We Know Nothing about Longevity Drug Interactions

Years ago, I worked for an energy conservation priest whose motto was, “anything worth doing is worth doing poorly.”  We were training unemployed young people to install fuel-efficient furnaces in the homes of people who couldn’t afford heat.  My boss’s point was that the new furnaces were so much more efficient than the old that even if they were installed sloppily they would save enough fuel to turn a profit.  

If you focus on the big picture and get it right, the details don’t matter so much.

In tests with mice, a dozen or so different treatments have been found to lead to modest life extension.  The most urgent need at present is to begin studying how these treatments work in combination.  But there are too many combinations, and tests with mice are expensive.  That’s why it makes sense to do a quick-and-dirty job testing all combinations at once.

(This is a research proposal, the germ of an academic publication that I have been working on in recent months, and plan to submit to a journal and to the NIA next year.  I am experimenting with the idea of publishing it first as a blog.)


I take about a dozen different pills for longevity.  There is some evidence behind each of them, but what we really don’t know is how they interact.  It would be nice to think that their benefits simply add, so that if one pill produces a 10% average increase in life span, then 10 pills increase life span 100%.

Fat chance.

Some of them are ineffectual, of course.  But for the ones that offer a benefit, most of the benefits are probably redundant.  (When different treatments work via the same pathway, we can’t expect that two together work any better than either one of them separately.)  A few may mutually interfere.  But there also may be a few magic combinations that synergize positively.   If they work via pathways that are substantially independent, we might hope that the life extension from the two together might be equal or even greater than the sum of the benefits separately.

Most of the life extension drugs that we have target a single pathway: they work through the insulin metabolism.  The remainder work to suppress inflammation, or re-energize mitochondria, or lengthen telomeres, or reduce TOR signaling.

 

Tests in Mice and Rats

There are many ways to extend life span in worms and even in flies.  Some of these have also been tested in rodents, and they don’t pass muster.  I have argued that we should concentrate on mammals.  Even though they are much slower and more expensive, longevity studies in mammals are a far better guide to what might work in humans.  When a drug is found that extends life span in mice, there is a good chance it will also work for people (though percentage increase of our 80-year life spans is likely to be smaller than the corresponding percentage in the 2-year life span of a mouse).

Caloric restriction and exercise work consistently to increase average life span in mice.  Several genetic modifications are known to work, too.  The drug and supplement treatments for which there is best evidence include:

The many drugs that show promise but need further testing include

    • Deprenyl
    • ALK5 inhibitor
    • Epitalon/Epithalamin
    • MitoQ/SkQ
    • Beta Lapachone (Pao d’Arco)
    • Spermidine
    • Berberine
    • Dinh lang (Policias fruticosum)
    • Pterostilbene
    • Gynostemma pentaphyllum (jiao gulan)
    • N-Acetyl Cysteine (NAC)
    • Ashwagandha
    • Turmeric/curcumin
    • C60
    • Oxytocin (not oral)
    • J147
    • NR and NAD precursors

(Most of these were discussed briefly in a column I posted in September, and in other past columns.)

Almost no work has been done with combinations of longevity treatments.  In 2013, Steve Spindler’s lab published a study based on eight different commercial formulas of vitamins and supplements.  Their data were beautiful–and the survival curves for each of the eight fell exactly along the survival curve of the control group.  I have heard that the NIA’s Interventions Testing Program (ITP) has tested rapamycin in combination with metformin, with successful results (to be published next year).

In a rational world, some of the billions of dollars that go into “me too” drug development and chemotherapy trials by Big Pharma would be diverted to test all of the above compounds, alone and in combination.  But in the branch of the multiverse where you and I live, this will not happen in 2016.  Hence “quick and dirty” (= cheap) alternatives look attractive.

Proposal

The plan is to screen for combinations of drugs that offer dramatic life extension in mice, using the minimum number of mice to test the maximum number of combinations.  Standard practice is to use 30-80 mice for each test in order to get a clean survival curve.  The innovation I am offering is to use just a few mice for each combination of treatments so that more combinations can be tested, albeit less precisely.  How many mice do we really need to be reasonably sure of not missing an outstanding combination of treatments?

