Pills that may promote longevity
http://mathforum.org/~josh/AgingAdvice/Pills.html
http://joshmitteldorf.scienceblog.com/index-to-this-blog/
Pills
Why so many supplements?
For general health, I believe in a conservative approach: the body knows what it is doing, and I’m cautious about interfering. I eat “natural” foods and avoid most pharmaceuticals.
But in old age, the body is genetically programmed for self-destruction. “Natural” means deterioration and death. I’m willing to take risks to interfere with the body’s aging process, and to try supplements once I think there’s a better chance they’ll help me than that they’ll hurt me – a rather low bar.
I’ve taken a bold approach. You may prefer to be more conservative.
Summary for the impatient*
Recommended for everyone
Vitamin D, megadoses, perhaps with vit K to help maintain calcium balance
Aspirin or ibuprofen, perhaps in alternating weeks
Melatonin at bedtime
Telomerase activators: (Milk thistle=Silymarin, Carnosine, Ashwagandha)
Curcumin=turmeric
Magnesium for neural protection, insulin sensitivity, and probably longevity.
Recommended if it is right for you
Metformin (prescription)
Deprenyl=Selegiline (prescription)
Resveratrol
Fish or krill oil
Acetyl L-Carnitine
Horny goat weed
Rhodiola
*caution: Impatience is a mortality risk factor.
Substances that have reduced mortality in epidemiological studies
This is the best evidence we could ask for that a substance actually contributes to longer life span. Unfortunately, there has been no systematic exploration of candidate substances, and these few for which we have evidence are lucky accidents, in that they happen to be widely consumed and mortality statistics were compiled for other reasons.
Metformin
As we age, we all lose sensitivity to insulin and begin, gradually or rapidly, to poison our bodies with excess sugar in the blood. This happens to almost everyone, and it is only when the symptom is particularly severe that it is diagnosed as (type 2) diabetes. Metformin is a drug that has been used to treat type 2 diabetes for 50 years, but it is only recently that epidemiologists have begun to notice that patients on metformin have lower rates of cancer and heart disease. Of course, cancer and heart disease were elevated to begin with in diabetics. But the question has been asked: will metformin provide a benefit for “normal” aging, and lower cancer risk for people who are not diagnosed with diabetes?
I’m betting it will work. Metformin is a weight loss aid and increases insulin sensitivity. Side effects are rare. Read more…
Aspirin
Low-dose daily aspirin was an idea born in the 1960s, based on the insight that aspirin prevents blood clots and blood clots are the proximate cause of heart attacks and stroke. These other benefits accrue, presumably, because of aspirin’s anti-inflammatory effects, which affect aging more generally. Millions of people were advised by their doctors to take aspirin daily, and as a result there was a large group of people available for long-term health studies. This led to an accidental discovery that aspirin slashes risk of many kinds of cancer and may have benefit preventing Alzheimer’s Disease. Today, the medical consensus still favors daily aspirin, but the benefit for heart health is secondary. Ibuprofen is in some ways preferable to aspirin, in others not as good. If you mix them, alternate weeks rather than days. Read more…
Vitamin D
Blood levels of vitamin D are associated with lower incidence of most cancers, heart disease, and dementia. Vitamin D protects against brittle bones and auto-immune diseases and dramatically lowers the incidence of cold and flu. Also “asthma, diabetes, stroke, multiple sclerosis, and cognitive decline.” The RDA of vitamin D is absurdly low, and also inconsistent with the recommended blood levels. Many people have to take thousands of IU daily to get their blood levels into the ‘normal range’ of 30-74 ng/ml, especially in the winter when there is no sun to supplement dietary vitamin D. Don’t be afraid of blood values over 100. An IU of vitamin D is tiny. The standard dose of 400 IU is only 10 micrograms, which is a barely-visible speck. Even mega-doses come in small pills.
The only potential down side of high-dose vit D is that it tends to raise levels of calcium in the blood. Adding vitamin K to the mix can prevent this.
Read more…
Why we should not be afraid of moderate sun exposure
Substances that have extended life span in rodent studies
Supplements in this class are an elite club. Many chemicals that extend life span in worms and flies fail when they get to mammals. Many more deserve testing in mammals but have not been tested, because mice are expensive to keep.
