New Database of Lifespan Trials

Human Ageing Genomic Resources announced last week their on-line database of animal studies that evaluated drugs and supplements for extended lifespan.  HAGR is a project of the University of Liverpool, spearheaded by João Pedro de Magalhaes, who has been an activist-scientist in aging research since his days as a grad student at Harvard.

The database is a great resource for researchers, and helps assure that we have no excuse for overlooking a substance or a perspective or a particular result.  Maintaining and updating it will continue to be an important and demanding project.

The full database covers 1316 studies, and I will review here just those on mice and rats.  My reason is that life extension in simpler animals turns out to be too easy.  There is much we can learn about universal biochemistry from studies in worms and flies, but most of the successes there fail when the (longer and costlier) studies are done in mammals.

Here is a spreadsheet extracting just the 93 studies on mice and rats.  You can view it online, and if you download it or copy it into your own GoogleDrive account, you can sort and edit and re-arrange it at will.

 

Old News

Rapamycin: Has the most studies and the best data.  Clearly works, but has side effects and it is not yet clear if it is appropriate for general use.  Make your own decision.  [read more]

Metformin: We have extensive experience with humans, and clear indications that it lowers cancer rates and ACM*, but there are dangers and side-effects. [read more]

Melatonin: Good evidence for modest life extension in rodents. For some people, it’s also a good night’s sleep; for others it can lead to grogginess or depression.

Aspirin:  The best evidence for lower cancer and ACM* is in humans.  Most people can tolerate a daily mini-aspirin without stomach complications.  

Epithalamin (and other short peptides):  This is work by Anisimov in St Petersburg, and it is so promising that I can’t understand why it isn’t being replicated all over the world. [read more]

Deprenyl:  Old studies, but they show consistent, if modest life extension.  It affects CNS in ways that you might feel, might like or might not.  [read more]

Vitamin E:  This is just one study, dosage equivalent to hundreds of pills a day, mice kept in shivering cold conditions.  [ref]  In a large human study, antioxidant vitamins increased mortality. [ref]

Acarbose: A diabetes drug that blocks the digestion of carbohydrates.  Side effects and toxicity make it less promising than metformin as a general recommendation.  [drug info]

C60 Fullerene:  Just one study in 6 rats, with spectacular results.  Replication has failed [private communication from Anton Kulaga].  Nevertheless, there are thousands of people experimenting on themselves. [read more]

Curcumin: There are major questions about absorption and dosage, but no question that anti-inflammatories are a good general strategy, and curcumin is a good anti-inflammatory. [read more]

Green tea:  Small but consistent life extension from polyphenols extracted from tea.  From a number of high-profile experimentalists, 2013.

Resveratrol: Works great in simpler animals, including some vertebrates, but in mammals life extension has been limited to overweight mice on a high-fat diet. [read more]

 

The New Part

BHT:  This is an anti-oxidant and chelating agent, which means that it is attracted to metal ions, it pulls them out of circulation and takes them out of commission.  This sounds good when it’s removing mercury or lead, but less good when it’s removing iron and dangerous if it’s removing zinc or other essential trace minerals.  BHT has long been used as a food packaging additive to preserve freshness, and it is still avoided by natural foods types. This Russian study [2003] found 17% life extension in mice. 

Creatine:  Used by body-builders, it encourages muscle growth by blocking myostatin.  It also increases nerve growth, and slows shrinking of the brain.  In one promising mouse study [2008], average lifespan increased 9%.

Icariin: This is an active ingredient in the traditional Chinese herb which in the West is known as Horny Goat Weed.  One mouse study, 6% increase in lifespan.

VI-28: Another Chinese herb.  Just one study, up to 14% increase.

Royal Jelly:  Queen bees are genetically identical to worker bees, yet they live 100 times longer.  Is it the royal jelly they are fed?  One mouse study [2003] showed a 25% increase in mean lifespan, but no increase in max lifespan.