I have been modeling the situation with computer-generated data, testing different statistical methods to see which works best, and how many mice are needed in order to be reasonably certain of not missing a great combination.  My definition of a great combination is that it extends life span in excess of 50%.  The test I propose will not be capable of distinguishing “which is better” among the rank-and-file of many treatments and combinations.  However, there will be enough statistical power to identify the really hot performers, which are of most interest to us.

Specifically, I have modeled experiments based on 15 different treatments.  In the most practical and successful of the methods, I combine all different triples among 15 treatments (there are 455 of them, from a well-known statistics formula Combin(15,3)).  I’ve assigned 3 mice to each triplet of combinations for a total of 1365 mice.

I use statistics to tease apart the effects of different treatments and different combinations.  Analysis is based on multivariate regression, but since MVR works best with just 2 or 3 variables at a time, I have been experimenting with the details of an analysis program that looks at 1 to 3 variables at a time, then does a smart search for “nearby” criteria that might do a bit better.

 

The Model

I generate sample data for 1365 mice, based on each mouse having a randomly life span drawn from a bell-shaped curve.  The center of the bell-shaped curve depends on what treatments the mouse is getting.  (This is the “right answer” that the analysis is trying to find.)  The width of the bell-shaped curve is between 20 and 25% of the average, because this is the scatter that the better mouse laboratories find in their life span data.

To generate the means, I assume that each treatment offers some random amount of life extension, also drawn from a bell-shaped curve.  I assume that the treatments interact in pairs and that the interactions are mostly destructive, but some of the treatment pairs interact synergistically.

For example, if a mouse is receiving treatments A, B and C, then I assume its mean predicted life span is the sum of A and B and C separately plus the three interactions (A,B), (B,C) and (A,C).  (To simplify, I have assumed there is no separate term for a purely three-way interaction of (A,B,C).)   This is the mean life span for that one mouse, and that mouse is assigned a life span that is a random number centered on that mean.

Since we are most interested in combinations that yield large benefit, I have adjusted the parameters so there is always at least one triple combination that (on average) has benefit of >50% life span extension.

 

Preliminary results

      • About 40% of the time, I hit the nail on the head and identify the best triple and the best pair.
      • About 85% of the time, the best triple is among the top 3 generated by my analysis
      • About 95% of the time, the best triple is among the top 6 generated by my analysis

 

Tentative conclusion

I think this looks promising.  I am working with Edouard Debonneuil, who will check my calculations and contribute some of his own.  Edouard has more experience than I have both in the practical business of managing a lab experiment and in the practical business of finding funding and sponsors.

I believe that using about 1400 mice in an experiment lasting about 3 years, we should be able to evaluate all combinations of 15 separate life extension treatments, and narrow the field to 6 candidate triples that show offer life extension in excess of 50%, and thus show promise for further testing.

 

…and in the Real World

The program I have outlined could be undertaken for less than the cost of testing the 15 separate treatments using traditional methodology, and I think what we would learn from the combinations protocol could be a great deal more useful.  The total cost might be $1 to $3 million, depending mostly on where the work is done.

The biggest risk is that the high-benefit “magical” synergistic combinations that this program is designed to look for simply don’t exist.  If they do exist and can be found, the public health impact is likely to be enormous.

But in today’s economy, who will fund this work?

National Institute for Aging in Baltimore has the Interventions Testing Program (ITP), funded at $4.7 million.  Because they have high overhead and because they fund elite institutions with American salaries and because they repeat each experiment in triplicate, they can test only 1 to 2 compounds a year.  There is no activity from pharmaceutical companies, except for the few compounds that can be patented.  Some private foundations and crowd-funding groups have stepped forward to try to fill the void.  The Glenn Foundation has cut back.  The SENS Foundation is spread pretty thin.  I’ve recently connected with the Major Mouse Testing Program (MMTP) of the International Longevity Alliance.

39 thoughts on “We Know Nothing about Longevity Drug Interactions

  1. This is an intresting subject which I have not seen discussed before. I take C60, metformin, asprin, and about 30 supplements daily, although that may seem high, every one is raved about as adding something, beiong in my seventies I can not wait for years of studys, Am surprised that many things here are not mentioned such as PQQ, Glucosamine, Glycine, etc that are given much credence by experts such as Dr Sears.,

      • Google “Glycine supplementation could reverse aging” Gist of it is that Japanese scientists made old human cells behave the same as young ones. I have since made it one of my priorities. Just a thought but I am tacking supplements that never existed before such as Ateron, pomi-t, mito-q, PQQ, Niagen, etc, if the claims made for them are only partial, it does seem all to good to be true. I can only say for myself that I am surprised to find I have more energy and feeling of health than I had 20 years ago. Although I am aware that the body seems programmed to destroy itself with age and any of the disceases of age could strike anytime.

