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
Discussion
73 reader comments
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Hi All
Many self-trialers here and its been over 3yrs since the last comment on this chain. Wondering what's the latest position statement on these molecules of Josh, Alan and others. I have just started to dabble and I found this article and the comments intriguing at the least. Thanks,
Jayesh
NAC may have a two fold mechanism of action. Within Mitochondria there are locations that cysteine bridges are formed. These Bridges may impair the production of ATP. This is likely to reduce the ROS. One big point is the gender difference in the NAC studies on mice. The effect was only dominate on male mice and not females. Another point is almost all LE modalities reduce testosterone levels.
Hi Josh,
I am looking for a discussion of any symptoms or side effects of taking NAC. I purchased and have taken NAC twice, one 600mg dose with food. Within 30-60 minutes felt a little more relaxed, slightly tired, a slight euphoria or buss, not unlike small amount of alcohol or cannabis. Hours later, on both days, I felt my heart to be pounding a bit harder than usual, and had stronger emotional reactions to fairly minor situations like parenting issue. At one point I felt like eating even though I was not really hungry. This was in sharp contrast to how NR make me feel lot of energy, need a little less sleep, reduced appetite, no cardio or emotional changes. Any thoughts or discussion would be appreciated! Erik
There are other methods to increase glutathione,such as milk thistle,green tea extract,pycnogenol(french maritime pine bark extract),vitamin c,tumeric with pepperine,selenium,alpha lipoic acid,rosemary,grapeseed extract,melatonin,betaine,l-carnitine,theanine,glycine and cruciferous vegetables. Advanced glycation end products(ages) are dangerous.They interact in the cell and cause havoc.They are from corn oil.safflower,sunflower,cottonseed,canola,palm,as well as other unnatural oils and sugar.Alpha lipoic acid,lycopene,grapeseed extract as well as adaptogens ashwaghanda,astragalus,rhodiola and schizandra attenuate these.Acrylamide is toxic.These also mitigate their danger.Any cooked high temperature foods,i.e.,snacks,baked wheat,potatoes,cookies and numerous other foods that produce acrylamide can be largely but not completely protected.Glutathione also recycles vitamins,c, and e. Also,all chronic illness shows a severe depletion of reduced glutathione and vitamin d.
Dear Josh, I did not see Nicotinamide Riboside (NR) in either the old news or New Part section. Is there not enough on it or has it been discounted? I have found it to be an excellent energy boost, and easy to not eat in AM for doing regular daily 14-hour fast. Also, any reason to not combine certain supplements like NR plus NAC?
Thanks
He does talk about NR Here: https://scienceblog.com/joshmitteldorf/2017/07/25/mitochondria-in-aging-ii-remedies/ saying "It may be awhile before we know for sure whether this leads to better health or longer lifespan. Niagen and Basis are heavily promoted with credible scientifists behind their products, and many early adopters offer subjective reports of short-term benefits. There is one mouse study claiming to pull a 3% extension of lifespan out of the noise, and perhaps I am less open to the finding because the article, published prominently in Science, seems so breathless in describing benefits."
Thanks Matt, I must have missed that section.
Some of the best benefits in NR for me seem to be that it promotes intermittent fasting, calorie reduction, and exercise. So maybe the 3% is after they partial out those factors.
Rapamycin extends lifespan male and female mice 23% and 26%, ameliorates or prevents atherosclerosis, cancer and alzheimer;s disease, prevents and decreases sensescent cells and controls TOR which acts as command and control of all cells in all living things on planet earth and is also safe when taken in a once a week dose. The big problem, as I see it, is rapamycin is a cheap, generic prescription drug; so there is no way an entrepreneur can figure out how to make big money from rapamycin. The result is remarkably little interest in using rapamycin, which would seem to have the potential to change the world as we know it; but huge interest in a hundred other drugs of dubious value.
Alan Green, M.D.
I wouldn't call Rapamycin "cheap", especially for the average person at roughly $1100 or more per year, but your point is well taken.
Thanks Alan,
Some of us with more time (maybe? age 53) have been waiting for more reports on side effects of Rapamycin, and also wonder about interactions. Do we stop taking everything else? Do we take exactly what you or Josh take? The consequences could be serious.
Metformin has been off patent for decades, yet the TAME study is going ahead.
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.
@ 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
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.
I will definitely read it. Thanks!
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
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.
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
http://sci-hub.bz/10.1038/nm.4222
Cardioprotection and lifespan extension by the natural polyamine spermidine
https://medicalxpress.com/news/2016-09-healthy-ageinglonger-healthspan-spermidine.html
Healthy ageing—longer healthspan with spermidine
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.
Best source of Spermidine is wheatgerm. There is spermidine group list dozen top spermidine foods. Not in any supplements, just real foods.
Real foods! Who uses real foods anymore? Very primitive. ;-)
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?
This is where I get my spermidine:
(pls excuse the alignment)
mg/kg
Wheat germ 243
Soybean,dried 207 (Japanese )
Cheddar, 1yr old 199
Soybean,dried 128
Mushroom 89
Rice bran 50
Green peas 46
Mango 30
Chickpea 29
Cauliflower (cooked) 25
Broccoli (cooked) 25
I take all except the cheddar ;-)
What about L-Depreynl?
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.
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?
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).