N-Acetyl Cysteine:  Glutathione is an antioxidant associated with mitochondria.  Unquestionably, glutathione is a good thing.  Too bad we can’t just eat it.  The next best thing is to take the precursor, NAC, which seems to lead to increased glutathione throughout the body. This one study [2010] came out of the same prestigious group at Jackson Labs that brought us rapamycin.  Mean lifespan increased a stunning 25%. Two reservations: (1) they used enormous dosages, and (2) the mice on high-dose NAC ate less, so they probably benefited from caloric restriction.

Ginkgo biloba: Extract from the stinky fruit of an ancient oriental tree.  Traditionally used as a neuroprotective and concentration enhancer, for which it is mildly effective.  In 1998, a single study found 17% life extension in rats.  Who knew?

 

The Bottom Line

Clearly there is a great deal of promise here, but there is also much work to be done before we have it sorted out.

  • Many treatments have shown promising results in just one study, and that needs confirmation.  My top priorities would be epithalamin, NAC, and royal jelly.
  • Other treatments inspire enough confidence that we should be optimizing dosage for human use.
  • As I have written, the most important work before us now is to see how these different treatments combine.  Most combinations won’t work together, but when we find the few that synergize we will have a candidate protocol for major life extension in humans.

If you’re curious, of the substances reviewed here, I personally take metformin, aspirin, creatine and NAC.  I season with turmeric a few times a week.  I have dabbled with deprenyl and rapamycin.

———————

* All-Cause Mortality

 

54 thoughts on “New Database of Lifespan Trials

  1. Update, About 2 weeks will open medical office to provide rapamycin based therapy for age-related disease (metabolic syndrome, obesity, hypertension. 14 months on weekly rapamycin with no side-effects has convinced me, Blagosklonny correct, weekly rapamycin is safer than aspirin (325 mg daily). Website going on line when open office: rapamycintherapy.com

    • While I do believe in self experimentation, I wonder very much if extrapolating expected results from short living rodent studies to longer living animals is a given. In Metformin’s case, we can find diabetics who routinely live longer than a normal lifespan even with diabetes, which would seem to indicate that Metformin potentially is doing something positive in respect to aging. However, in rapamycin’s case, do we even know of one transplant recipient taking rapamycin that has even close to a normal lifespan expectation? How about any human who is taking rapmycin?

      Have you noticed any beneficial changes and/or bloodwork taking it?

      • I think the prolongation of life “after angiotensin II inhibitors” a nd metformin is comparable with rapeseed oil and fishoil.
        I had to stop taking metformin because of diarrhea. I prefer products that prolong the life of 100% or more and no side effects. More interesting would be something more efficient. Even if you take by 200% life-prolonging medicine, then in 10 years you get older by four years.

  2. Angiotensin II inhibitors used by millions for treatment of hypertension dramatically increase lifespan of normotensive rats and doubles the lifespan of hypertensive rats and genetic knock-out of Ang 1 receptor increased lifespan mice 26%. So common prescription drug ACEI Enalapril and ARB Losartan are very powerful lifespan extension drugs unrelated to effect on hypertension. Apparently HAGR study mostly interested in food supplements. As regards metformin, when combined with rapamycin almost doubled lifespan extension compared to rapamycin alone in 1 of two strains in NIA study. So as regards prescription drugs rapamycin, angiotensin I inhibitors and metformin are top drugs for lifespan extension. Three excellent ant-aging drugs,

  3. Creatine also has some credibility as a nootropic:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1691485/pdf/14561278.pdf
    http://jtoomim.org/files/Ling_2009-Cognitive_effects_of_creatine_ethyl_ester_supplementation.pdf

    The mechanism is possibly the same as for muscle cells: when ATP starts being depleted, ADP recycled to ATP by grabbing a phosphate group from creatine monophosphate. Given what we know about anaerobic metabolism in tumors (which is very damaging to cellular machinery..), maybe creatine cuts down on this in cells that are borderline cancerous / senescent, but still barely functional, which has to be a common state in aged creatures.

