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Healthy Aging in a Pill

To extend life span, scientists envision a drug that mimics the benefits of a near-starvation diet

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1:14pm, May 20, 2011
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Animals live long and prosper when eating from a menu that puts them just this side of starvation. So far, experiments with yeast, worms, flies, spiders, fish and rodents all have shown the antiaging power of severely restricting calories. And research in rhesus monkeys suggests similar benefits in primates: One study found that monkeys eating 30 percent less than their cage mates appeared to be protected from age-related diseases and had lower mortality 15 to 20 years later. At this moment, human volunteers at three different U.S. sites have given up 25 percent of normal daily calories to test whether the less-food, longer-life phenomenon applies to people as well.

Yet even if the human experiment confirms that it’s possible to diet your way to a 120-year life span, a society accustomed to supersizing probably isn’t going to replace an order of fries with a stick of celery. So scientists are looking for shortcuts that people could use to achieve the antiaging windfall of calorie restriction without actually having to do it — a way to eat your cake and survive it, too.

A drug that postpones aging could also have profound health benefits, since most common diseases (such as cancer, heart disease and dementia) accompany old age. “That’s what’s driving us,” says Donald Ingram, head of the nutritional neuroscience and aging laboratory at Pennington Biomedical Research Center in Baton Rouge, La. “We would like to see some kind of a product that would promote healthy aging.”

So far, scientists have singled out a handful of synthetic and natural compounds that appear to trigger the same biochemical mechanisms that kick in when cells are partially starved of nutrients, part of a coping mechanism that protects against stress. Some, such as resveratrol (a substance found in red grapes and wine), have already reached an almost pop-star status because of their antiaging potential. Others are lower profile but similarly promising. It’s still too soon to know whether any of the compounds will work at all, much less work safely.

Interestingly, the race to put time in a bottle has not been deterred by the fact that the mechanism of growing old is still largely a mystery. So too is the way that a drastic drop in calories pushes the slow-motion button.

“I’ve been in the field 15 years now, and it’s amazing how theories come and go very quickly. There isn’t a central agreed theory about what aging is at the moment. But I think in the next decade we’ll know,” says David Gems, a biologist at the Institute of Healthy Aging at University College London. When it comes to caloric restriction, “the thing you have to understand is that we don’t really know how it works.” Much of the research is housed at universities and government research labs, but a small antiaging biotech industry (populated largely by current and former academics) has also sprung up.

When food is scarce

Many leaps into the antiaging market seek to mimic biochemical reactions that occur naturally in cells when eating slows way down. While the script remains incomplete, research has uncovered some key molecular players — such as the family of enzymes known as sirtuins, which are the target of resveratrol. When food intake plummets, emergency alarms go off inside a cell. “There are energy sensors somewhere that turn on some genes and turn off other genes,” says George Roth, formerly at the National Institute on Aging and now the CEO at GeroScience, a Maryland-based biotech firm trying to develop an antiaging drug. This genetic fire drill appears to protect tissues from normal wear and tear. To scientists, each gene switched off or on offers a possible antiaging bull’s-eye.

“A lot of compounds have come down the pike,” says Ingram, who helped found GeroScience. Some approaches have already lost favor, such as the idea of short-circuiting aging solely through antioxidants, chemicals that neutralize damaging molecules called free radicals. Many “were built around the antioxidant hypothesis, and just have gone nowhere.”

The antioxidant approach probably didn’t pay off because it was too simple an answer for a complex problem. The body ages for many reasons, and more than one are tied to calorie intake. During times of plenty, the body doesn’t seem to protect itself as much from the harmful by-products shed during the business of daily living. When food is scarce, protection matters most.

Overeating probably also fuels disease in indirect ways, by inciting inflammation or raising insulin levels, which in turn helps stoke energy-hungry tumors. Ingram and Roth wrote in the February-March Experimental Gerontology that any antiaging drug must have a global impact on chemical reactions in the body, just as calorie restriction does. “Our perspective has always been that aging operates on multiple mechanisms,” Ingram says.

The GeroScience research focuses on the processing of glucose, the body’s source of energy. Of special interest is mannoheptulose, a compound which occurs naturally in avocados, though Roth says it degrades quickly once the fruit ripens. Mannoheptulose partially turns off hexokinase, an enzyme that ignites a series of chemical reactions, known as the glycolytic pathway, when glucose enters a cell. Starving a cell of hexokinase is like sending a chemical memo that less energy is coming in. At a meeting in 2009, Roth reported unpublished data showing that mice fed mannoheptulose lived about 30 percent longer on average than normal mice, even though the groups consumed the same number of calories.

