The Most Effective Personal Anti-aging Program

What are the most effective things you can do to slow the aging process and extend your life expectancy?  This is the question being asked by a clinical trial that I am organizing, and which seems to be rapidly taking shape.  But before the study begins, we have to have candidates to evaluate. We should begin with hypotheses about what we are evaluating.  My idea is to consult some experienced experts, and also to crowd-source this choice, and to ask for your help in selecting the supplements and life habits to be evaluated.


Details of the trial were described in two blog posts last spring [One, Two] and a more technical manuscript submitted in May.  Outcome will be evaluated based on a variant of DNA PhenoAge, taken from a blood test before, amid, and after the two-year trial.  We use methylation pattern differences rather than mortality or health outcomes because the latter take a long time to reveal themselves, and make anti-aging trials prohibitively expensive.  Using methylation clocks as an endpoint is a new idea, and we don’t know if it will work, but if it does, it will be 100 times cheaper and 10 times faster than previous methods. We will have enough bandwidth to test a dozen different measures at once, which itself is a revolutionary step.  

Many measures are known that are thought to increase life expectancy by a year or a few years each.  Of course, we want to know which ones offer their greatest benefits. But even more important, we want to know how they interact, synergize, and interfere with one another.  If any one of these measures offered major benefits—say 20 years of life—its effects would be so apparent that we would probably know it already. Likewise, if these measures added up to 20 years of extra life, we would all know some people who are obviously younger than their chronological age.  Realistically, we must assume that most of the things we do are redundant. Combining metformin with berberine and gynostemma may offer little additional life expectancy compared to any one separately.  A panoply of different anti-inflammatory strategies may be little improvement over an aspirin a day.

But we hope there are exceptions.  If two different measures act via completely different metabolic pathways, we have reason to hope that their effects should compound.  For example, perhaps life extension interventions based on mitochondrial health synergize with interventions based on rebooting the immune system.  Then we might hope that the life extension available from these two measures together is greater than the sum of what we get from the two separately.

 

Study design

We will not tell the people who sign up for this study what to eat, what pills to take, or how much to exercise.  We will ask people what they are doing, what they are eating, and what supplements they are taking in a detailed questionnaire.  We will select subjects so as to represent a broad array of different strategies and different combinations among these strategies.

Broad, but not too broad.  We will have enough statistical power to estimate the interactions among every pair of measures out of 12 that we take as our independent variables.  These 12 should be chosen in advance, so the study has a clear focus. If there are more than 12, the number of interactions increases rapidly beyond what we can hope to distinguish (with multivariate statistics).  I’ve decided to start with 15, and winnow the list as people sign up for the study and we see what

Here are the criteria I propose:

  • Each measure, separately, should have either human mortality data or longevity data to back it up.
  • The measures should be easily available to all (excluding intravenous drugs or transfusions)
  • The measures should be well-enough known that they are already in common use (and we will have no trouble identifying a diverse group of subjects who use them)

I find that it’s hard to limit the list to 15.  It may make sense to include a few measures that are so well established that every participant will be required to comply in order to be included in the study.  In this category, we might put

  • Non-smoking
  • Limited alcohol consumption (or none)
  • Vitamin D at least 5,000 IU daily
  • Multi-mineral supplement with magnesium, zinc, chromium, and selenium
  • Exercise equivalent to minimum 5 hours a week of walking or yoga

Body weight (BMI) is an important longevity factor, but difficult to account.  Studies show that maximum lifespan is associated with BMI between 21 and 25, but in my interpretation, lower BMI is always beneficial for any given individual.  

BMI Mortality versus age

The reason for the apparent paradox is that individuals have genetic disposition to be overweight or underweight.  Those who are genetically underweight tend to overeat, because they can do so with no social stigma. Those who are genetically overweight feel compelled to diet all the time (women more than men), and they may be restricting calories just to keep their BMI at 25.  These dieters get the most benefit from Caloric Restriction, despite the fact that they don’t look thin.

List of things that lengthen your life

  1. Love.  Men who are married or in close relationships have 7% lower mortality than singles.  The number is 4% for women [ref].  These numbers correspond to less than a year of life expectancy.  A different study finds loneliness increases mortality by 50%, corresponding to almost 5 years of life.
  2. Empowerment: Staying employed is worth up to 14 years, and I like to think this is more about being needed than making money.  This study claims that the big difference is wealth.
  3. Anti-inflammatories: Aspirin, ibuprofen, curcumin, or fish oil.  This study attributes about a year of life expectancy to daily aspirin.
  4. High fiber, a proxy for healthy gut flora.  We know that they are important, but don’t yet know how to manage the biota for maximal life expectancy.
  5. Vegetable-based diet This review concluded that vegetarians live 3 years longer, but methodologies and results vary considerably.
  6. Meditation This is difficult to evaluate, and data is unreliable but encouraging [ref].  The only careful study linked meditation not to mortality but to telomerase activity.  I confess I am including meditation in the list from my own intuition and experience.  
  7. Intermittent fasting Extends lifespan in mice and lowers mortality in nursing home studies [ref].
  8. Interval training Reputed to be the most efficient path toward cardiovascular fitness [ref], and there is limited documentation of benefit for all-cause mortality [ref].
  9. Donating blood This is another quirky inclusion on my part, but there is data to support it, which I reviewed a few years ago.  
  10. NAC just one study — 30% increase in lifespan of mice
  11. DHEA Lower blood levels of DHEA are clearly associated with greater age and higher mortality at the same age, but the direction of causality is in dispute.
  12. Metformin Prescribed for diabetes for decades, this drug also lowers mortality from cancer and heart disease [planned clinical trial].
  13. Rapamycin The most convincing data available for any supplement for life extension in mice.  Early adopters are beginning to experiment on their own.
  14. Quercetin + Dasatinib (or other senolytics).  Senolytics are the best near-term hope we have for a breakthrough in anti-aging medicine; but the combination of quercetin +dasatinib is not yet discriminating enough to be safe for humans, meaning it kills too many regular cells.
  15. Epithalamin  Very promising data from Russia [ref], both in rodents and in people, but there is no one trying to reproduce them in the West.
  16. Ashwagandha [many benefits, but no mortality or rodent lifespan data]
  17. Selegiline (deprenyl).  In classic studies from the 1980s, lifespan of rats was extended.  Data in humans is contradictory [ref].

Perhaps we should begin with a guess about which combinations are likely to be highly redundant.  In this way, we could cluster together different strategies and condense more strategies into a manageable list.  It might look like this:

  1. Anti-inflammatories (aspirin, ibuprofen, statins, omega 3, curcumin, boswellia)
  2. Blood sugar control (metformin, berberine, gynostemma, chromium)
  3. Social factors (family, employment, wealth, community support, marriage, sex, communing with nature, empowerment)
  4. Mitochondrial supplements (NAC, CoQ10, PQQ, NR, melatonin, glutathione, carnosine, ALA)
  5. Immune support (reishi mushrooms, cistanche, andrographis, goldenseal, echinacea)
  6. Adaptogens (rhodiola, ashwagandha, bacopa, silymarin, pycnogenol)
  7. Telomerase activators (silymarin, astragalus, ashwagandha, horny goat weed)
  8. Senolytics (quercetin, dasatinib, fasting)
  9. Diet (everything from high-protein to high fiber to vegan to paleo in one cluster?)
  10. Limiting and intermittency of diet (long- and short-term fasting, CR, BMI)
  11. Exercise (aerobic, strength, interval, walking, competitive sports, yoga)
  12. Mental focus (meditation, prayer, yoga, tai chi, spiritual practice, cafeine)
  13. Neuroprotective (ashwagandha, rhodiola, ginkgo, melatonin, bacopa, selegiline, gotu kola, coffee, tea, blueberries, chocolate)
  14. Multivitamin supplements (including mega D, mega-C, B12, carotenoids and tocopherols)
  15. Sex and steroid hormones (DHEA, prostaglandin, progesterone, SAMe, testosterone)
  16. Angiotensin inhibitors (Lotensin, captopril, enelapril)

Or—the best of both worlds—we might structure the study in such a way that it can be analyzed after the fact either with individual strategies or clusters of strategies.