  4. @Josh, all,
    Regarding taking NAC as a supplement – are you aware of a study that suggests NAC might not be as safe as was once thought to be. The study, widely reported in the press, reports “Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia.” The effect is imputed to result from NAC falsely signalling that an oxygen shortage exists in the body. According to Dr. Ben Gaston, pediatrician and researcher who led the study. “We found that an NAC product formed by red blood cells, known as a nitrosothiol, bypasses the normal regulation of oxygen sensing. It tells the arteries in the lung to ‘remodel’; they become narrow, increasing the blood pressure in the lungs and causing the right side of the heart to swell.” It is unknown whether this effect also applies to humans at customary dosage levels.
    https://www.ncbi.nlm.nih.gov/pubmed/17786245?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

    I look forward to seeing if you are concerned at taking NAC at ‘normal’ doses (I assume at 600m per day or less),

    SIncerely,
    Aslan

    • I saw this study too and was worried about it. However, scaling the NAC dosage to humans yields 20g (20,000mg) a day, and other studies on NAC seem to suggest that, if anything, its effects would reduce the chance of PAH in humans. Good summary here:

      http://www.lifeextension.com/magazine/2010/5/n-acetyl-cysteine/page-01

      Note of course that Life Extension sells supplements. But they are very good about providing references for their claims.

      • Thank you Charles for setting us straight on NAC. I looked at the links provided above and was puzzled. The Life Extension article about NAC is excellent

        • This is a study on “spontaneously hypertensive stroke prone rats (SHRSP)”. When we have a model disease / model organism like this, frequently there are treatments that work for the model disease but don’t work in humans for the real pathology, and the same can be said for negative effects of attempted interventions like NAC; they are even less likely to apply to humans than effects observed on normal rats / mice.

          Other things that make me less worried about this study:

          1. the authors say the change was “significant” but don’t list the magnitude. Frequently this is because the magnitude wasn’t exciting, but was barely statistically significant (so they can publish!). So we may be looking at something like a 5% plaque increase that would wash out if they’d used more rats. If someone can get behind the paywall, we could find out.

          2. plaque only accumulated in the cortex, and specifically did not appear in other regions like the hippocampus. This is different from human dementia / Alzheimer’s, again suggesting a different pathology and/or that the results for the cortex were very minor

          3. amyloid plaques are a necessary but not sufficient condition for Alzheimer’s, dementia, etc. There are a lot of people walking around with plaque and no symptoms. Unless you have a family history of early-onset dementia *and* secondary hypertension, NAC’s other benefits may well outweigh a little extra plaque even *if* it does slightly promote plaque (a big if).

          • I agree, you have to be cautious in interpreting this study as a model for human NAC supplementation.

            However, caution in the other direction is warranted as well. Increasing the permeability of the BBB is never a good thing, and any increase in Aβ plaques are certainly troubling.

            Do these results map to humans? Who knows unfortunately.

            I’ve personally started to look at GliSODin a little more carefully. Maybe I can get the benefit of increased glutathione (and SOD and catalase) without these potential issues. Not taking either at the moment though.

  5. Josh,

    You mention acarbose toxicity, yet I was unable to find discussion of toxicity on the link you posted, PubMed, or other sources. Can you please elaborate on why acarbose is toxic, and where I can read more on the subject?

    Thanks.
    Matt

  6. Josh, I just spent some time looking at the HAGR database, I do not wish to rain on some one’s work, however when I did some searching for supplements or drugs which are commonly used by folks seeking life extension, I got bizare results.
    The following generated more than one result : arginine, glycine, pregnenolone, vitamin E & folate.

    However all the following ( which I know about and on occasion use ) generated either zero results or just one result : Magnesium, fish oil, citrulline, Vitamin D3, Vitamin K2, Ubinquinol, DHEA, Niacin, Alpha lipoic acid, Acetyl carnitine, & Berberine…

    What’s going on here ? Is it still in it’s infancy as a comprehensive date base ? Or does it simply reflect what has been researched by folks at at the University of Liverpool ?

    Very puzzling.

