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.

Is Aging a Disease of Stem Cells?

Is aging a disease? And if it is a disease, what “causes” it? Is it simply natural for bodies to age over time, or is something wrong with them, something that could be “fixed”?

In a report in the January 3 issue of Nature Communications, researchers at the University of Pittsburgh School of Medicine report on work with mice that are bred especially to age quickly. The mice have a version of progeria, a disease in humans that causes children to age well before their time.

The research team looked at differences in stem cells or progenitor cells, which healthy bodies naturally keep in reserve as a source for new cells to replace worn-out cells. Not surprisingly, they found that the progeria mice had fewer progenitor cells than their healthy counterparts. What’s more, the few progenitor cells in the progeria mice failed to function normally. For example, they didn’t produce replacement cells as needed.

If that’s the problem, can it be “fixed”? The researchers, led by senior investigators Johnny Huard and Laura Niedernhofer, injected the rapidly-aging progeria mice with progenitor cells from the muscles of healthy mice. The result was pretty amazing.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said in a press release issued by the University of Pittsburgh. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer—some even lived beyond 66 days. They also were in better general health."

How did this work? Did the injected cells start producing replacement cells? Possibly, but the main effect of the injected cells seems to have been to change the host cells in the body of the progeria mice. In other words, the injected healthy progenitor cells changed the progeria mouse’s own cells into more healthy, more normal cells.

"This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue," Dr. Niedernhofer said. "In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved." Fascinating!

What about mice that are aging normally? Would the injection of progenitor cells from younger mice, for example, also “rescue” non-progeria but aging mice?

Whether anything like this could be done safely in human beings is a big question that will require a lot more research. It may turn out that injecting progenitor cells into a human patient with premature aging might help stall the aging but might also create other problems, such as cancer. In time, it may be possible to get the benefits while managing the risks.

The Pitt research, although dealing with mice with progeria, opens profound questions about humanity, aging, enhancement, and the possibility of extending the human lifespan.

The biggest question of all is whether something like this would slow the aging process in normal or healthy human beings. In other words, is this yet another possible pathway to human enhancement? Could this be used to “treat aging as a disease”?

Is aging a disease? Dr. Niedernhofer’s comment is revealing: "Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals," Dr. Niedernhofer said. "That tells us that stem cell dysfunction is a cause of the changes we see with aging." A dysfunction? A disease? A difference?

On the question of religion and the morality of extending the human lifespan, probably the best book on the market is Religion and the Implications of Radical Life Extension, edited by Calvin Mercer and Derek Maher. I have an essay in the book reflecting on the question from the standpoint of Christianity.

My take? Extending the human lifespan is not immoral or obviously wrong, but Christians hope for a transformation, not an extension. More of the same is too little.

The report appeared in the January 3 issue of Nature Communications. It is entitled Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model and is available free to the public.