Fauja Singh, centenarian marathon runner

The best way to design a study is to start at the end.  I imagine I am two years down the road, taking my first look at results from 5,000 life-extenders.  The first thing I will want to do is to look for outliers. Are there a few people who stand out from the bell curve, aging much more slowly?  If so, what do they have in common? The advantage of this approach is that it gives maximal flexibility in telling us exactly what we most want to know.  The disadvantage is that it is easy to fool ourselves and imagine patterns in a small set of random errors. When there is no initial hypothesis, there is no objective way to calculate a probability that what we find is the result of chance.

Our null hypothesis is that there are no systematic outliers, but only a smooth tail to the probability curve.  If there are a few scattered individuals in 5,000 who are aging much more slowly than the rest, we will not find any common thread in what they are doing, and so we must explain their data as anomalies or mistakes.  If this is our result, it will be disappointing, sobering, but liberating as well. Those of us who are compulsive about one or another life extension strategy can ease our discipline.

But there is a chance we will find something more interesting.  We may find that there are dozens of outliers, that their life extension strategies all overlap in some clear and unambiguous way.  We will then have, for the first time, a solid foundation for our personal life-extension habits, and a clear hypothesis for further experiments.

What are your thoughts?  Please comment.

138 thoughts on “The Most Effective Personal Anti-aging Program

  1. How often will you question participants about the various supplements and activities they are doing?

    I find myself tweaking supplements on a fairly regular basis, although that may have stabilized somewhat in the last few months.

    Also, people’s social support network can change during two years – divorces, death of loved ones, job loss, etc.

    What age ranges will you be looking at? Could interventions with middle age men not work with senior men?

    • We’re still discussing this, and your input is welcome. I think we can’t bug people with a new questionnaire more than once every 6 months, but we hope to supplement the questionnaire with a cell phone app that lets subjects report their food, supplements and exercise in real time. Would you be willing to do this for a week every 6 months? 2 weeks every 6 months?

  2. Hi Josh, I wonder if I may be an outlier – at least my test results and lsit of supplements may be of interest.

    May 2018 Zymo tested my urine sample as (70yrs) minus 13 years & retested w/blood in June 2018 as (74 yrs) minus 9 years. June 2018 Teloyears tested average telomere length as (66) minus 18 years.

    I am 83, excellent health, married, exercise daily, tennis three times weekly, and have consumed supplements since the Durk and Sandy days – precursor to LEF. In addition to the drug listing below, I take a number of LEF’s supplement combinations.

    Prescriptions, Vitamins, Herbals
    (Robert H. Olander Apr. 2018)
    (Note: Started and continued usage for ten or more years unless otherwise noted)

    Prescription Medicine:

    Nexium – – 40mg 2x daily (GERD)
    Celebrex – – 100 mg 2x daily (Arthritis pain)
    Lipitor – – 10mg each evening (Maintain low cholesterol)
    Jalyn 0.5 – 0.4 each evening (Control BPH, relax sphincter) Started 2017
    Carafate – – 1gm 4x each night (Protect from GERD)
    Cytotec – – 100mcg 2x each night (Protect from GERD)
    Retin A, 1% – – Apply every other evening (Clear skin)
    Aspirin – – 162 mg once daily (Thin blood)
    Metformin – – 2 gm daily (Control slightly high A1c)
    Synthroid – – 75 mcg daily (Boost sluggish thyroid)
    Toprol 12.5 mg daily (Maintain low blood pressure)
    Vitamins, Herbals, Supplements:

    Life Extension Foundation (LEF) mix (see separate sheet) at least 30 years
    LEF Booster (see separate sheet)
    LEF Cognitive mix
    D3 – 10,000 IU daily (plus in LEF mix)
    DHEA – 75mg daily
    Curcumin – 400mg daily
    A.L-Carnitine – 1,200mg daily
    Melatonin – 12mg nightly
    B12, sublingual – 5mg daily
    COQ10 – 200mg daily
    Omega 3 – EPA: 700mg; DHA: 500mg
    Magnesium – 144mg daily (plus in LEF Mix)
    Carnosine – 1gm daily
    Resveratrol – 250mg daily
    Extracts: Blueberry, Grape, Pomegranate, Cruciferous Veg, Provinal, ++
    Creatine – 3gm daily
    Fiber supplement– 6gm daily
    NAD+ booster (Niagen) 250mg daily (Nicotinamide Riboside) Started 2015
    Acidophilus every morning
    Desatinib (100mg, once monthly) w/grapefruit juice – – Started 2016
    Rapamycin 2mg once weekly w/grapefruit juice – – Started 2015
    ALT711 – 100 mg daily (anti-fibrotic)
    Green tea extract 725mg daily
    J147 – 10mg buccally. Started 2014 intermittently
    Reishi mushroom 980mg daily
    GHK applied topically

    • Pretty amazing results Robert. Out of interest, where do you get your dasatinib, how did you decide on the dose, and any side effects? It’s possible that quercetin with tocotrienols May be as effective as dasatinib as a senolytic, but I’m not sure.

      I notice that you take nexium daily. Have you seen the studies on proton pump inhibitors and mortality rates? Might want to consider ranitidine.

      • Good morning Paul, I bought the Desatanib at a pharmacy in Guadalajara three years ago during our winter vacation in Mexico. Sorry, my supplement list is incomplete – I do take Quercetin (about 10-1) with the Desatanib and I’ve taken LEF’s tocotrienols for many years.

        The winter of 2015 when I started Desatanib at 100mg two consecutive days each month, I developed a rash on my back and chest for each of the first few months – I cut back to 100mg once monthly and have had no sides since.

        I’m not entirely happy with Nexium but I’m trying to fend off a recurrence of Barret’s Esophagus – you don’t want that! I alternate with Cimetidine (sometimes Ranitidine)

        • Thanks Robert
          Good information.
          You’re on a very interesting and comprehensive cocktail. Did any one thing or combination make a significant difference in how you feel?

          • Hi Paul, I’ve never expected nor noted an immediate effect from any supplement except perhaps Rapamycin and Desatanib, which I started at roughly the same time three years ago. Both seem to affect energy level, and perhaps even memory in a positive way. My supplement list has changed considerably since the early days of mostly vitamins 45 years ago – one of the first non-vitamin supplements I added was DHEA back in the mid-70’s, and a year or so later, Deprenyl for just a brief period. That was a long time ago!

          • Great job Robert
            Very fascinating self experimentation.
            Would you mind sending me an email so we could discuss all of this in more detail?

        • With regard to reflux might consider Gaviscon triple action with ph water in the eve. Latest info I’ve seen is pepsin is the problem worth reading up on and to which ppi’s do not address.

    • ALT711, J147?

      How on earth do you get this stuff?

      My feeling is that the older you are, the more it is possible to diverge from the accelerating aging process. Just a hunch, but it will be interesting to see what Josh’s study uncovers.