Metformin See above
Deprenyl
Deprenyl is a neuro-protective drug discovered in Hungary more than 30 years ago. It has prolonged life span in many rodent studies, and also in dogs. In the 1990s, under the brand name Selegiline (also Eldepryl and Zelapar) it became a standard treatment for Parkinson’s Disease. Parkinson’s patients who take Selegiline live longer than matched patients who take only the other standard treatment (L-Dopa). More recently the same drug (branded as Emsam) has been prescribed for depression and ADD. There is a small cult of people who take it daily for life extension, with good rationale (in my estimation). But it has an effect on mood and personality that not everyone will appreciate. Read more…
Melatonin
Melatonin is best known for regulating our daily sleep cycle. If you take it, it should be at bedtime. I find that 1 mg helps me fall asleep, but more than that gives me apnea, funny dreams, and morning grogginess.
We make less melatonin as we age. Melatonin not only extends life span in rodents, but has also been linked to reduced cancer risk, neuroprotection, and healthier immune function. Read more…
Sk-Q
This is a molecule invented by celebrated Russian biochemist Vladimir Skulachev (hence the Sk). It is a CoQ10 molecule at one end and a positive ion that pulls it into mitochondria at the other end. Mitochondria are the energy factories within cells that use CoQ, and they have less of it as we age. In lab tests in Russia, SkQ has been used to reverse diseases of the eye (presbyopia, cataracts, glaucoma) and to restore youthful pliability to skin. Fed to mice, it extends life span by about 10%. It is presently available only in Russia, and only in tiny quantities, as eye drops. But a similar product is marketed in New Zealand as MitoQ and has just (2014) become available in the US, both as capsules and a skin cream.
(Dinh lang) is a Vietnamese herb that was reported to increase life span in rats 30 years ago, and I have not been able to find out more about subsequent studies, or find a source where it can be purchased.)
(Rapamycin)
Rapamycin is a powerful immune suppressor, useful in organ transplants. In a spectacular lab result reported in 2009, Rapamycin was found to boost life span in mice, even when it was adminsitered only late in life. This is an intriguing recommendation, but rapamycin is too powerful a drug for common use. There is every reason to fear that taking it would expose you to infections and every kind of bacterial disease, because it compromises the immune system. Rapamycin is also ridiculously expensive.
(Fullerene or “Buckyballs”)
These are molecular spheres of 60 carbon atoms in exactly the configuration of a soccer ball. In a single experiment reported in 2012, fullerenes dissolved in olive oil doubled the life span of a handful of lab rats. Impressive, exciting results waiting for confirmation. There are some people who have been early adopters, experimenting with fullerenes themselves. Here is their discussion group. Read more…
(Dinitrophenol) is a weight loss drug that has extended life span in mice, but is toxic and has caused death in humans.)
Insulin sensitivity and Caloric restriction mimetics
We lose insulin sensitivity both with age and with weight. Loss of insulin sensitivity is both a symptom and a cause of aging. Supplements like Metformin, Alpha Lipoic Acid and Chromium can help preserve insulin sensitivity. Other substances trick the body into thinking it is thinner than it is, and so they work to increase life span via the same pathway as CR. These are some of the surest bets we have, but on the other hand we may “max out” on the benefits of CR. That is to say they are less effective if your weight is already low, and adding more CR mimetics is not likely to offer further benefits.
Metformin see above
Resveratrol—thought to be the ingredient in red wine that protects against heart disease. Since its discovery in 2002, remarkable benefits were noted in several animal studies, including life extension for worms, flies and fish. Some of the excitement about resveratrol waned when it failed to offer life extension in normal mice. Still, resveratrol extends life span in obese mice, and improves health and stamina in all mice. Recently, there is epidemiological evidence for reduction in cardiovascular disease in human trials of resveratrol. Take care of dosage; there is some indication that optimum dosage may be a modest 100 mg /day. See article.
Alpha Lipoic Acid
A commonly-available supplement that has been used to treat diabetes with some success, and has reliably increased insulin sensitivity in rodent studies. ALA has been reported to increase glutathione concentrations both in cell cultures and in live mice.