Products based on mannoheptulose may be years away from use in man, but maybe not in man’s best friend. Roth and colleagues reported at the 2010 Experimental Biology meeting that mannoheptulose appears to be biologically active in dogs. The team won’t discuss further details because GeroScience has now joined with Procter & Gamble’s pet food division to explore commercial use.

An antiaging dog food wouldn’t just allow people to keep their canine companions longer. Since dogs have shorter life spans than people, an antiaging effect would be evident sooner in dogs. “We think that a compound like mannoheptulose or a glycolytic inhibitor is going to be superior to any of the products that are out there, because of the fact that it does work somewhat similarly to true caloric restriction,” Ingram says.

But mannoheptulose isn’t the only natural substance that appears to mimic a state of calorie restriction. The most headline-grabbing compound of the bunch has been the sirtuin-targeting resveratrol.

Celebrity compounds under fire

In cells, sirtuins have a day job of stripping acetyl groups (small carbon-rich chemical bunches) from proteins. Most important, the enzymes are particularly busy during times of mild stress, such as when calorie intake drops. Somehow, for reasons that are still being worked out, cells awash in sirtuins are more protected from damage.

“When we are obese, the body gets lazy and turns those protections off,” says David Sinclair, who studies aging at Harvard Medical School in Boston. A decade of research has suggested that sirtuins may help shield the body from a number of afflictions, including diabetes, stroke and even neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Sirtuins’ path to stardom began in 2003 with a report in Nature, in which Sinclair and his colleagues announced that resveratrol could artificially stimulate sirtuins. Thus began the quest to develop an artificial, more potent incarnation of resveratrol. In 2004, Sinclair helped form the company Sirtris with this goal. (The pharmaceutical giant Glaxo­SmithKline bought Sirtris in 2008 for $720 million.) Although seven different forms of sirtuins exist in humans, most antiaging research has zeroed in on one called SIRT1.

The role of sirtuins in aging is still highly debated, so much so that in August of last year Science featured a pointed letter volley over whether it was justified to omit sirtuins from a review of the biology of aging published a few months earlier. The problem is that resveratrol and the sirtuins haven’t convincingly shown that they can lengthen life, as opposed to simply protecting against diseases that shorten life prematurely. The distinction may sound trivial, but in antiaging research, the two concepts are very different.

Adding to resveratrol’s woes is the fact that some scientists have raised doubts about whether the results seen in studies of resveratrol and its experimental cousins are valid. For example, in 2010 in the Journal of Biological Chemistry, researchers from Pfizer Global Research and Development described experiments questioning whether the effect was a testing artifact or resveratrol and three other Sirtris compounds actually activated SIRT1. “Our present data are significant for the field as we provided strong evidence that neither the Sirtris series nor resveratrol are direct SIRT1 activators,” the team wrote.

Sinclair points to a follow-up study published in the same journal in October 2010 from Sirtris scientists that reached the exact opposite conclusion. So at Sirtris, the research continues undaunted. Last December, the company abandoned a study of one SIRT1 activator called SRT501, but testing of other activators is continuing in human trials. SRT501 was being tested in patients with multiple myeloma, some of whom developed kidney problems.

Targeting cell growth

Less controversial, but toting its own baggage, is the drug rapamycin. It has the advantage of already being on the market and having an almost undisputed record of lengthening life span in animals. The drug has long been prescribed to transplant patients because it helps guard against rejection. It has also been investigated in cancer treatment because it has the capacity to starve tumors of nutrients — and indeed, transplant patients taking rapamycin appear to have a lower cancer risk.

Rapamycin inhibits a series of reactions in a cell that begins with a protein called (in a practical bit of nomenclature) “target of rapamycin,” or TOR. The TOR chemical pathway is one of life’s fundamental processes; it exists in some form from yeast to mammals, where it is designated mTOR, and helps regulate cell growth, the production of ribosomes (cellular protein factories) and protein turnover. mTOR, in turn, activates a protein called S6K1.

In 2009, a team led by British researchers reported in Science that mice with mutations that left them without any functional S6K1 lived longer. Just as significant, genes in the mice were switched off and on in patterns consistent with calorie restriction. A study in Nature in 2009 reported that rapamycin could extend life span in mice, even when the drug was given during older age. Last year, writing in Cell Metabolism, European researchers reported that rapamycin also extends the life span of flies, while another report in the American Journal of Pathology described an extension of life span in cancer-prone mice.