      • Hi Mark, I get the ALT711 in 100mg capsules from Legendary Pharmaceuticals.

        You’re certainly right about the divergence at older ages for telomere lengths, even a study that showed lengthening telomeres above age 80 – but that also seems to at some point fly in the face of a Hayflick limit. I don’t place much value on my 66 teloyear results. I included it since I think Josh explained it in reference to DNAm as, “If the gaters don’t get you the skeeters will!” At the moment I seem to be in a sweet spot.

        I’m dying to learn the results of Josh’ study – perhaps something in a year or less.

    • Robert – You help illustrate the kind of problem we’re undertaking. On the one hand, you have amazingly positive results, and we want to understand that. On the other hand, you are taking many different supplements, and only a subset of them is actually contributing to your benefit. How can we decide what is working and what is coming along for the ride? We will need at least 100 people with a program that is working and 100 people with a similar program that is less effective in order to distinguish a difference and come to a conclusion. We will have to select a set of experimental subjects carefully to get enough diversity.

      • Perhaps your friend Vince Giuliano would be willing to submit a sample to Zymo – his results would be most interesting – of course along with his most recent list of supplements.

        I noted that DNAm reads the age of donor blood, so the results of some celebrities like Ray Kurzweil who employ more exotic interventions might not prove useful – but there are a lot of self experimenters out there –

        A retrospective look at DNAm Deltas of heavy supplement users (and their supplements) would give you some ideas on which supplements to emphasize in your study.

      • I agree, Josh, that without a control group it will be difficult to draw valid conclusions.

        One problem with self-experimenter is that we tend to use so many supplements and drugs, known or suggested, to have a positive effect that it becomes difficult to separate the wheat from the chaff.

        Excellent information in your article, though. This sums up all the known life-extending factors.

        I am not surprised that continuing to work is “worth” 14 years.

        From an experiential perspective, I do notice that friends family and acquaintances who retire on time or worse early, tend to decline mentally rather rapidly.

        Regarding love, I think it’s important to emphasis that the love factor need not be a spouse.

        Some studies show that any creature that makes us feel connected can help our health. That includes pets as well as people with whom we resonate.

        I agree, as your article stated, that loneliness is a big factor in shortening life and health span.

        Some family can actually be toxic to health. Therefore the love need not come from a family member, nor even a human.

        • About control groups: In this kind of study design, everyone who doesn’t take supplement X is a control for those who are taking supplement X. It’s the job of the statistician to tease apart all these factors and see if there is any robust information that pops out of a web of interconnected data. The subject is called “multivariate statistics”. It has its pitfalls, but also it can be surprisingly effective.

          Analogy: When you get a traditional x-ray, every point on the screen corresponds to one beam of the x-ray source, and represents one place in your body. But when you get a CAT scan, every beam goes through every part of some slice of you. The raw image from a CAT scan is actually not even a 2-dimensional picture, but just a 1-dimensional list of numbers. It is a computer algorithm that re-mixes and re-combines the data to make millions of pixels of create a high-resolution image, and it works pretty well. The magical algorithm is called FFT.

          Multivariate statistics works in an analogous way, but because of the the uncertainties and inherent noise in the data, we are limited to a handful of factors, and we can’t separate millions at once.

          • Josh:

            Thank you for the information. I agree regarding the control group. I was simply thinking out loud.

            I think your attempt at evaluation is an excellent Idea, despite any pitfalls.

      • I think u need a form and blogging system that can fill out and be uploaded into an excel spreadsheet and part of a wiki page that collects the data from each health blog

        I think the idea of organizing the confounding variables is part of the blog itself; from raw to pin point. I would take a loot at the early mit wearable computing people Like steve Mann and work on the idea of “glogging” or life glogging and somehow find a way to standardize fit bit info and weight info and bmi and just organize it all; I’ve been on metformin to 1500 in am but don’t take any at night but recently added reservatrol to losartan at night and added nmn and lowered my niagen in am to try and capture the circadian rhythm of and amplify and deamplify different things and to fast once a week for 36 hours; lots of things I’m doing but no standard way to capture how

        I am and to show it to others my concepts that I am picking and choosing from; how I feel and how I look physiologically can be quantified w consumer tech; just need a way to reengineer the consume tech to data mine;

    • Just a couple of minor comments- #1 – you’re EPA and DHA could be much higher (unless you’re getting plenty of omega 3 from walnuts and or ground flaxseed- heh heh Webber from Costco of course kept in the freezer).
      Comment #2 I also think you’re magnesium intake could be low but not sure without knowing your diet;
      As Jeff T Bowles is keen on- and I agree with, a vitamin D3 with Vitamin K2 and magnesium combination is critical and synergistic.
      I sincerely appreciate your post and wish you well, brother.

      • Aslan:

        Robert mentioned that he is taking a magnesium supplement plus the lifeextension mix multi-nutrient product. That LEF product contains a significant amount of magnesium.

        Also, the Life Extension Booster product contains the complete K complex.

        Robert:

        You wrote that you are taking:

        “Desatinib (100mg, once monthly) w/grapefruit juice – – Started 2016
        Rapamycin 2mg once weekly w/grapefruit juice – – Started 2015”

        Robert:

        Are you taking it with grapefruit juice to slow the metabolism of those two drugs?

        • Hi Heather,
          I thought I was saving money by getting roughly twice the effect – thanks to this blog I’ve learned that it simply extended the time to clear both C1 & C2, flattening the curve, and have therefore stopped.

          I will continue to drink grapefruit juice with my monthly Desatanib since Desatanib is much more expensive and I haven’t heard of any downside.

          In fact, I’m looking for an inexpensive source of non-prescription Desatanib –

  3. Great idea- Ater a health hacker brought it to my attention – I’ve started taking molecular hydrogen! ( after doing my homework on it) It’s only been 4 weeks- I now feel my breathing getting stronger. This is the real thing- definitely worth looking into

  4. Re “Limited alcohol consumption (or none)”, scores of studies show that light to moderate drinkers live longer than non-drinkers. Even when the non-drinkers are life-long, so as not to include former alcoholics, the relation holds, as it does when people of the same socioeconomic status are compared, such as physicians and other health professionals.

    Alcohol increases insulin sensitivity, raises HDL cholesterol, inhibits mTOR, and decreases platelet adhesiveness, which rises with age. Polyphenols in red wine may offer additional benefit, such as inhibition of cancer.

    • I know what you say is true, and I think I’m letting my personal bias (as a teatotaler) affect my science. Should we bring alcohol in as one of the variables? Should we only accept moderate drinkers and not teatotalers or lushes?

    • Probably best to only exclude those whose weekly intake is > 14 units, and that is where the (self reported) inflection point seems to be, atleast for dementia.

    • Hi PD

      Yes that recent study regarding alcohol was intriguing. The operative words being light to moderate.

      The inhibition of cancer was a surprise as the previous studies did not indicate that benefit.

      A Paracelsus if famously reported to have said: “The right dose differentiates a poison and a remedy.”

      Acetaldehyde is produced by the liver as it breaks down ethanol. the acetaldehyde is the carcinogen. It depletes S-adenosylmethionine. So supplementation with that when drinking may mitigate damage???

      Some people have a defect in the gene for alcohol dehydrogenase that slows the metabolism of the acetaldehyde and are exposed to more acetaldehyde than people without the defect.

      N acetyl cysteine and Vitamin C can mitigate some damage by helping to more quickly clear acetaldehyde from your body, if taken prior to drinking alcohol.