It has not been shown to increase life span in rodents. Get the pure R form rather than mixed L and R. Read more…
Green Coffee extract and Irvingia
Both products work when taken before a meal to suppress the insulin spike, signaling the body to burn the calories ingested rather than to store them as fat. Studies show they are modestly effective.
Chromium picolinate increases insulin sensitivity and may be useful for food cravings and binge eaters.
Magnesium increases insulin sensitivity and has other benefits as well. Most of us get less magnesium than we need, and there is no down side to getting extra magnesium.
Anti-inflammatory
Aspirin, ibuprofen See above
Naproxen is a more powerful NSAID than aspirin and ibuprofen, but with more risk of side-effects. It is the strongest NSAID available without prescription (sold as Aleve and generic equivalents). Wiki article
Fish oil
Oils and fats are categorized according to the number and position of double bonds in a chain of carbon atoms. Omega-3 fatty acids are the active ingredient in fish oil, while omega-6 are the fatty acids that we get from most vegetarian sources of polyunsaturated fat. Theory is that we eat too much omega-6 compared to omega-3, and there is good evidence that supplementing with fish oil lowers inflammation and protects brain cells. There is good evidence for lower risk of heart disease and some evidence for beneficial effects on arthritis. Krill oil may provide additional benefits to fish oil in inducing youthful gene expression. Omega-3s don’t increase life span in rodents.
Curcumin (turmeric)
Many studies have associated curcumin with lower inflammation and protection against cancer and Alzheimer’s Disease. Eating turmeric with black pepper helps bioavailability. Read more… On the negative side, there is some indication that curcumin blocks telomerase in cancer cells, and concern therefore that it may interfere with telomerase activators.
Anti-oxidant
I don’t assume that because a supplement is an anti-oxidant, it therefore contributes to life extension, or that it does us any good at all. While it is true that there is oxidative damage that accompanies aging, particularly in the vicinity of our cells’ mitochondria, this damage seems to be under the body’s control, and it is an effect of aging rather than a cause. Free radicals (or ROS) are chemical bi-products of energy production in the mitochondria that attack sensitive biomolecules and lead to oxidative damage. The trouble is that these same ROS are also signals that stimulate the body to replace damaged cells and to repair tissues.
There have been a great many tests of anti-oxidants for life extension in humans and in animals, and almost all of them have failed. Sometimes anti-oxidants have shortened life span, as in the most extensive study to date, the Finnish ATBC study. Exercise has been known to help preserve insulin sensitivity, it was found in lab studies in the mid-2000s that anti-oxidant vitamins can block this benefit.
Exceptions: Anti-oxidants that are targeted to the mitochondria have been found to extend life span in rodents. Glutathione is an anti-oxidant that seems to be beneficial with no down side. Read more…
CoQ10 AKA ubiquinone plays a key role in chemistry of the mitochondria, including as an anti-oxidant. We have less CoQ as we get older, and our mitochondria function less well, producing less energy for us. It would probably be a good thing to get more CoQ into our mitochondria, but supplementation with CoQ10 is a very inefficient way to do that. CoQ is poorly absorbed, and then it is dispersed through the body, with very little of it reaching the mitochondria where it is useful. Ubiquinol is a more bio-available form of CoQ that helps with the first part of this problem, but not the second. CoQ supplementation in humans has been shown to lower risk of heart disease, but CoQ does not extend life span in rodent studies.
PQQ (Pyrroloquinoline quinone) is an anti-oxidant which has been found to have neuro-protective and cardio-protective benefits. It looks promising, but was only discovered in 2002, and information is still sparse.
Sk-Q (see above) is a synthetic CoQ targeted to mitochondria, very promising but not yet available outside Russia.
N-acetyl cysteine (NAC) is available both as a drug and as a generic supplement, and is known to have positive effects on glutathione production. N-Acetyl Cysteine increases life span in flies but not mice.
Glutathione (abbrev GSH) is an anti-oxidant with other beneficial functions, which is manufactured by the body, but we make less of it as we grow older. Cataracts in the eye are associated with low GSH levels. Glutathione cannot be taken as a supplement, because it does not survive the digestive process. Intravenous GSH has been used to treat various diseases.