    • Bill –
      This is a list of animal studies. I don’t know how complete it is. If you know of animal studies for any of the supplements you mention (Mg, fish oil…berberine), then I’ll pass them on to Joao Pedro and Diogo, or you can write to them yourself, through the HAGR website.
      – Josh

  7. I have taken Acarbose but have discontinued due to the severe gas that it causes. It delays break down of sugars until the food hits the intestines where bacteria ferment it. It works by reducing insulin and blood sugar spikes and feeding good bacteria in the bowels which increase FGF21 and Klotho. But the gas! As for NAC. It has been shown that ROS are important for signalling genetic repair and autophagy. NAC prevents some of the benefits of exercise, fasting and hormetics. I think the body needs cycles of feast and famine. During feast, take NAC and antioxidants, during famine cycle, fast and exercise and take hormetics and avoid NAC and antioxidants. I cycle through this twice per week (5:2 fasting).

  8. Just looking for some ideas and this seems like a good place to ask, for people with Multiple Lipomas, would there be any protocols or supplements that anyone can recommend?

  9. Also missing, Spermidine (ref Cardioprotection and lifespan extension by natural polyamine spermidine, Eisenberg, 2016). 3 pathways to extend lifespan are inhibition mTOR, the inhibition of angiotensin I system (a 500 million year old system) which preserves mitochondria, inhibits ROS and involved in superoxide and nitric oxide signaling and third pathway, promotion autophagy. Spermidine of great importance as promotes autophagy by pathway outside mTOR. In 2012 paper, Wang, Autophagy activators rescue and alleviate pathogenesis in mouse model with proteinopathies of the TAR DNA-binding protein TDP-43). They are talking about rapamycin and spermidine ameliorating symptoms and pathology in mouse model of fronto-temporal lobar degeneration (2nd most common cause of dementia under 60. A treatment for FTLD would of been of great interest if done by brand name drug or new super drug; but spermidine found in foods like wheatgerm and rapamycin is generic; so nobody interested. In study spermidine as effective of rapamycin in promoting autophagy.
    ASG

    • What are some ways of getting spermidine? I just spent several minutes searching and haven’t found it other than through tightly controlled suppliers like Sigma Aldrich et al.

          • Seriously, why can’t we purchase spermidine commercially as a supplement (aside from a name that might be off putting to some)?

            It is a natural substance found in foods. Why can’t I go to Amazon and order it?

      • Hi DdR,
        No opinion about L-Depreynl. I just stick two two classes of substances; things can write prescription for and fill prescription at local drug store and things that are real foods and buy in supermarket. So maybe I’m just real old-fashioned and I take rapamycin once a week.

        • Alan,

          I assumed (not sure why) you took 1mg of Rapamycin six days a week.In reality you take 6mg at one time, once a week? Why do you prefer this over taking 1mg six days a week? Thanks.

          • Hi Jason,
            mTOR physiologically is supposed to go up and down. If you take rapamycin daily you keep mTOR at constant low level. This is needed if you want to have somebody stick a foreign kidney in you; but associated with many side-effects. If take once a week, this is like intermittent extreme fasting as regards effect on mTOR and prevents side-effects. To slow down disease-of-aging want mTOR mostly at low physiologic levels consistent with not eating a lot of meals; like maybe you make a big kill once a week and gorge yourself (no refrigerators) and then went hungry to next big kill a week later. To keep mTOR happy need to let it go up to high physiologic levels once a week; otherwise will bite you. Transplant patients can’t do this as soon as mTOR up to high level; acute rejection, no more kidney.

          • Alan,

            Many thanks for explaining that. Do you “feel” anything positive or negative the day you take the 6mg or is it undetectable?

          • Hi Jason,
            Basically feel nothing. If sensitive have slight speedy effect life caffeine. Long-term, subtle increase in mood. As regards lab results; will post 14 months lab results on web site.

        • Umm, l-deprenyl is prescription-based. Called selegiline as well. It’s considered the first-treatment option for Parkinson’s and secondary treatment for depression. Plenty of animal studies backing up greater life expectancy. Josh wrote an article on it a few years back.