  5. Just some brief comments:

    1. ginseng should be in there under adaptogens and possibly other categories

    2. BMI has the issue that many longevity enthusiasts do strength training and so will show up with an inappropriately high BMI. This could be mitigated with a simple waist size measurement so we can sort the bodybuilders from the couch potatoes. Or you could request that people estimate body fat using the pinch method.

    3. even your short list of seemingly obvious minimum requirements would knock me out, due to alcohol and because I prefer to eat well vs take a mineral multi, and because I vary vitamin D based on sun exposure. Non-smoking might be a deal breaker for cannabis users? Anti-aging enthusiasts are such a varied crew that going with no minimums might be best.

  6. I would love to donate blood and did for years, but now the Red Cross won’t take me. For one thing, I’m a gay man. For another, even though I was, am & remain HIV-, I tested false-positive on the hair-trigger ELISA HIV-antibody test used in the late 80s. I am permanently barred from their donation drives. Are there doctors or services which do a modern form of blood-letting?

    • Ask your PCP about therapeutic phlebotomy. From what I’ve read many of the benefits of donating blood come from reducing iron levels so you could alternatively take iron chelators (such as quercetin or curcumin) or eat food that reduces iron absorption with meals (such as eggs, coffee, wine).

      • As side note I think I (male) have got good result using IP6 on my ferritin level (iron store) keeping it lower than 100 mcg/l. It might change during periods where you have higher inflammation e.g. in response to infections etc. So I feel it might be considered as as addition to the other chelators.

  7. Some great ideas there. Some of us do some rather extreme things either in kind or degree. For instance, methylene blue may be a very good mitochondrial rejuvenator and melatonin may regenerate the thymus at doses of 15 to 20 mg. Regular heat exposure in a sauna at 104 degrees F may kill off most pathogens and cancers. Modified rice bran may be the best immune supporter through NK cell activation. Rapamycin of course.
    It would be helpful to know if any or all of these more unusual methods matter.

    I’d be careful with the exclusion criteria. Four of the five would knock me out of the study .

    • These are great ideas, Paul. I had heard from Rhonda at FoundMyFitness about benefits of saunas, but I don’t remember running across the claim that they nip cancer in the bud. I plan to investigate all these ideas.

      I also wonder how prevalent they are, and whether we are going to find enough people doing them (minimum 100 needed) to include them in the study.

      • Hi Josh,

        Rhonda does describe reduced cancer risk with Sauna 78 C dry sauna I believe.

        I have personally been using the sauna 78 C dry on average 3 times a week for that last 3 months and of all the interventions I have done over the years, (exercise and supplements since the 1980’s, sauna has had the quickest and most profound effects antidotally. ) With the effects of heat shock proteins and its conservation across species in evolution I think this is a good item to include. ?

        I do currently take methylene blue, (1 year), NR, (1 year) , broccoli seed extract, melatonin, carnosine, and other things. It seems to me that the sauna has been more impactful on me.

        Thanks Josh and any one else having the time to read and consider this. I would be interested in others experience with sauna.

        Kevin

  8. Great idea, I’m all in! I’ve been on metformin/rapamycin for 19 months and I have full pre/post lab results. I am very interested in any other aging measurements. Alcohol consumption should be included.

  9. Count me in. I am a 62 year old male. Today, a very young, attractive Korean girl, who was doing my amended tax return said, “You look so young.” Also, I am periodically doing The Epimorphy myDNAge™ epigenetic age test. Which is the better test? LOL.

  10. Dear Josh,

    I would like to mention FOXO4-DRI to the senolytic list, I think it is the best bet even compared to D+Q (or combined with them).

    Also, sulforaphane would be one of my preferred NFR2 inducers to be considered, either by dietary means and/or supplementation (although not many options available). I think it should be worth considering it in the list as could be one big changer in the long run affecting results if not included.

  11. I think the idea of an App for entering in supplements and exercise, alcohol, diet, etc. on weekly basis is a good idea.

    That way you could relax the entry requirements a little.

  12. If:
    -1) you let participants to take any pills, exercise, and diet themselves freely (plus many other unavoidable differences in individual lifestyle),

    And if:
    – 2) your sample size is only around 2-3 for each treatment (as you mentioned to me last time), I cannot understand how can you get confounding-free sound statistically significant results.

    (And please do not simply say that that”s your work as statistician…)

    • Gustavo – We will need about 100 people representing each independent variable. But those 100 people don’t necessarily have to be doing the identical program. In our study, we expect each individual’s program to be unique, and yet we will be able to find patterns such as “90% of all those whose aging is slowed by more than 30% are taking both glucosamine and NAC.”

      • How do you plan to discover substances blocking others from their life extensions work? Like grean/black tea/tea extracts blocking telomere extension? I compiled own list of herbs (pubmed and other sources), and most of it is absent from your list. So maybe some poll what is considered ‘as working’, with few “wild cards’ for those that looks promising but lacks thorough scientific evidence so far?

          • only personal experience so far. It seems to be un-researched field. But, last years’ Spain study on TA-65 gave too wide range (shortest telomeres extented by lengths that translate to range from 2 to 8 years of telomere attrition). 4 times a range on subjects similar in age on the same dose seems too wide a range if uninterferred with something that blocks it. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178008/

          • Lengthening telomeres at this time seems too risky, IMO. Presently maintaining telomere length is our best bet, until we know more.

            As an example, Chernobyl cleanup workers have more telomerase activation and higher cancer incidens (as a chromosome healing mechanism following damage) than the average population.

          • Herbs and herb extracts activate telomerase too weakly to gain anything than slowing telomere attrition. Csipr is confimed to cause cancerous tumours too :<
            I found only data for certain tissues. TA-65 is 3.3 times in white blood cells, sylimarin and baicalin are 3x times in liver. But, taking sylibinin and baicalin together amplify their regenerative effect on liver by 5-15%, so i guess they may work better on telomeres when taken together. Sulforaphane is also confirmed to amplify telomere extension when taken toghether with astragalus, rhodiola and d3, one study claims to amplify telomerase withe these four to up 4 times.

  13. Just a comment on NAC:

    In mice, it appears that the use of NAC can cause BBB breakdown, thus accelerating the failure of vascular and perivascular clearance of Aβ plaque.

    On MRI scans, the majority of people above the age of 60 shows signs of small vessel ischemic changes in the brain, and I am wondering, if the use of NAC in humans could potentially have the same negative effect?

    https://www.ncbi.nlm.nih.gov/pubmed/24898644

    • Thanks Ole,

      That reminds me of much lab. experimental work on NAC performed by Juan Sastre and Jose Viña at Valencia Univ. (Spain).

      THEY nicely showed many beneficial effects of NAC (including those on mitDNA oxidative damage).

      But I remember Juan also advicing and warning me about various strongly snd serious bad effects of NAC at slighthly higher concentrations!

      That’s typical of many antioxidants. They act like “two edged swords”. Can be bad or good depending on dose, environment etc. Just redox chemistry: powerfull and dangerous.

      And for ANY substance just remind Paracelsus:

      “There is not poison. Poison is in everything. It dependends on the dose…”

      (That’s why after a full life of research with molecules, I do not take ANY pill “for longevity” myself. I find it very dangerous, and I have just one single body…). That is the best in my experience that I can offer to you.

      That’s the message of this ¿over?- prudent European to the many ¿Risky?-prolongevity USA enthusiastical “believers” on this Blog.

      (I understand thay you the USAs- and the Russians- won the last World War). Is this perhaps the reason why you -naively perhaps?- think that you “CAN DO IT”. That you can “live forever”… JUST NOW!