Alpha lipoic acid (see above) has also been shown to enhance intracellular glutathione. Melatonin (see above) has been shown to stimulate a related enzyme, glutathione peroxidase, and silymarin (see above) has demonstrated an ability to replenish glutathione levels in lab rats. Selenium is a trace mineral, and Se is incorporated as part of the glutathione molecule. The most effective supplement for enhancing glutathione may be a patented combination molecule D-Ribose, L-Cysteine, which reportedly passes through the digestive system and boosts glutathione more than NAC or any of the other supplements above. It is sold as RiboCeine out of New Zealand.
Mark Hyman on Glutathione
Astaxanthin is an antioxidant pigment derived from krill and related crustaceans. Its impressive power as an antioxidant does not imply that it has long-term health benefits, and evidence for these is yet to be presented. Astaxanthin may have anti-inflammatory benefits.
Telomerase activators
I believe that telomere length is one of the body’s primary aging clocks. Lengthening telomeres is the most promising avenue toward life extension that we know of today, and activating the body’s own gene for telomerase is certainly the way to do it.
But herbal telomerase activators that are available now are not strong enough to prevent the ongoing loss of telomere length with age. We can hope that in the future, designer molecules will do better than today’s best herbs.
Are the herbs effective enough to be worth anything at all? The very limited clinical and lab data that we have suggests that they are doing more for us than we had any right to expect. This is very promising indeed.
The best information that we have on telomerase activation is for a product called TA-65, sold by TA Sciences in New York. This company has funded most of the research, demonstrating
that TA-65 works to slow shortening of the shortest (most dangerous) telomeres in the human body
that TA-65 added to food improves health and lengthens life span in mice with no increase in cancer incidence
TA-65 is widely rumored to be cyclo-astragenol, a trace ingredient in the Chinese herb Astragalus.
No corresponding data is available for any other substance, even for generic cyclo-astragenol. Cyclo-astragenol is available from other companies for a fraction of the cost of TA-65.
Though TA-65 is the only product for which there is animal and human data, it may be that it is not the most effective telomerase activator. In cell cultures, several herbs are far more powerful than TA-65. Leader in doing these cell culture assays for telomerase activity is Sierra Sciences in Reno, NV. Sierra has designed and licensed a mix of the most effective herbs found in their extensive tests. This is sold as Product B by Isagenix. The top ingredients in Product B are Silymarin=Milk Thistle extract, Ashwagandha (a traditional medicine from India), and Horny goat weed=Epimedium, an ancient Chinese precursor to Viagra. All kidding aside, horny goat weed has been used as an aphrodisiac in the Orient for centuries, which might or might not be what you want in an anti-aging supplement. Active ingredient is thought to be icariin. Sexual activity is pro-longevity .
The herbs that comprise Product B are available individually from several suppliers, at less than the cost of Product B.
Carnosine is a “minimalist” protein, consisting of just two amino acids. It is found in young human cells, but we have much less as we age. Carnosine slows the loss of telomeres in human cell cultures, as well as appearing to reduce the telomere shortening rate.
In animal models carnosine has been shown to retard cancer growth and protect against alcohol-induced oxidative stress[21] as well as ethanol-induced chronic liver damage. Carnosine has shown potential as a neuroprotective agent as well. It extends life span in flies, and there is one study (1999) on a particular strain of mice that yielded tentatively positive results. If there is any rationality in the world of science funding, replicating and extending that study ought to be a high priority.
Carnosine is best utilized on an empty stomach.
Fish oil has also been found to slow the rate of telomere attrition.
Telomerase and cancer. There is a common belief in the gerontology community that telomerase therapy will increase the risk of cancer. It is based on erroneous theory, and all the experimental evidence we have points in the opposite direction: that cells with short telomeres add substantially to our cancer burden, and that lengthening the telomeres all around will lower cancer risk dramatically. Here is my own journal article on the subject.
Methylation
Different genes are expressed at different times of life, and I believe that restoring a young profile of gene expression is a powerful anti-aging strategem. DNA in each cell is tagged with methyl groups that help determine which genes to express. Methyl groups hide a gene, so that it is skipped over and not expressed.