        • This reminds me of my 6 year old son. He is hardly eating any vegetables or eating fish (for healthy fatty acids). Eats lots of sugar and refined/inflammatory food. Yet, he is full of energy. Jumps around like a crazy. He doesn’t feel like taking a nap in the afternoon like I sometimes do. How come? Afterall, he is definetely not getting adequate amounts of micronutrients. What about his mitochondria? In theory they must be starving to death Yet, his mitochondria seem to produce more energy than ever. Clearly, the ever growing list of supplements doesn’t seem to be the answer to preservering vitality at old age (although it probably can’t hurt). The body knows how to restore old energy levels. It just needs the right signalling environment, right??

  2. Josh:
    In the model building phase I recommend a logically justified solution to the problem of generalizing from specific instances, the philosophical problem that is called “the problem of induction.” There is a tutorial on this problem and the solution that has been found for it at my Web site. Absent this solution one is prone to drawing less information from the observational data than is available in it or more.

  3. If it is of intrest, research has been done by “Live cell research” that carnosine increased production of the bodys stem cells by 43%, but when combined with blueberry extract it was 87%. You are on to something here.

  4. I would like to nominate you to coordinate this study yourself, Josh; and crowd funding it. What if you hire a few grad students or any biology students with experience caring for mice or maybe a university would donate space and or equipment? Maybe there’s a PhD candidate that would take this on as a thesis. How many followers of this blog do you have -1000? How much would it cost to get the equipment and supplies and get started? I bet your readers would be willing to donate at least $100/year to fund this study. How about an adopt-a-mouse program to raise money? With some university or even corporate donations, could $100K/ year for 3 years get it done?

    • Neil,

      I do believe that you are on to something. I for one would gladly give $100 for the year toward supporting Josh with this important study. Lets see who else agrees with us!

      • Neil and Magda –
        Thanks for your encouragement. I know what I’m good at and I’m a much better statistician than fundraiser. I would dearly love for someone else to take on the job of a funding campaign.
        Since this morning, I’ve been advised that a reasonable estimate of the cost is $700,000. That’s just for care and housing of the mice, assuming that the academic work is done by colleagues and myself without compensation.
        – Josh

    • What I can not make out with this research is for example the C60 experiment from years ago that came up with the most amaxing figures yet seen in longevity. research. Ever orginisation and private fortunes that are now put into longevity research would be duty bound to fall over each other to replicate what would be the biggest breackthrough yet made in anti-aging. There has since not been a peep from anyone. Does anyone have any idea as to what is going on?

  5. I spend thousands of dollars a year on supplements most of which may be wasted in the ways you describe.
    So I too would be happy to donate to this project; I also think you should look to crowdsourcing in general. The Longecity forum should also be approached, there are many members who would happily help fund the venture and Longecity itself could start a donation matching project (they do several a year).
    $700,000 to $3,000,000 is not really a great deal of money even if the number of donors is relatively small.
    If you set up a payment portal I will send money, but do it properly so the money doesn’t go to some Nigerian “prince” or Russian mobster.

    All the best for Christmas
    Mike

  6. Thanks to everyone who wrote with suggestions and offers to contribute. For now, I’m going to proceed on two fronts that are already established. I’ll submit the proposal to NIA-ITP in January, and I’ll continue to work with International Longevity Alliance to try to incorporate these ideas into the Major Mouse Testing Program, for which they have already begun fundraising.
    http://longevityalliance.org/
    http://longevityalliance.org/Act!/Groups/TabId/110/ArtMID/508/ArticleID/55/ILA-LP-Funding-a-major-mouse-testing-program.aspx

    • Yes I think there is a high chance we can incorporate some of these into the program Josh. I think there is a fair chance we will do some rat and mouse work too based on what people are saying.