      I do too!(in spite of my European soul). But I just think now, it is TOO EARLY TO TRY THAT SAFELY….

      • I tend to agree with you Gustavo. Again, it’s a very high risk, if all we gain is 10-20% lifespan extension. I am hoping that diet, intermittent fasting, protein restriction, exercise, mediation and sleep will increase my healthspan and perhaps also marginally my lifespan. I will save my money for true rejuvenation and skip the pill popping, which currently only slows down aging.

      • Gustavo:

        You wrote: “(That’s why after a full life of research with molecules, I do not take ANY pill “for longevity” myself. I find it very dangerous, and I have just one single body…). That is the best in my experience that I can offer to you.”

        Gustavo:

        I agree dosage is important as is individual body chemistry.

        Still, if a person is in tune with their body, I think they can fine tune dosages of nutrients based on how the nutrients make them feel and what their blood parameters show afterward.

        For example Paul Rivas frequently notes here that Metformin makes him feel tired, so he stopped taking it. That is likely a good thing.

        OTH, Metformin makes me feel stronger and less hungry. So I continue to take it. If I had the same reaction as Paul I would stop taking the Metformin.

        I have been taking nutrients since birth and I have benefited by continuing to take those that improve my stamina, and based on bloodwork ,appear to improve health parameters.

        My goal, at this point is increasing healthspan, rather than lifespan.

        Most nutrients reportedly only increase lifespan by a few more years, anyway.

        I think Crispr will be the way to increase lifespan and healthspan.

        I am very interested in seeing the result of Josh’s reporting on people’s self-reported nutrient/medicine, regimens.

      • Gustavo
        I can certainly see and appreciate your point regarding safety, but I personally believe that it will take extreme measures to defeat, or even slow, the relentless aging monster and all of its dreaded consequences. Often those measures involve a fair amount of risk taking and out of the box thinking.
        In fact, my main concern with Josh’s study is that there aren’t enough people doing such extreme things to be able to identify them and their methods.

  14. Josh, All,
    I humbly suggest you strongly consider evaluating the impact of Glucosamine Sulfate. Based on the human epidemiology studies (FAR superior to testing of cells in-vitro, in-vivo or on flies, worms or rodents) it reduces total mortality better than anything else that I’m aware of; certainly better than any vitamins or minerals as demonstrated by the 2010 publication “Total mortality risk in relation to use of less-common dietary supplements” (also see the fantastic summary of Glucosamine on Professor Vince Giuliano’s blog; http://www.anti-agingfirewalls.com
    If proof of life-extension in rodents is valuable then consider the 2014 publication “D-glucosamine supplementation extends life span of nematodes and of ageing mice”.

    • Good call. I believe Glucosamine works by competing with glucose metabolism, so making mitochondria switch to burning fats. So like a ketogenic diet, almost. I believe Vince talks about this being hormetic, as this results in higher ROS (ETC is less efficient than when using glucose ), but a NRF2 response then leaves you better off than before. So the benefits might overlap with sulphoraphane and curcumin to some extent.

      It also probably wouldn’t be advisable to use it alongside berberine or metformin, which inhibit mitochondrial complex I, which then upregulates glycolysis (which glucosamine also inhibits). I never actually tried this, but I expect it would make you very tired.

    • Thanks Aslan,
      Ok. But I think just the other way around.:
      Shen looking for truth, animal SCIENTIFIC and well done experiments are enormously supetior to Epidemiology.
      Is Epidemiology really any science at all?

      I mean: HARD SCIENCE

      • Gustavo,
        Absolutely – I don’t disagree with you;
        I’m a structural engineer by day and simply have a strong personal interest in health & longevity (very strong interest in fitness, strength-training, etc. as well).
        My arguement about ‘epidemiology’ being superior to in-vitro cells or worm/fly/rodent results was more perhaps for us folks reading this to be aware of glucosamine for consideration to add to our own ‘regimen’ since it seems very safe; and perhaps it is less useful for this study,
        Best Regards,
        Aslan

  15. All,
    Just on a sidenote regarding (I presume) our shared desire for optimal health & maximum longevity, I would like to recommend you consider using a daily app to keep track of what you are eating & drinking (to monitor your micronutrient intake). I was pointed in this direction while on CR forums and Michael Rae helped consult on the ‘cronometer’ app.
    It is FREE and can give you a detailed summary of all of your macro & micronutrient intake; if a person uses this to ‘improve’ their diet to ensure at least RDA-level intakes of micronutrients, (as per Dr. Bruce Ames micronutrient triage theory of aging) I expect that this could have a significant beneficial impact on health/lifespan.
    Best Regards,
    Aslan (in Narnia)

    • I also use the cronometer app to track my macronutrients. Very useful tool. We may talk to Michael Ray about building a system whereby study members’ results from conometer could be uploaded to a study data cluster. At study’s end, machine learning algorithms could be loosed on the dietary data (which would be connected with the DNA Phenoage results) to find strong dietary correlations that might not show up in the diet-questionnaire-based statistical analysis.

      Similarly, there are many blood glucose apps out there that upload daily blood test measurements to the cloud. A system could be developed that could access these measurements via cloud APIs and add them to the data cluster, providing even more data for the machine learning algorithms to munch on.

      Last suggestion in this area would be to ensure that the DNA material gathered to do the DNA Phenoage testing be preserved for later sequencing. I believe that once results start to appear from this dataset, it will be of sufficient value/interest to entice some group to fund adding full DNA sequencing of the 5000 participants to the dataset. This would add yet another dimension of analysis and would give study participants a reward for their time and effort – their personal DNA sequence.

      Out of the 5000 participants I would think there would be a handful of us that are fairly cloud/machine-learning literate that could volunteer time and efforts in this area.

  16. I think a requirement for participation in this study should be consistency. Each participant should agree to maintain their current diet, exercise and supplement regime for the two year duration. Each must decide on their regime and stick to it. If circumstances force a change then the participant would need to report that and be eliminated from the study. Without this, it will be impossible to analyze the data or obtain real meaningful results.

    Thank you Josh for undertaking this monumental task! It is long overdue. I am glad you are taking the time to carefully set up this massive experiment to maximize the results and hopefully get it published in a peer reviewed journal. I also hope you have a top statistician on board with experience with this sort of thing.

  17. in my opinion to ingest herbs, fungi, etc. or to mix them, you have to take into account the dosage (directions for use) of the different medicines and herbs that are ingested and other factors more delicated..
    Effects do not have to be cumulative or neutral; in Traditional Chinese Metdicine – and the same is true in Ayurvedic and Siddha medicine – there are complex complementary and cross-modulating functions that include even weather, sex, ingestion disorders, etc. see http://www.shen-nong.com/eng/principles/holism.html
    On the other hand there are TCM formulas that have an immense regenerating power like Erzhiwan, I do it at home with herbs grown in my home https://link.springer.com/article/10.1007%2Fs11655-010-0565-2, http://www.americandragon.com/Herb%20Formulas%20copy/ErZhiWan.html

    Don’t forget to incorporate the humble Lippia citriodora that Induce Sirt1 Activity, https://www.hindawi.com/journals/omcl/2018/2731289/ or the powerful Reishi and Cordyceps.

    No one on the blog has ventured into Rasayana treatments? humm, https://www.nature.com/articles/s41598-017-09225-x

    Enjoy, with care
    Greetings.