  10. Josh,

    I personally think there needs to be a differentiation between health span and life span. While we assume that they are the same, experience, at least in humans, seems to indicate otherwise. Meaning, what good is a longer life span if you feel old while doing it?

    HGH is a great example of this. Its effects are nothing short of stunning, and will make you feel 10 to 20 years younger. Weight control becomes effortless again and exercise ability all go back to what it was when you were in your mid-twenties / early thirties. Immune function is dramatically improved. Cholesterol profiles improve. I could go on and on. Testosterone (TRT) is another one that also has impressive results on insulin levels in addition to synergistic effects to HGH.

    If the supplements above in these clinical trials actually increased lifespan, one would logically think that they would have similar results (at least over the long term as the rodent ages), yet I have not personally seen any supplement that has this effect. In fact, Metformin crushed my testosterone levels (hurting my fitness levels) and even with B12 and calcium put me in a mental fog.

    Thoughts?

    • Of course. Where there are tradeoffs between quality and length of life, our personal choices are going to differ. Even more important, the tradeoffs themselves will differ, as different bodies respond to the same treatments in different ways.

  11. Hi Thomas,
    I’m 74 so I’m into prevention of age-related disease. I had age-related disease and it really sucked. Now I don’t have age-related disease and feel excellent. You should read “TOR-driven aging: Speeding car without brakes”. (Blagosklonny). He talks about car driven 80 mph. Slow car down to 20 mph, slow aging and age related disease. Everything you mentioned are designed to keep car going 80 mph. Depending on your age, makes a big difference if want to drive 80 mph or 20 mph. When young, just want to feel younger; when old just happy to stop aging.

    • Dr. Green,
      A few questions please,
      Are you still taking 6 mg of rapa per week, and 500 mg Metformin daily or have you increased your dosage after 1 year without side effects?
      I’m 70 years old.

      Thanks

    • Hi Alan,
      So is the main benefit from your regime weight loss (leading to improvements in health at any age), or can you actually point to an improvement in some other age related metric?

      Thanks in advance,
      Mark

  12. @ Josh, all, Regarding Vitamin E
    Gentlemen, reports of vitamin E that cause prostate cancer, as a recent (unnamed) study published in JAMA (The Journal of the American Medical Association) suggested OR cause an increase in all-cause mortality as far as I have seen typically have only used 400 IU/ day of all rac-alpha-tocopherol acetate instead of a complete vitamin E supplement, with mixed tocopherols and tocotrienols, which better emulates the vitamin E found in fruits and vegetables.
    A “complete” vitamin E supplement preparation of mixed tocopherols can help to reduce atherosclerotic plaque.
    Here is a good summary regarding complete vitamin E (all 4 tocopherols and 4 tocotrienols from LifeExtension). I would appreciate anyone’s comments/feedback on this. According to the LEF report:
    “Question: if you are 100 years old and all your friends who were born around the same
    time as you are now dead, what do you have that they did not? According to one study,
    the answer is vitamin E. This study tested 50 biochemical markers in the blood and urine
    in relation to all-cause mortality of people aged 90 to 100. These biochemical,
    hematological, and biological parameters were measured in six- to 12-month intervals.
    Serum vitamin E was the only vitamin that was significantly higher in the people who survived.”

    Reference: Solichova D, Melichar B, Blaha V, et al. Biochemical profile and survival in nonagenarians. Clin Biochem. 2001
    Oct;34(7):563- 9.
    http://www.lifeextension.com/Magazine/2005/3/report_killer_e/Page-01

  13. Josh: How much reduction in beneficial results from a daily IF at 16/8 (to 18/6), as compared to FMD. (Will talk to Valter and let you know what his estimate is.)
    Pls use “nugget” as name if you publish this q.
    Also, your view on Valter’s remark that FMD is as effective as rapamycin, w/o risks.
    Many thanks for all your work. Just talked to old friend, head of a major lab in MTOR field, who knows you—and exudes high praise. Best, Peter
    P.s. Any chance for a direct reply, just in case I were to miss your views elsewhere? Thanks.

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