      My two cents worth is I would like our second lab to run this kind of thing to scout out the lay of the land and then have the other two labs follow up with more robust work on any positive hits we get.

      As with anything we start small but as we grow we can become more ambitious with this work.

  7. Hi Josh,

    Great article. I’ve been wondering lately why we aren’t seeing a multi-faceted approach to mouse rejuvenation. It’s great to see you take this on. The three I’d like to see in conjunction would be:

    1. Crispr Telomarese induction/lengthen telomeres
    2. Crispr – Over expression of NAD+. I heard George Church mention that this can be easily done with Crispr, instead of supplementing with precursors
    3. Senolytic drugs for clearing senescent cells. Assuming telomere lengthening isn’t perfect

    I’m a total lay person so this may not make sense but I find these three interesting.

    PS: I’d gladly give some money if there’s a crowd funding project started.

  8. I would be interested to know the interactions of longevity drugs. I am taking so many at this point, I wonder if they can be harmful when taken together. I am 51 years old and have been into bio-hacking for some time, but now looking more into longevity. I am in great shape, muscular (like a fitness model level) with about 8.9% body fat. I have adopted an approach where I deal with this in stages. For example, every six months I spend 2 weeks performing a detox regimen where I use supplements and chelators (STS, MSM, Magnesium Oxide, Cilantro, EDTA, Senna, etc.) to remove accrued toxins and heavy metals (lead, mercury, flouride, etc.) and finish that period with probiotics (orally and through enemas). I use Niagen, pterostilbene, resveratrol, R-lipoic acid, GliSODin, acetyl-L-carnitine, L-carnosine, etc. for mitochondrial health. I tend to use that through all periods. I am planning to try the C60oo in the future. For telomere lengthening, every 90 days I do a 10 day session of 10mg/day Epitalon. I also use 20mg/day Astragaloside IV and 5mg/day Cycloastragenol (relatively cheaply available from research chem sites). The R-lipoic acid I take is also shown to be a telomere lengthener. Additionally, I like to have some of my hormone levels mimic levels of a much younger man so I do my own Testosterone Replacement Therapy (250mg/week Test Enanthate along with 25mg/daily Aromasin as an Aromatase Inhibitor) and cycle between HGH secretagogue peptides and exogenous HGH. The next HGH period I will include the DHEA similar to the protocol to regrow the thymus. To prevent a fatty liver from the TRT, every 3 months I do a 30 day regimen of 1500mg/twice daily of choline/inositol. What I have described so far does not include the various nootropics that I experiment with (several people in my family have died at a young age due to Alzheimer’s – I hope to forestall that in my case).

  9. Hi Josh, I wonder if this ( scientific ) experiment will provide any real ‘outcomes’ in the next couple of years..And so be of benefit to folks ….
    Teasing out all the impacts of multiple supplements by different human individuals with varying diets, lifestyles and DNA’s over the long term is near impossible…

    I wonder if we could benefit more from asking for anecdotal reports of lots of actual people taking anti-aging supplements along with info about diet, lifestyle etc.. and data basing all that info…

    • It’s a good idea because the database is large. Someone would have to collect reports and put the results in some standardized form so that a statistical analysis could be done. If you’re up for collecting and formatting the data, I’ll do the statistics.

      • Hi Josh
        As my own life is in the midst of considerable flux ( due to a new relationship & probable shift in home to the Philippines) I am unfortunately not in a position to offer to do collect & format such data. Sorry.

        I am also following the comments on this post about Iron and it’s relationship to increased longevity in calorie restriction. In three years of reading the research on longevity I have never read this before.Interesting !! I wonder if any one knows of published research on this.

        • If you google the “longevinex” site their is a four page article which proposes that iron chelation supercedes all other theories of aging and the reasons why.

      • I think the only way to nail down these interactions is to do a well controlled double blind study (or sequential smaller studies) on short lived mammals = mice. My biggest confusions on longevity supplement actions are:
        1) Curcumin, ECGC, Resveratrol, Pterostilbene, Quercetin and other common life extension supplements have been shown in many studies to suppress telomerase. Many of these studies are regarding cancer cells, but does it make you wonder if they are counter-productive to longevity?
        2) Most of the proven maximal life extenders like caloric restriction, protein restriction, metformin and rapamycin all reduce cellular and mitochondrial activity. Why then are many of us taking things that increase activity, like COQ10 and NAD+ precursors like Nicotinamide Riboside, since they haven’t yet shown to increase mammalian lifespan and have the opposite effect as the proven one’s. Am I missing something? The complexity of cellular functions is such that it seems impossible to understand it. So I believe the best way, is to cut straight to the results by careful testing.