    • Thanks for all these ideas, and for the information about TCM. Personally, I believe that TCM holds great promise for life extension, but that it is difficult to evaluate by Western methods, for the reasons you mention. Typically, an herbalist will prescribe different combinations for each patient, based on criteria that Western medicine doesn’t even measure.
      Can TCM Help You Live Longer

  18. Will you be relying solely on the methylation age, or is it worth trying to relate that to other “lifetime variables” that might inform an individual’s innate aging rate? There’s obviously FOXO (etc) genotype, but also other markers of aging, such as whether/what age your hair started/completed graying/balding.

    Also, will this be a US-only effort or worldwide?

  19. Just wish to congratulate Josh for taking up this monumental task and the many folks here: the little I am doing just pale in comparison.

    I just wonder if people blood tests can be taken into account maybe in a second phase of the study. E.g. aging.ai results might be checked to correlate with DNAm.

  20. I recommend use of entropy minimax pattern discovery in construction of the model, if feasible, as this would deliver to a user of this model the maximum possible information about the outcomes of the events of the future.

    • It’s not obvious to me how to use those methods, but I’m happy to learn from you if you refer me to a web page, or if you want to email me. In any case, raw data will be on the web, so it is probable someone will do a better job than I extracting information from the data.

  21. App that might work for the Aging study:

    Hi Josh,

    I agree that the recording of data by study participants would best be accomplished by a smart phone app that will make it convenient and allow the participants to record their supplement taking and other study compliance in real time.

    To this end I have such an app that runs on apple and android phones and also functions the same way on Mac’s and PC’, linux, anything that can run a standard browser. This software platform has been used by hospitals, schools, universities etc for many years.

    This app allows users to record the taking of supplements with a simple push of a button on the app. Once pushed the app’s server (hosted on the internet), records the data. At desired intervals these data files ( CSV ) file format can automatically transfer the information to you and your team for compilation and analysis.

    The App is very flexible and easy to use. So if a participant starts taking NAC and you allow NAC to be part of the study, the user will be able to drag the NAC button out of the dropbox at the bottom of the app to include NAC as one of their supplements to track.
    So when the user take a dose of NAC they will simply press the NAC button and the system will make a record of the action. The app then set a flag on the NAC button so the participant can tell that they already had taken the supplement within the last three hours for example.

    Additionally the system also has the ability to notify people by text message, email, even phone call if desired that they had missed recording their exercise, or had forgot to take their 81mg aspirin for the day.

    If this is of interest I am willing offer this platform at no cost minus perhaps the cost of keeping the server hosted by an internet server hosting site.

    The software is flexible and scaleable and customizable which would allow for the addition of more participants over time and support more than one kind of study or study population at the same time.

    Kevin Brown
    President MessageNet Systems Inc.

  22. I assume you just looking for a consistent individual delta between actual age and methylation age over the 2 year trial. If you are you looking to see the methylation age change over the 2 years there would need to be a significant washout period prior to starting for those already on their own protocol. I guess I answered my own question, but it may be worth explaining this aspect a bit. Thanks!

  23. Hi Josh,

    I would be very interested in participating in this project.

    Is there already an evaluation protocol in place where interested contributors can apply with their list of lifestyle interventions and the supplements they are taking, age, etc?

    Thanks,

    Stephan

  24. Hi Josh

    There is a global factor that dwarfs all the individual measures for prolonging life: economic prosperity.
    This period of economic prosperity makes possible to apply all those treatments you describe. But in the case of a deep crisis, one will be thankful to have what to eat (which the exception of the rich).

    Your treatments don’t actually extend “effective life” The time gained by those treatments is less than the time and energy needed for. those treatments and measures

  25. A couple of more comments.

    Suggestions for daily or weekly logging of supplements and activities are unrealistic. There will be too many people who will fall out of the study if the reporting is too burdensome. Also, suggestions that people are required to be completely consistent don’t work either. Our ideas of what is best for us can easily change over two years, aside from the things that c an change that we have no control over.

    Regarding Vitamin D, I have recently begun to suspect that some of the benefit attributed to it might be related to sunlight exposure and nitric oxide release from the skin since many studies showing Vitamin D benefit are measuring blood levels which could in many people serve as a proxy for sunlight exposure. So something about sunlight (working outdoors, hours of exposure, sun bathing habits, etc) might be useful to capture.

    I think the 5 hours of exercise equivalent is a little of the high side without better specification of the types of exercise. Three fairly short HIIT sessions a week might be equivalent to several hours of walking. And yoga and stretching exercises probably have different effects from cardio-related exercises. I think it might be better to omit an exercise requirement for entry into the study or make it a pretty low bar and then capture the amount and types of exercise as a variable.

  26. Thanks to everyone who is offering feedback on our proposed protocol. During the next month, we will be finalizing the questionnaire, inclusion criteria, and study design. If all goes well, we will be able to start signing people up around October.

  27. Hey everyone.

    Would add Turkey Tail mushrooms in the immune support category; perhaps stronger than reishi.

    Certain plant extracts have been studied that move the life extension needle. This study makes bold claims http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=7665, but didn’t list the extracts. So I did some googling and found them, which I report in this blog post https://www.garmaonhealth.com/6-anti-aging-plant-extracts/.

    No mention of NAD+, or did I miss it? Elysium Health conducted one of the few human trails to test a supplements effectiveness and found their Basis product (nicotinamide riboside (NR) and pterostilbene) to increase NAD+ https://www.elysiumhealth.com/basis-clinical-trial-results. I’ve been using it for about 2 years and even doubled my dose (https://www.garmaonhealth.com/i-increased-my-nad-levels/), but for reasons Josh mentioned in the Comments, hard to know what’s doing what when you’re taking a bunch of stuff, which I am.

    Hey Josh, almost finished with your book (good stuff) and I’ve now isolated myself in a remote sea-side town of Sweden on an Alpaca farm to make some headway on my own book: http://www.ageproof.me. You’ve been an important, much appreciated resource.

    -Joe

  28. Hi Josh:
    I have followed you for several years and compliment you on this exciting, innovative initiative. If I can help by joining I very enthusiastically volunteer.

    I emphasize that I am not an aggressive anti-aging practitioner. My efforts are:

    – A high level of gym based aerobic exercise 3-4 hours per week (ellipticals, stair climbers). Plus other recreational exercise. Hiking, bike riding. etc.

    – Supplements (Silymarin via milkweed extract, 10 mg Melatonin at bedtime, turmeric/curcumin, 5000 D3, 100 Ubiquinol, 81mg Aspirin, Omega-3, Folic Acid)

    Until 6 months ago I was intermittently fasting once per week but I was partially doing that for weight loss and I found weight watchers much more effective (like 40 pounds worth). If it helps to broaden your protocol base I would be happy to do it again.

    I also would be happy to add just about anything to my protocol that I have convenient access to. You name it if it helps with the study by providing sufficient participants for that metric.

    I am 73 years old however. I suppose that is another data point on the graph. Still working. Not a medical professional (masters in physics).

    I am curious as to what the fees will be for the periodic blood marker testing?

    Great work Josh.

  29. Josh,
    Congratulations on an exceptional site, and this new anti-ageing program.
    There’s a well-known joke about a tourist in Ireland who asks one of the locals for directions to Dublin. The Irishman replies: ‘Well sir, if I were you, I wouldn’t start from here’.

    I healthy American man ought to live to be more than 76-years old and less healthy man less than 76 years.

    I’m 60 years old (British man) and have a chronic, incurable illness from which the great majority die within eight years of diagnosis. Like the tourist in Ireland I’d prefer not to start from here but, of course, I have no choice.

