Image: Photographs by Evan Kafka
In Brief
- In 2009 scientists discovered that a drug called rapamycin could significantly extend life span in mice, doing so by interfering with the activity of a protein called mammalian TOR, or mTOR.
- The finding is the most compelling evidence to date that mammalian aging can be slowed pharmaceutically, and it galvanized interest in mTOR’s role in the aging process.
- The result also highlighted a mystery: Why would suppressing cellular growth and replication—oneeffect of interfering with mTOR—extend life span?
- Research into that question could lead to medicines that postpone or mitigate aging-related disorders—from Alzheimer’s disease to cancer to heart failure—and perhaps even extend how long humans can live.
On a clear November morning in 1964 the Royal Canadian Navy’s Cape Scott embarked from Halifax, Nova Scotia, on a four-month expedition. Led by the late Stanley Skoryna, an enterprising McGill University professor, a team of 38 scientists onboard headed for Easter Island, a volcanic speck that juts out from the Pacific 2,200 miles west of Chile. Plans were afoot to build an airport on the remote island, famous for its mysterious sculptures of enormous heads, and the group wanted to study the people, flora and fauna while they remained largely untouched by modernity.
The islanders warmly welcomed Skoryna’s team, which brought back hundreds of specimens of plants and animals, as well as blood and saliva from all 949 of the residents. But a test tube of dirt turned out to be the biggest prize: it contained a bacterium that made a defensive chemical with an amazing property—the ability to prolong life in diverse species.
This article was originally published with the title A New Path to Longevity.
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Add CommentCurrently there are several pharmaceutical agents available for the treatment of cancer which inhibit the mammalian target of rapamycin. Here is a list of some of their side effects: asthenia, fatigue, mucositis, oral ulcerations, diarrhea, nausea, vomiting, anorexa, increased risk of opportunistic infections such as pneumonia, other bacterial infections, and invasive fungal infections, pulmonary toxicity in the form of cough, dyspnea, fever, pulmonary infiltrates, skin rash, myelosuppression with anemia, thrombocytopenia, and neutropenia, hyperlipidemia, hyperglycemia, and mild liver toxicity.
Reply | Report Abuse | Link to thisSounds like there's a lot of work to be done developing an mTOR inhibitor suitable for retarding aging that wouldn't actually end up shortening a lot of people's life spans!
The way to take Rapamycin or a similar medication to reverse or slow down aging is to take it intermittently for short periods at a time. In this way you still get the anti-aging benefits as well as prevent the bad side effects.
Reply | Report Abuse | Link to thisIt would be interesting to find out what the side effects would be of small, intermittent doses of rapamycin or another mTOR inhibitor given to healthy adults, as ligero suggests. (Note: I'm not advocating that this be tried, just speculating that it might tell us something unexpected.) The current long-term side-effect profile of rapamycin and its derivatives is based mainly on trials in which older people in pretty bad shape on multiple drugs, such as transplant patients, took sizable doses of mTOR inhibitors -- not necessarily a good way to judge the effects of smaller doses given to healthy adults. Further, I find it very interesting that these purported potent immunosuppressants (mTOR inhibitors) can be (and are) used to fight cancer -- immune suppressants are supposed to increase the risk of cancer, not reduce it. My point is that we don't really have a good handle on the risk/benefit profile of these drugs as possible, broad-acting preventatives for diseases of aging -- they are capable of defying the conventional wisdom and surprising us. Further, it's interesting that another mTOR inhibitor, metformin (which hits other enzymes besides mTOR), appears to have a much more benign side effect profile than rapamycin and has been chronically taken by millions of diabetics -- perhaps indicating that there are safer ways to inhibit the mTOR pathway than via rapamycin and like drugs.
Reply | Report Abuse | Link to thisDo you have any evidence that intermittent use of mTOR inhibitors slows aging in humans?
Reply | Report Abuse | Link to thisThe European Commission has created its first european partnership on "Active and Healthy Ageing". A total of about 460 million Euros will be spent on Research & Innovation projects on the topic in 2012, through their "FP7" funding program.
Reply | Report Abuse | Link to thisAlso, I am wondering if another path to longevity isn't anti-aging drugs for cats and dogs, included in their food. It might be much cheaper and much faster to test; and once our cats and dogs live longer due to their food, this would be very appealing for everyone.
Reply | Report Abuse | Link to thisThis is a great idea, and a little over a year ago it was actually proposed at a gerontology meeting I attended. The idea was to enlist vets, pet owners, pet-food companies, and pet-owner groups to combine forces with gerontologists to test chronic doses of possible anti-aging agents after preliminary work to check possible toxicity. I don't think the proposal has gone anywhere, but I know of at least one group of gerontologists who have collaborated with Procter & Gamble's pet food unit on a possible calorie-restriction mimetic for pets. If you're interested, more can be found by Googling the words Procter and mannoheptulose.
Reply | Report Abuse | Link to this"Why would suppressing cellular growth and replication - one effect of interfering with mTOR—extend life span?"