  10. I have tacken daily the supplement “longevinex” (resveratrol) since its inception. I wondered if as many people who have done the same could be found, if there could be any health outcomes to be shown against non users. I realise it would not be bona-fide evidence, but it could be evidence of what mat be happening in the lives of real people. One example of my own experience is the surprise at having the desire to want to run everywhere rather than walk, being in my seventies. This energy coincided with tacking PQQ. Where as with tacking Niagen, I have never felt any reaction. I continue tacking Niagen on the hope that what is claimed for it. In short, I would find it helpfull if what was happening in the lives of real peoples experiences could show up real differences in health outcomes.

    • ray
      As people like yourself are participating in a large sample experiment and at their own expense it is worth thinking about substituting this experiment for a more costly one in a sample of mice. A barrier to thinking about this possibility is a philosophically unwarranted bias among biomedical researchers and regulators under which anything other than a placebo-controlled trial is unscientific.

  11. As far as I can tell, calorie restriction hits most of the pathways that these drugs/treatments listed do also.

    And as far as I know, virtually all calorie restriction experiments in mice have been done with highly iron-fortified food. It’s also known that CR animals end up with far lower iron levels than controls.

    Therefore, the longevity experiments with mice should be sure to use feed that supplies only the minimum requirement for iron for mice (about 35 mg/kg food).

    An iron chelator should be tested for longevity. Iron depletion extends C. elegans lifespan and iron supplementation decreases it.

    • Thanks, Dennis – this raises an issue I hadn’t been aware of. Are you saying that part of the life extension benefit of CR in mouse experiments comes simply from the fact that they are not overdosing on Fe?

      • I think that could very well be the case. At least, it seems a huge confounder to me. CR seems to decrease iron absorption on its own, but the fact that CR animals end up with less iron and are also eating less iron is quite the coincidence.

        Another reason I say this is because so much attention has been given to growth hormone, which when given exogenously, strongly down-regulates hepcidin, the main iron-controlling hormone. Fasting up-regulates it. So here’s another iron connection.

        Since iron is a highly reactive metal and can cause damage if not locked down in ferritin and hemoglobin, its accumulation with age, simultaneously with increased rates of oxidative stress, looks very suspicious to me, much more so than growth hormone which declines with age.

  12. This is true as well. We don’t know much about how the drugs work together, if they are helpful together or quite harmful.

    On the note of glycine, it has been suggested (I will need to look for a link later on) that although it is not an essential amino acid, that we may not make enough for our needs. In the paleo world, I have read recommendations before that people eat foods higher in glycine. They usually recommended bone broth, gelatin (ideally from grass fed animals), or perhaps organ meats (paleo is big on head to tail, versus eating just the lean meat portions).

    I do have one more topic – I’ve been thinking about what you said about iron. It may be worth exploring the idea of taking something to reduce iron, particularly for males as we don’t lose iron through menstruation. Deferoxamine comes to mind as what might be worth exploring.

    I wasn’t able to find much about this – just this paper:
    http://www.febsletters.org/article/S0014-5793%2803%2900894-9/pdf

  13. Thanks for all of the information in this blog. I have spent many hours reading it and the posts. A couple of items that I have read recently may be of interest to you- although you may also be aware of them- and have raised my interest. Firstly, you suggest Metformin as a possible life extender. Recent research suggests that it adversely affects the gut biota. This seems a serious shortcoming as I had considered taking it even though I have no sign of diabetes. http://www.nature.com/nature/journal/v528/n7581/full/nature15766.html

    Another supplement that seems to be showing promise is Xanthohumol
    eg http://www.sciencedirect.com/science/article/pii/S0003986116300601

    https://www.sciencedaily.com/releases/2005/11/051125105426.htm

    Do you have any views on this supplement as I am thinking of ordering it?

    Again, thanks for all your work on this important topic.