Methylation patterns change with age, so that some genes are overexpressed and others underexpressed. Curiously, there is much more of the former than the latter. DNA becomes de-methylated, and this results in overexpression of genes (e.g. inflammation factors) that contribute to aging. The bottom line is that maintenance of methylation in our DNA is an anti-aging function.
SAMe (s-adenasyl methionine) is a supplement in the US, a prescription drug in Europe, used for depression and arthritis. The Me in “SAMe” stands for “methyl” and SAMe can be turned into the enzyme that adds methyl groups to DNA. SAMe is effective as prescribed and may have other benefits for liver and heart. There have been no trials, to my knowledge, for life extension in rodents or studies of mortality in humans.
B vitamins (folate, B6 and B12) are a first-line defense against de-methylation. (See article by Mark Hyman)
Arthritis
Arthritis is an auto-immune disease. The line between osteo-arthritis and rheumatoid arthritis has blurred in the last decade. Anti-inflammatories are our best defense. Glucosamine has recently raised a red flag.
Glucosamine has been established as an alternative treatment for arthritis, and is moderately effective. Recently, there is concern that a side effect of glucosamine might be to increase insulin resistance.
The following are all helpful for arthritis:
Aspirin, ibuprofen See above Naproxen See above
Fish oil See above Curcumin See above
I also want to mention…
Rhodiola has been tested by modern methods for fostering alertness, memory and stamina. Longer term, it is neuroprotective. According to ancient Oriental tradition, it is also a life extension herb. In 2013, it was tested for the first time in fruit flies, and found to extend life span by 20%. It has not been tested in mice, and its mechanism of action is unknown. If it works to extend life span in mammals, it may be via a mechanism which does not overlap with the insulin pathway that underlies most other life extension drugs. Read more…
DHEA (dehydroepiandrosterone), the most abundant hormone in the body when we are in our 20’s, declines to a small fraction of its prevalence when we are old. At any age, males have more than females. Manuractured in the adrenals, DHEA is chemically related to sex hormones and steroids, and there is evidence that they are transformed into these forms in our bodies.
There are some studies showing cancer suppression in mice from DHEA. But DHEA is peculiar to human biochemistry, and it is scarce in mice and rats. This is a reason to question whether there is a basic relationship to aging, and also whether we can extrapolate from studies of DHEA in rodents.
Some human studies show lower rates of heart disease and cancer when DHEA levels are higher; others find no effect. If there is a benefit, it may be small enough or contingent enough that it is difficult to disentangle from secondary associations.
HGH (human growth hormone). Stay away. It may make you feel younger, but is associated with increased mortality rates.
Ginkgo biloba is a common Chinese herb with a long tradition.
There is controversy over whether Ginkgo improves memory or not, and better evidence that it is neuroprotective.
Acetyl L-Carnitine (not to be confused with Carnosine) is another minimalist protein that is common in young cells and declines with age. It protects brain neurons and memory function. In combination with Alpha lipoic acid (See above), it has been promoted by Bruce Ames, a Berkeley biochemist whose name justly carries weight. Claimed benefits include health and vitality, mediated through mitochondrial function. A 2013 study found substantial benefits for heart arhythmias and reduction in all-cause mortality for heart patients taking ALCAR.
Vitamin C
(ascorbic acid) has been studied extensively, and there are more than the usual number of contradictory claims about its benefits. It is cheap and may protect against colds and flu. There are reasonable claims that it protects against cancer, although it is difficult to get a clear statistical signal when vitamin C intake is so tightly intertwined with other nutrients in fruits and vegetables. There is one study in which vitamin C is found to promote telomerase. I have seen no evidence that vitamin C is a life extension drug, but there is also no harm in taking it if you believe it helps you. The only downside I have seen is the bewildering finding that vitamin C can block the beneficial effects of exercise on insulin metabolism.
Vitamin E
(alpha tocopherol), like vitamin C, is a well-studied anti-oxidant and not a life extension drug. In the the Finnish ATBC study, treatement with vitamins E and C was discontinued after a slight increase in mortality was detected. Life Extension Foundation has claimed that a variant of vitamin E called gamma tocopherol has more consistent benefits for health than the usual (alpha) form.