    The life extension actions I take are twofold: I seek to prolong the healthy functioning of those bits of me that are ageing naturally, and I try to mitigate the deleterious effects of my illness. What’s good for the first action isn’t necessarily good for the second action. I will, no doubt, die before the average age of 76, but if I live beyond the eight years after diagnosis that will be a personal triumph.

    Many people have some debilitating medical issue, the result of genetic or environmental factors. And the percentage only increases with age. For them, like me, the average age of lifespan has no meaning. We are destined to be the under-achievers in the lifespan race. The ones who depart early to make the average possible.

    Nevertheless, our life extension actions may be among the most significant and have far reaching implications. Is an epigenetic biomarker capable of showing this?

      • Thanks, it would be interesting to find out the mechanism because since in this meta-analysis it is related to DM so
        it might be the reduction in Microalbuminuria that is causing the lower all-cause mortality?
        If it was a reduction in blood pressure then I think calcium channel blockers would be a better alternative?
        If it was for reasons other than blood pressure then I would take the ACEi low dose as long as I don’t get a dry cough

        As an aside:
        In the article under the Discussion section it says “According to this meta-analysis, ACEIs significantly reduced the risk of all-cause mortality by approximately 13% and CV deaths by approximately 17%. In contrast, ARB treatment did not significantly affect all-cause mortality and CV death.” but then later in the same paragraph “The results were similar when ACEIs and ARBs were compared with placebo or active treatment for all-cause mortality and CV death outcomes (P > .05 for interaction for all comparisons).”
        I’m confused about what it is trying to say..

        • Justin:

          Some people may be able get blood pressure under control measurably with natural substances. This may avoid drug side effects. If blood testing shows them to be effective.

          Some natural Angiotensin inhibitors are:

          French maritime bark extract
          Melatonin
          EPA/DHA
          Anthocyanins
          magesium
          Resveratrol
          Acetyl L carnitine

  30. Check out Dr. Sinclair talking about unpublished lifespan increase in mice from both NR and NMN. About 58 minutes in.

    • Thanks Bill
      Fascinating talk by David, though I wish he were a little more specific about the exact things that are extending the lifespan of mice in his lab, and also some idea of dosing would be helpful as well.
      It seems that he’s fairly sold on resveratrol,NR, and metformin.
      He’s also very hopeful for significant life extension advances in the not so distant future.

  31. Josh,

    Observational studies are worthwhile, but the range of interventions being evaluated will be limited. Are you are aware of anyone doing ex vivo cell culture studies using known or suspected geroprotectors and the epigenetic clock? This would seem like the most economical way to rapidly screen for drugs and drug combinations that could slow the epigenetic clock. It should be possible to try out hundreds or even thousands of potential interventions reasonably cheaply. Promising leads could then be followed up with through RCTs and/or animal studies.

    • Alex – it’s a neet idea, I agree, but I suspect that aging has a systemic basis (not just cellular), and it may turn out that what works in a petri dish fails in an animal. Just sayin’.

    • Horvath tried this and it didn’t really make sense – some forms of senescence stopped the clock, others didn’t – telomerase immortalised cells continued to advance the clock but we’re otherwise unimpeded. And these were cells in standard cultures. But how would you model human tissues? Much lower glucose and O2 levels? Held arrested to mimic post mitotic cells? You’d be there forever. Not to say there is no merit in in vitro tests, but you’d have to figure out a protocol that gives you what you need.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890984/

      I also suspect that Horvath’s clock is an average of methylation across different cells, so an abundance of stem cells would reverse it, somatic cells that have been around for a while would make the clock advance. So this would mean you’d have to modify any in vitro protocol to include a realistic amount of progentior cells and then itl becomes all about how you stimulate stem cell renewal Vs tissue differentiate and replenishment.

      Not simple, is it?

      • I’m wondering if it may be more feasible and just as enlightening to just do one spot check of DNAm but on more subjects. Instead of following say 10000 people over a two year period, where their regimens may be in frequent flux, what if you check 15000 subjects one time only and see who stands out and if any patterns emerge in their list of supplements.

    • Observational studies are definitely worthwhile in living people, as well as the cell cultures.

      For example: Life extension foundation did a review of the numerous supplements the Jack La Lanne took. He died at 96. He still functioned well albeit his skin was very photo-aged. Perhaps because he worked out outside a lot. He also appeared to be losing bone mass

      Life extension noted that he was missing the K complex. Perhaps that contributed to the loss of bone mass?

  32. I would have thought that a program which encompasses as diverse a background of subjects as possible in terms of age range is more likely to discriminate aging related factors.

    Do you have any idea what the age range is of those who would be likely to participate? Do you have so many to choose from that you can reduce diversity (all factor diversity) in the population to make it more likely that individual choices will stand out from the noise otherwise induced due to causes you wish to exclude (e.g., location??)? Will you be forced to make compromises over your ideal set of participants due to the number you end up with? How will you modify your strategy if you only have 1000 participants instead of the ideal number?

    I appreciate that you are likely to have already given consideration to these issues.

  33. Which methylation clock does myDNAge (epimorphy) use?
    The website says >500 loci so is that Hannum’s 71CpGs or Horvath’s 353CpGs or Levine’s 513CpGs? or another one altogether?
    Is it optimised for the chronological or phenotypic age?

    The website doesn’t provide much information

    • Zymo is the corporation that offers MyDNAge. They licensed Horvath’s original 2013 clock from UCLA, and then they modified it in ways that they haven’t documented in detail. The full methodology of the Horvath and Hannum and Levine clocks are publicly available in the literature, but the details of the Zymo clock are a trade secret.

      Zymo’s technology requires much less DNA than the Illumina technology on which the published clocks are based. Because the quantity of DNA is so small, there is often a lot of missing data, and their algorithm fills in the missing points by using other, nearby sites which are not missing.

      • Okay Zymo’s should have approximately the same correlations as the blue line in figure 1 of your technical manuscript? and do you know you know where I could find the supplementary data for the details on the construction of the radar plot?
        Do you know if there is any difference between the blood and the urine one? which is more reliable?

        Does that mean you will be using Zymo’s for your study or are you waiting for DNAm PhenoAge to be commercialised? I personally think the classic Horvath clock would be a more useful clock because biological age is important to know than a mortality-based measure clock which could be measured indirectly via blood test already (e.g. lipids, CRP, insulin).

        Because of your theory of aging it should be impossible to reverse the calculated epigenetic age, so will you be looking for an intervention where there is no or low increase in the estimated biological age? i.e. do you have a cut off e.g. <5 years (based on standard error) increase over X period of time or Are you looking for subjects who are below the y=x trend line and seeing what those people are doing?

  34. In the exercise category you do not mention Pilates and how the fascia affect health, lots of new research coming out on this. The basic idea is that since nerves and blood vessels , the lymph system, all are affected by how tight our fascia are and tight fascia inhibit both blood flow, lymphatic drainage, nerve impulses as well as the amount of energy and nutrition our muscle cells are able to absorb. And both flexibility and balance are very important in quality of life assessments. Another important factor that relates to inflammation is stress. Stretching definitely works on that. And there is a lot of theory about how trauma is retained in the fascia, see work of John Barnes; myofascial therapist

  35. Regarding the “broad but not too broad” section in your write-up …. Since you are not doing a controlled experiment, the only benefit to collecting data on fewer variables is reducing the survey response burden on the participants. Limiting the number of items to 12 of course does not mean the other items do not have influence in such a setup. All it means is the stasician is forced to act as if their influence is zero, rather than learn it. Limit data only based on burden to respondent. Don’t cripple your statistician, or as in my case econometrician. Econometrics is all about analysing data from non-RCT settings. We have the tools to do this, and limiting the data to lend “focus” in entirely counterproductive. Of course, that does not mean a kitchen sink approach should be used either in data gathering or analysis. But if there are reasonable prior grounds to believe an item might matter, don’t toss it out in advance. That doesn’t help the analyst. What might help lend credibility though is disclosing only half the data to the analyst at first for model selection, and once that is done and documented, model fit is done on rest. That’s not essential, but it can be a useful discipline. And of course all the data is still available.