    • I have been taking high dose melatonin for over 2 years..No effect on gut bacteria at all.
      PS your link/source is not readily available.. have to subscribe.. garbage !

    • Sue –
      The way I read this article, it’s not necessarily a recommendation against metformin. What it says is that some of the benefits and some of the side-effects of metformin seem to be mediated through changes in the gut biota. Knowing this, we might be able to use probiotics to enhance the benefits and mitigate the side-effects.
      – Josh

  14. Josh, I greatly admire all you do in health-span extension analysis, & proposals. I’m
    not nearly as qualified academically as you, but I have had a life long interest in prolonging health, vitality, of both mind & body. As I approached my 75 birthday, over a 10 month period of on line bio-science reading, I came up with a plan, and have put it into effect for myself, and 3 other friends. We are either long term metformin
    users within the VA medical umbrella, or more recently,older people who knew us, & wanted to join our research efforts as they could see the progress we seemed to be making. All of our progress is reflected in actual VA formal lab testing, or in
    more personal way such as greatly increased ability to work out more or walk very fast, or climb several flights of stairs with little stress or discomfort.. ‘All suggesting
    real improving our health. We have urged them to also take at least a small dosage of the metformin, with the idea of warding off developing pre-diabetes. I’ll
    site my results. Weight loss 46 lbs. a1C going down from almost 8 to just over 5
    in only 5.5 months. I have kept the weigh off for another 6 months. I do 600 10 lb.
    arm curls daily. Never worked out prior to this. 20 year ago I weighed much more,
    (247 lbs.) I’m 6’1.5″. I take metformin 24 hour release type, with NO gastric problems, also Ptero-pure version of pterostilbene 100 mg daily, Niagen NAD+
    precursor 100mg, Optimized resveratrol, with ptero-pure, & quercetin in the cap.
    Also Optimized Quercetin (500 mg), Omega 7 oil, also Krill oil with astaxanthin,
    CoQ10, and conventional vitamins. I each about 2000 calories daily after the weight loss was accomplished. The quercetin is both a fine anti-flamation source,
    but has been found to provide some protection against pancreas cancer. As a VA
    patient I also take blood thinner for AF, and other standard rate & bp meds. Tomorrow I will be meeting for the first time with an endo specialist with the VA
    to see if they would consider doing the kind of many sided combo tests of metformin with the none prescription meds my little group is testing. These are
    not regular placebo, double blind tests, but pre testing with former fighting men
    who want to see better results in the war against disease related to aging. There
    are millions of us in the VA program, & hopefully a few thousand would choose to
    commit to helping with the tests. Vets are human, but also gutsy enough to speed
    up the process, by taking a slight risk to help other VETS and the general population. We need to get they non-prescribed substances on a tax rebate list,
    which costs low income VETS an arm and a leg or two to fund personally. Not fair
    to stick only to shop worn therapies and out dated drugs & surgeries. What say you
    Josh?

    • A month ago when I posted an over-view of my small scale informal
      “testing” of extended release metformin, along with certain non-Rx,
      dietary sups. such Ptero-pure, (U.S. government developed & human tested, & patented by the USDA) This is the pure synthetic version of pTerostilbene. It is chemically very similar to resveratrol , but has a 4 times longer bio-availability. My little group is also testing, Niagen, the precursor to NAD+, & quercetin, a powerful natural product from apples, that has been found by Mayo Clinic, working along with Scripps Inst. of Medical Research in Jupiter FL.
      It has been characterized by Mayo & Scripps, as a senoletic agent.
      That is to say, that it helps the aging body to carry on apoptosis, or
      the cullin-out of senolescent cells, especially in the endo-lining of
      mammalian arteries. This can be very important, if it can be proved in humans. I want to clarify, we take metformin because the VA
      urges us to do so. We don’t want anybody to take this unless their
      primary care doctor agrees, but there is a good deal of convincing
      evidence, that metformin is probably useful in extending “health-span”. A wide range of diseases of aging are going to be studied in the proposed TAME studies. With 3000 people, not diabetic, who will
      be taking metformin. Hopefully, significant results will serface in tests of mammalian cancers, cardio-vascular disease, as well as
      a possibility related to dementia or even Alh… LETS WISH THE EFFORT SOME POSSITIVE FINDINGS. Thanks Josh…You are
      the man, in my opinion.

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