“As far as rapamycin goes, it works,” says Luigi Fontana, a physician and calorie restriction researcher at Washington University in St. Louis. “By giving rapamycin, you are telling the cells that there is not enough energy.” But rapamycin has its drawbacks. Most notably, the drug is given to transplant patients because it suppresses the immune system. This hasn’t been an issue in mice because the animals are housed in pathogen-free environments. “Human beings are not living in pathogen-free facilities,” Fontana says. “I would never take rapamycin.”

The immune system concerns will probably keep the drug, at least in its current form, off the antiaging market. “It will not be prescribed to healthy people because it is labeled as an immuno­suppressant,” says Mikhail Blagosklonny, a scientist studying cell stress biology at the Roswell Park Cancer Institute in Buffalo, N.Y. “This is enough to make people scared.” Blagosklonny (who has helped form a company, Tartis-Aging, to develop rapamycin as an antiaging drug) believes that in the smaller doses that would be given to healthy people, rapamycin would not dampen the immune system. Writing last year in Cell Cycle, he even went so far as to say that “taken together with its ability to suppress cellular aging and to increase life span, this may call to re-label rapamycin from immuno­suppressant to aging­suppressant (gerosuppressant).”

If that doesn’t happen, the body’s biology offers plenty of other targets for drugs. Acting on the body’s system of glucose detection and insulin production, the diabetes drug metformin has also been an attractive antiaging candidate. And in the future, scientists may be able to capitalize on the signals from mitochondria (a cell’s energy factories) that affect life span independently of calorie restriction. In January, researchers from the Salk Institute for Biological Sciences and the Scripps Research Institute, both in La Jolla, Calif., announced in Cell that they had pinpointed a chemical distress signal put out by mitochondria that lengthened the life span of worms. In the experiment, the signal was produced only in the intestine and nerve cells, yet affected the entire organism.

Should any new compound reach commercial development, scientists acknowledge that the resulting antiaging drug would still face hurdles to reach the aging public. A drug that might be taken in otherwise healthy people, perhaps for years, would need to demonstrate it was safe beyond doubt.

Calorie restriction exists at the twilight between health enhancement and outright starvation, so a compound would have to be precisely calibrated. If the body gets too strong a signal that energy is low, organs may fail. Scientists have known since a study in 1950 that people who reduce calories by 50 percent can experience depression, apathy, slower movement and other detrimental effects.

It’s also clear that tinkering with the aging mechanism might have unexpected side effects. Ingram and colleagues identified one promising glycolytic inhibitor more than a decade ago, while he was still at the National Institute on Aging. Called 2-deoxyglucose, it fared well in early tests but was later found in animal studies to be toxic to the heart and to increase mortality.

So for now, people are left to protect their aging bodies the old-fashioned way, by exercising enough and not eating too much. In the battle against aging, it remains to be seen whether the future will offer a bigger menu.

View larger image
Averages and outliers Jeanne Calment of France was 122 when she died in 1997, making her the longest-lived person known. That a small percentage of people live beyond 110 raises the possibility of extending average human life span and motivates scientists’ search for antiaging drugs. For 2009, global average life span was 68. But substantial differences exist: The map shows average life expectancies for people born between 2005 and 2010, broken down by country.
Credit: Geoatlas/graphi-ogre, adapted by Janel Kiley ; Source:Guinness World Records; WHO World Health Statistics; UN World Population Prospects: The 2006 Revision


Longer life for all
Drastically reducing daily calorie intake has successfully slowed aging in many organisms. Now scientists are finding out whether drugs and genetic tweaks that mimic this dietary restriction have similar life span–extending potential.

Organism

On caloric restriction

Using drugs or genetic modifications

Yeast

Lives three times as long as normal.

Inhibiting the TOR nutrient-sensing pathway by deleting TOR and related genes produces a several-fold increase in life span.

Fruit fly

Lives two times as long as normal.

Reducing activity of the insulin/insulin-like growth factor signaling (IIS) pathway through genetic deletions extends life. So does using rapamycin, a drug that acts via the TOR pathway.

Mouse

Lives 30 to 50 percent longer than normal.

Mutations that reduce activity of the IIS pathway or the TOR pathway, called mTOR in mammals, increase life span. So do rapamycin and the diabetes drug metformin. Mannoheptulose, which slows metabolism of glucose, may extend life by 30 percent.

Monkey

Less age-related disease and lowered age-related mortality after 15–20 years.

No published results of experimental drugs.

Human

Long-term study of 25 percent reduction in calories is ongoing.

Not yet determined. Some researchers have hopes for rapamycin and mannoheptulose, among others. Studies of resveratrol and SIRT1 activators, which both stimulate sirtuins, and metformin are ongoing.

Credits: From left: Biophoto Associates/Photo Researchers, Inc.; et_engineer/istockphoto; GlobalP/istockphoto (mouse and monkey)

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