Rapamycin: Extended Lifespan, Extended Decline?

Ever since 2009, it has been known that the drug rapamycin extends the lifespan of mice.  The journal Science identified this discovery as one of the top 10 research breakthroughs for that year.  The news was all the more exciting because rapamycin already has FDA approval for other uses.

So researchers want to know just how rapamycin extends the lifespan.  Does it actually slow the entire aging process?  Or does it just slow down certain diseases, such as cancer?  

New research testing the effects of rapamycin on mice suggests that the drug probably does not slow the aging process itself.  It does slow the development of cancer and a few other diseases.  But rapamycin is no fountain of youth.  In fact, if it were used just by itself to extend the lifespan of human beings, it might merely draw out the aging process.  In other words, it might extend the lifespan but not extend the healthspan.

Photo: Public domain through Wikimedia. Thanks to Rama.

The research was conducted by a team led by Dan Ehninger and his colleagues at the German Center for Neurodegenerative Diseases. It is published in the August 2013 issue of The Journal of Clinical Investigation, which is freely available online.  In addition to the research article, the journal is publishing an expert commentary that warns about any drug that brings an increase in lifespan that “is accompanied by more disability and disease and a greater loss of physiological functions, i.e., a reduced quality of life.”  By itself, rapamycin could do just that.

On the bright side, the new study shows even more conclusively that rapamycin extends the lifespan of mice by the equivalent of almost a decade of human life.  It also provides a small benefit for cognitive function.  So despite the mixed results, the journal commentary advocates clinical trials involving human patients, perhaps those with dementia.  According to the journal article, the research supports “the feasibility of clinical trials to study the efficacy of rapamycin in treating diseases of the elderly, especially those that are debilitating and for which no current treatment is known, such as Alzheimer’s disease and other neurodegenerative diseases.”

Advocates of anti-aging research will see this new study as something of a set-back, but it is not likely to slow down basic work in the field.  Opponents of anti-aging research are likely to renew their warnings about the prospect of more years of declining health.  Any effort to enhance our humanity, whether it is by increasing cognitive ability or extending the lifespan, is always accompanied by a down-side, by side effects so costly that true enhancement is impossible.  The warning is serious, but advocates of human enhancement are not likely to be convinced.   

The research article is entitled “Rapamycin Extends Murine Lifespan but Has Limited Effects on Aging.”  The commentary is entitled “Rapamycin, Anti-aging, and Avoiding the Fate of Tithonus.”  Both are available free to the public in the August 2013 issue of The Journal of Clinical Investigation.

Extending Healthy Lifespans? A Pill on the Horizon?

Resveratrol, the much-hyped ingredient found in red wine and sold widely as a nutritional supplement, is known to improve the health and extend the lifespan of mice. Can it do the same for humans? Without nasty side effects? And at what dose?

A study published today in Cell Metabolism helps unravel a few more of resveratrol’s mysteries. In particular, researchers have shed new light on how resveratrol works. Key to its effectiveness is a gene known as SIRT1, found in slightly different forms in species as different as yeast and humans. SIRT1 plays many roles, some tied to core metabolic processes. The new study shows that in mice, even a low dose of resveratrol interacts with SIRT1 to improve metabolism.

What makes this study especially interesting is that researchers had to create a special strain of mice in order to test whether SIRT1 is necessary for resveratrol to work. If mice have no SIRT1, they do not develop properly. So two graduate students, Nathan Price and Ana Gomes, developed a novel strain of mice with an unusual copy of the SIRT1 gene, one that could be switched off at adulthood.

By administering a drug (tamoxifen), researchers can “induce” or switch the SIRT1 gene on and off, a strategy that will likely be used in other studies. "This is a drug inducible, whole body deletion of a gene," David Sinclair, the study's senior author, said in a press release from Harvard Medical School. "This is something that's rarely been done so efficiently. Moving forward, this mouse model will be valuable to many different labs for other areas of research."

Photo by R. Cole-Turner

In this case, the switchable SIRT1 mouse provided proof that SIRT1 is key to resveratrol’s effectiveness. Why is that important? Because resveratrol is a complex molecule that interacts with the body in many unknown ways. While it may be beneficial, it may have unwanted side effects. So researchers are trying to design a more simple molecule that provides the benefits of resveratrol without all the risks. One strategy is to boost SIRT1 activity. By proving that SIRT1 is involved, this study provides support for that strategy, which is already being pursued by pharmaceutical firms.

"The results were surprisingly clear," said. "Without the mitochondria-boosting gene SIRT1, resveratrol does not work."

Are we any nearer a magic pill that slows aging or promotes longevity? Perhaps. The headline of the press release from the publisher, Cell Press, claims that this work “restores hope for anti-aging pill.” Remember, of course, that the work reported here is entirely with mice.

Even so, the paper itself concludes with this statement: “This model supports the enticing possibility of designing and developing potent small molecules that provide the health benefits of resveratrol by activating SIRT1 and downstream pathways to treat metabolic and other age-related diseases.”

The treatment of age-related diseases, including diabetes, is a huge target for pharmaceutical firms. But beyond that lies that even bigger market for human enhancement, specifically for enhancing the span of healthy decades.

The study, "SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function," appears in the May 1, 2012 issue of Cell Metabolism.