    • Yes, Michael – I’m coming around to your view, and the latest draft of the questionnaire will have many more variables than 12. We will try as we recruit subjects to get some consistency as well as some diversity, so that the data analyst isn’t at a total loss when trying to figure out to what he can attribute a subgroup’s success.

      • I’m going to echo mward’s comment. It’s pretty incredible what the genome people have been able to tease-out using enormous numbers of variables and letting computers chew on the data. If you aren’t already familiar with Steve Hsu, his infoproc blog has reasonably accessible posts describing state of the art there and what’s being learned.

        Just as genes are lots of little vectors which produce a Gaussian effect, the health interventions we all are experimenting with are probably lots of little vectors likewise producing a Gaussian effect.

        The real difficulty is, as wmard indicated, practical methods for surveying the respondents. Maybe Kevin Brown’s sw can redefine what is feasible in that regard.

        For example, PD Mangan has written considerably on iron being a vector for aging. To my mind a very interesting question is whether the acute drop in iron from giving blood somehow has considerably more effect than mere chronic low ferritin from aspirin, tea, and similar-acting dietary chelators. Keeping those “interventions” separate among the survey data might reveal surprising distinctions in places we’d have never thought of in advance.

      • Michael is right. The genomic guys have made incredible finds of late dealing with millions of variables each of small effect and letting the computers chew on the data to tease-out the causalities.

        The limit on your variables should be the ability of survey respondents to accurately report their usage, which hopefully technology can help here too, such as the offer of Kevin Brown above.

  36. I’m new to this, so don’t know if this is the proper place to ask this question. The half life of sirolimus , for a man, is about 62 hours, for evirolimus about 30 hours. Does this mean that equivalent doses for sirolimus and evirolimus would be about 1/2 to 1?

    • I’m pretty sure that no one knows what the optimum dose of rapamycin is, and I’m pretty sure that it varies greatly from one individual to the next. Rapamycin has been studied extensively in genetically identical rodents, but hardly in diverse humans.

        • Very interested if anyone has had personal experience with Dr. Green. His website is quite compelling but I live in the Pacific NW and it is quite a schlep for an initial consult (I am 83).

          He said that the program should be manageable locally after about a year from the initial consult. I didn’t want to bother him about the need to travel to JFK in the interim as it may depend on many factors. If several of you can substantiate his bona fides it would be worth a try. I would very much any input.

          • I have been taking Rapa for almost 2 years. 6 mg once weekly with no side effects. Look out for mouth sores, and cut back if necessary. Every person is different. Sweet spot seems to be in the 4-6 mg range. I’m 72 yo. male. Women need less. Also take 1000 mg of Metformin daily along with 1 mg. Melatonin and NAD precussor,
            Nicotinamide plus Riboside powder 1000 mg. of each 2-3 times weekly. Have made multiple buys from dropshipmd.com in India for Sirolimus 1 mg. x 300. (Bicon brand) They have always made prompt shipments of quality product. Pay $1.65 mg + $8 shipping. (No Rx. needed) Have to wire money.

            After appointment, Dr. Green will write you a Rx for Rapamycin and Metformin, but Rapa will be bought from Canada which is about $3-4 mg. I saw Dr. Green, but I lived in Boston at the time. Up to you if you feel that you need the consult.

          • I am taking Sirolimus 5 mg once weekly for almost a year. Side effects are mouth sores and skin rashes. I am 73 years old. I am planning to add Metformin but I can’t get prescription from my doctor because I am not diabetic. I live in Canada. Can we exchange blood test results for comparison? My email is [email protected]. I welcome anyone who takes rapamycin to email to me blood test results.

          • Is there any other sites like dropshipmd.com? how did you find it?

            I’m trying to find niclosamide to use off-label as a cheaper mTORC1 inhibitor.
            https://www.ncbi.nlm.nih.gov/pubmed/22474287
            It is no longer available here in Australia presumable because it is no longer needed, but I assume India would still be needing it.
            (from my research Niclosamide is safe to take and as an antihelminthic it might clear your of any parasites as a bonus)

  37. Hi – this is a very cool idea. It would be great to see phenotypic age across these “combinations”.

    And at minimum you have a wonderful catalog here to test against. Can you use the “statistical power” against a group derived from your list of “combinations”? ( I immediately gravitated towards this ). Wondering if this is a reasonable approach to find outliers.

    A sample group might include the first item from each – like this:
    – aspirin (anti-inflammatory)
    – metformin (blood sugar control)
    – family (social factors)
    – NAC (mitochondrial supplement)
    – reishi
    – (etc.)

    The 2nd group would be from 2nd item in each combination :
    – ibuprofen
    – berberine
    – CoQ10
    – cistanche
    – (etc)

    Would it be reasonable to turn the questionnaire into a checklist? This is your combinations printed sheet from top to bottom. Respondents check items off the list they take _daily_. Unsure how you also ask for dosages; perhaps in ranges like this:

    ___ aspirin ( __ 100 – 300mg, __ 301 – 600mg, __ over 600mg)
    ___metformin ( __ 1 – 2g, __ 2-4g, __ over 4g)
    – (etc)

    But again will this meet your goal? …to find phenotypic age “outliers”?

    Looking forward to your progress.

  38. A small point regarding the possible redundancy of similar acting supplements is that listed together as Mitochondrial Supplements are NR and PQQ. It seems to me that these two are unlikely to be redundant, as I believe that NR (or any NAD+ precursor) enhances mitochondrial fission and mitophagy, while PQQ enhances mitochondrial fusion and biogenesis. Please correct me if my understanding is incomplete. Thanks!

  39. Great blog; thank you for all your exceptional research work!

    Reading your latest entry, I was wondering – regarding Glucosamine – if the ‘N-Acetyl’ form also offers life extending benefits? Additionally, does it matter if Glucosamine is derived from corn, or shellfish? Thanks!

  40. Hi Josh,
    Very impressed by your work. I’d like to be a participant but am not sure I will make your age cutoff. I’m 69. Just got my Teloyears tested and my cellular age is apparently 75 so I’m behind the eight ball. I’m retiring in three months so will have the time and money to mount an all out assault on my aging. I do want to live long enough to enjoy my retirement! I’m a little skeptical of the telomere results as I am exceptionally healthy. I have no chronic illnesses, take no medications, and am strong enough to have successfully recently climbed Mt. Kilimanjaro! Plus, everyone in my family lives into their 90s. I will implement your regimen, including donating blood and/or plasma, and see if it helps. If my age misses the inclusion criteria for your study, I would still be interested in how you will measure your dependent variable blood markers so I can at least do it for myself to monitor the effectiveness of my own interventions.

  41. For example what effects does adding leucine to the metformin in the am have on breaking a fast and recovery of muscle strength after prolonged fasting

    Or adding resevetrol to losartan and then adding rapamycin on rate of nail growth and grow back after cutting nails

  42. You should replace fish oil with algal oil. It’s more ethical and lapdoor reports less peroxidation with algal dha epa. It’s also where fish get it from.

    Aside from that excellent article

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