Reply | Report Abuse | Link to thisThat's a good question, because we'd better hope that if human longevity can be increased that our replication also be commensurately decreased. Based on historical extrapolations, the global population is currently expected to increase by two billion people by 2050 - imagine what extending increased longevity to the world's population would do for those projections! Not that any such drugs would likely be developed or marketed with the expectation that they be made available to everyone!
Two billion more people seems like a manageable increase over the current 7 billion people, until one considers that the global population has already increased from 2.5 billion in 1950. The global population had never reached 1 billion people prior to around 1830, but what difference will another few billion make?
The Malthusian argument expressed by jtdwyer against efforts to improve late-life health and longevity is familiar to researchers on aging. Here is an eloquent response to this view by one such scientist, Richard A. Miller, excerpted from a 2002 essay he published in The Milbank Quarterly:
Reply | Report Abuse | Link to this"The current, alarming population crisis and depletion of nonrenewable resources has come about without the slightest aid from biogerontologists...It follows inexorably that placing obstacles in the path of aging research will not help resolve the population crunch. Proposals that do address the root causes of the problem--solutions based on access to birth control information and hardware, strong incentives for resource conservation, and changes in social attitudes toward optimal family size, the scheduling of reproductive effort, and the proper role of the human female--typically elicit strong opposition from powerful religious, economic, and political factions...Perhaps there are some who, after sober and deliberate contemplation, feel that our Malthusian ills are best addressed by strategies that constrain the productive life span of healthy adults rather than by controlling the supply of new people. Were I a member of such a group, I would suggest that it devote its energies to removing seat belts from automobiles, insulin and antibiotics from pharmacies, and antismoking campaigns from schools, because compared with these interventions, picking on biogerontologists has a pretty low yield."
I only point out that any significant increase in longevity will (unless other factors are reduced) inexorably increase the population. As stated in http://en.wikipedia.org/wiki/Population_growth
Reply | Report Abuse | Link to this"Population growth is determined by four factors, births(B), deaths(D), immigrants(I), and emigrants(E). Using a formula expressed as
∆P≡(B-D)+(I-E)"
If the annual number of deaths were significantly reduced, for example to zero, while the births, immigration and emigration remained constant, the population growth rate would increase significantly.
I suggest that we focus on quality of life rather than longevity. I personally support efforts to reduce births, even to the point of imposing severe welfare restrictions and tax penalties for more than 1 child per mother. I also personally wish that physician assisted life termination be allowed. Unless death could be eliminated (with enormous consequences), everyone must eventually face death.
Drug companies are motivated to invest in the development of highly profitable life extending drugs - there being such potentially high demand... Essentially everyone fears death, especially as health conditions deteriorate.
By the way, are you quoting Richard A. Miller, M.D., co-founder of IDEC Pharmaceuticals, founder of Pharmacyclics, Inc., currently on the advisory council of Vantagepoint Capital Partners? Perhaps he has some vested interest in this issue...
I may not be elegant but the point is valid, disregarding any attempts to dismissively label it as "Malthusian".
The Richard Miller I quoted is a gerontologist at the University of Michigan, not the one you mentioned.
Reply | Report Abuse | Link to thisYou suggest that we focus on the quality of life--that's exactly what preventive drugs that slow aging would do, just as drugs that lower blood pressure help ward off heart disease and strokes. You also suggest we should be anxious about the possibility that annual deaths will vastly reduced, perhaps to zero--along those lines, as I've written elsewhere, we perhaps should also get worked up about the possible future outsourcing of American jobs to a race of robots in the Andromeda galaxy.
Sorry I guessed the wrong guy.
Reply | Report Abuse | Link to thisThis issue of SA is subtitled "A New Path to Longevity", not 'Improving preventative health care' or such. Please read the "In Brief" summary above.
If some drugs are developed, as suggested by articles in this issue, that significantly increase longevity by addressing the fundamental biological mechanisms that directly produce aging, availability and price would be the only factors limiting demand by every one of how ever many billions of people are around at that time.
Any significant increase in longevity made available to significant numbers of people would indisputably increase the population, all other factors being equal.
The suffering and economic impact associated with the degeneration and death of 100,000 people per day are more immediate and real-world problems than the hypotheticals associated with extending healthy lifespan.
Reply | Report Abuse | Link to thisThanks for pointing that out. The side effects are tell-tale: seems that the drug impairs immune function which is vital for survival. Also suggests that our own immune system contributes to ageing.
Reply | Report Abuse | Link to thisYour comment on the immune system contributing to aging is insightful. In particular, the inflammatory aspect of immune action seems to contribute to aging. This makes sense from an evolutionary perspective: we're evolved to have hair-trigger immune systems that flare up at the slightest hint of infections to enable our reproductive success early in life. Later in life, as inner control systems, which keep immune reactions in check, get a little flaky, this hair-trigger system winds up setting off lots of low-level inflammation that contributes to diseases of aging, including, ironically, the aging of the immune system itself, esp. via untoward changes in blood stem cells. mTOR inhibition may extend mammalian lifespan, in part, by helping to prevent inflammation-driven aging processes. It's interesting to note that both calorie restriction and rapamycin have immunosuppressive effects, but also appear to slow immune-system aging.
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