In a paper published late last year, a cautious and expert biochemist reports that none of the most popular “life extension supplement” mixes actually extend life span in mice.
Stephen Spindler, biochemistry prof at UC Riverside, has been warning us for years that supplements, herbal extracts and nutraceuticals are, on the whole, ineffective for healthy adults, and that some may actually shorten life expectancy. Spindler’s lab has done many life extension studies on mice (summary), almost always with negative results. One recent report included separate life span tests on extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin.
One of the themes in his papers is that caloric restriction is the only thing that works consistently, and that many of the treatments that seem to offer life extension are subtley inducing caloric restriction, (and this goes unreported by the investigators). But there are so many substances to test, and each lifespan test in mice is so expensive, that Spindler has suggested gene expression profiles as a shortcut to identifying candidates for further testing.
Another approach is to test many substances at once in a mouse life extension cocktail. Another rationale for this kind of testing is that we know that natural fruits and vegetables contribute to a long and healthy life, so perhaps it takes a complex combination of nutrients to be effective. Late last year, Spindler reported on his experiments, feeding commercial “life extension” mixes to hybrid mice. The results are a bracing cold shower for those of us who take a variety of carefully-chosen supplements each day – and a personal caution to me, since I have recommended supplements on my Aging Advice web page. [Link to Spindler combinations paper]
Seven of the eight graphs of survival time in the paper look like this.
The mice that ate the supplements and the mice that ate ordinary mouse chow had exactly the same pattern of mortality.
(The agreement between treatment and control is so perfect that, if it were a scientist of less integrity, I would suspect the data had been doctored. But in Spindler’s case, I think the consistency of the results bears witness to his expertise in all aspects of mouse husbandry and experimental desgin. Clearly, his lab has benefited from a lot of experience, and has adopted methods of caging, feeding, watering, temperature and light control that eliminate a lot of the usual experimental scatter. Even choice of the mouse strain was subject to thoughtful analysis.)
The eighth treatment group showed slightly shorted life span.
Our results do not support the hypothesis that simple or complex combinations of nutraceuticals, including antioxidants, are effective in delaying the onset or progress of the major causes of death in mice. The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals. [Spindler]
What substances were tested?
There were eight test groups with different mixtures of supplements, one control group fed only standard mouse chow, and one calorically restricted “positive control” that got less mouse chow (and lived longer). There was some overlap among mixtures of compounds in the eight test groups. The list of substances included is long. Here are highlights:
Alpha Lipoic Acid
Silymarin (milk thistle)
Vitamin A complex
Various B vitamins
Two of these substances (metformin and melatonin) have a credible history of life extension potential in past experiments with mice. Spindler doesn’t comment, and I leave this as an open question. There is credible data in humans for two more (vitamin D and aspirin), both of which have been shown to lower all-cause mortality. I am not aware of rodent life span studies of vitamin D or aspirin, but I trust that one of you, my readers, will point me to a reference.
Notably absent were prescription drugs that have been shown to lengthen mouse life span in the past: deprenyl, metformin, and rapamycin. The first two are, in my opinion, suitable for general human use.
Fish oil responsible for shortened life span
Why did experiment #8 actually shorten life span (by about 9%)? Spindler speculates that it might be due to the way mice respond to omega 3 fatty acids (fish oil). He cites not-yet published data in which fish oil alone was found to shorten life span. Another possibility he mentions is the well-established fact that plant compounds can mimic the effects of mammalian hormones, and that indiscriminate overdoses of plant extracts can throw the metabolism into dysregulation.
Caveats: Mice are not humans
Some things about aging metabolism in mice are the same as humans, and some are different. One principal difference is that aging mice die predominantly of cancer, while aging humans die of cardiovascular disease, cancer, and Alzheimer’s disease. Aging mice, like aging humans, are flooded with hormones that dial up inflammation that destroys healthy tissue and heightens risk of cancer [ref]. So the failure of anti-inflammatory ingredients (e.g. omega-3 fats, aspirin) in these mixes to have a life extension effect is particularly puzzling. Unlike humans, aging mice do not suffer from short telomeres, so we might hope that telomerase activators (e.g. silymarin, astragalus extracts, ashwagandha, bacopa) would benefit human life span even if they do not help mice.
A partial explanation for the null results is that some of the combinations include anti-oxidant vitamins, which have been shown generally to shorten lifespan. This could be counteracting the benefits of some ingredients that might provide benefits on their own. Likewise for the fish oil that was included in one of the ineffective combinations.
What does this leave us?
There is epidemiological evidence for mortality reduction in humans from small doses of NSAIDs (ibuprofen, aspirin) and for large doses of vitamin D.
There is evidence from rodent experiments that melatonin, metformin and deprenyl extend life span. There are reports from one lab in Russia that SkQ should be added to this list, but it is not yet commercially available.
There is anecdotal evidence and theoretical support for telomerase activators: astragalosides, silymarin, other herbs, carnosine, etc. We expect these might work better in humans than in mice, though evidence is yet thin.
Everything else is speculative, and many anti-aging supplements will help some people but not others. There is also the disturbing potential for actual harm, as Spindler emphasizes. None of us wants to think that the mix of supplements we take might be shaving years off our life expectancies.