this one interestingly designed to be used during the day in order to enhance slow-wave sleep at night. The USA Today article I happened upon didn't include references to scientific studies supporting the idea the way a post from Michael would. 🙂
  15. Great find Michael---thanks for sharing. All cause mortality would be nice instead of just CVD. Is there a price in terms of increased diabetes or dementia, or increased death from infectious diseases?