New findings rejuvenate age-old drug development field.


longlife

On the internet, antiaging therapies abound. Longevity clinics peddle supplements and growth hormones. They advertise vitamin cocktails and antioxidant-rich diets. They offer chelation therapy. People who’ve tried such treatments talk glowingly of renewed vigor and rejuvenation. But none of these therapies have been shown definitively to make people live longer or dramatically improve health. Some can even cause harm.

The scientific literature contains even more experimental age-fighting therapies that have yet to fulfill their promise. That doesn’t mean the quest has been in vain, however. Over the past two decades, researchers have identified several pathways that seem to play a key part in longevity. The hope is that these pathways will lead to new drug treatments that slow the aging process and ward off age-related diseases such as cancer and Alzheimer’s.

But bringing therapies from the lab to the clinic won’t be easy. Here, Nature Medicine looks at the three of the most talked-about lines of investigation among scientists in the aging community.

Counting calories

Perhaps the surest path to longevity in lab models involves calorie restriction. Cutting calories seems to lengthen lifespans for protozoa, yeast, flies, worms, fish and mice. However, the data in primates are mixed. A 20-year study by researchers at the Wisconsin National Primate Research Center in Madison showed that calorie restriction could extend the lives of rhesus monkeys1. But cutting calories failed to provide any survival benefit to monkeys in a 25-year study conducted at the US National Institute on Aging (NIA) Laboratory of Experimental Gerontology in Dickerson, Maryland2. Why that might be isn’t entirely clear.

Demonstrating that calorie restriction extends age in humans will be even more difficult, considering the length and cost of such a trial. So, researchers have instead looked at the effects of calorie restriction on health outcomes that have been linked to aging, including body temperature, metabolic rate, inflammatory markers and insulin resistance. In 2007, the NIA funded three laboratories to look into some of these markers. The two-year study, which included 220 nonobese participants and wrapped up last year, compared a typical diet with one that curbed calories by 25%.

Trial results were scheduled to be released late last month (after Nature Medicine went to press) at the annual Experimental Biology meeting in Boston. The trial investigators, including Eric Ravussin, an obesity researcher at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, declined to provide specifics ahead of time, although Ravussin says: “We reproduced a lot of the observations shown with caloric restriction in rodents.”

Rich Miller, associate director for research at the University of Michigan’s Geriatrics Center in Ann Arbor, sees no reason why calorie restriction shouldn’t extend longevity in humans, but it still may not be a feasible antiaging approach. In a world filled with a plethora of finger-licking combinations of fat, salt and sugar, few people would choose to cut their caloric intake by a quarter. Nonetheless, caloric restriction research has helped point researchers toward promising molecular pathways.

Sirtuins in the spotlight

One such mediator of caloric restriction is a family of proteins called sirtuins. Just over a decade ago, Leonard Guarente and his colleagues at the Massachusetts Institute of Technology in Cambridge showed that calorie restriction extends the lifespan of yeast, but the effect wasn’t present in mutants that lacked one of the sirtuin proteins, Sir2 (ref. 3). Guarente’s lab had already linked Sir2 to longevity in yeast, and this new research suggested a mechanism.

A media frenzy erupted in 2006 when a team led by one of Guarante’s former trainees, David Sinclair, a molecular biologist at Harvard Medical School in Boston, reported that a chemical found in red wine, known as resveratrol, appeared to make overweight mice live longer by activating SIRT1, the mammalian equivalent of Sir2 (ref. 4). The idea that swilling red wine might be the path to longer life was tantalizing, but Sinclair’s research soon came under fire. Some questioned whether the mouse model his team used was appropriate. Others couldn’t replicate parts of Sinclair’s results.

Sinclair published a rebuttal to the naysayers earlier this year in which his team outlined a proposed molecular pathway through which resveratrol acts5. Yet, even if resveratrol does in fact activate SIRT1, it does not seem to help healthy mice that aren’t obese live longer, according to two studies that supplemented standard mouse chow with varying doses of resveratrol beginning at 12 months of age6, 7. “We tried two different doses at three different labs,” says David Harrison from the Jackson Laboratory in Bar Harbor, Maine, who led one of the studies as part of the NIA-funded Interventions Testing Program (ITP). “There was absolutely no hint of an effect.”

Sinclair admits that resveratrol is not very potent. “I do believe that we can do better,” he says. Sirtris Pharmaceuticals, a company Sinclair helped found in 2006 that was purchased by the UK drug giant GlaxoSmithKline two years later, has already developed several compounds designed to modulate SIRT1 that are structurally distinct from resveratrol. The lead candidate, SRT2104, has been tested in a phase 1 trial and seems to be safe8. Whether it will also prove effective in people still remains to be seen.

Rapamycin on trial

Although resveratrol failed to have an effect in normal mice, another immune-suppressing drug called rapamycin emerged victorious from the ITP. “To everyone’s delight, it had a big effect, the biggest effect of any of the compounds we’ve tested so far,” Harrison says. Administering rapamycin to mice in their food starting at nine months of age increased median survival by at least two months on average in males and about twice that in females7. Similar age extensions were seen in mice exposed to rapamycin from 20 months of age9. If rapamycin worked as well in humans as it did in these mice, “it would give us about ten more years of healthy lifespan,” Harrison says.

However, the effects weren’t all positive. The mice that received rapamycin had more severe cataracts and greater testicular damage than the control mice10. The drug, which is currently approved to prevent rejection in organ transplant recipients, also tends to increase the risk of infectious diseases and diabetes in people. So, physicians are reluctant to give rapamycin or any of its many mimics, known as rapalogs, to otherwise healthy individuals.

A study published last year by Joseph Baur, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, and David Sabatini, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, suggests there may be a way to separate the good effects from some of the bad. Rapamycin inhibits the protein mTOR, short for mammalian target of rapamycin, which exists as part of two separate complexes, mTORC1 and mTORC2. Rapamycin’s beneficial effects appear to be due to inhibition of mTORC1. However, Baur’s and Sabatini’s research suggests that the drug also disrupts mTORC2, and that this disruption may explain the insulin resistance seen in mice11. A compound that targets only mTORC1 might have fewer side effects.

New leases on life

Aging researchers continue to test other potential life-extending compounds with demonstrated safety profiles. For example, Harrison and his ITP colleagues recently gave mice green tea extract, a component of the spice turmeric, a triglyceride commonly found in coconut oil and other health supplements with purported longevity benefits that are known to be safe in people, but they didn’t see any effect on life span in the animals12. Now on the researchers’ plate is metformin, a drug used to treat type 2 diabetes. At an aging conference in San Antonio last year, Rafael de Cabo and his colleagues from the NIA reported that a low dose of metformin extended the lifespan of mice. A high dose, however, was toxic.

Developing an antiaging pill with absolutely no side effects may simply be unrealistic, notes Matt Kaeberlein, an aging researcher at the University of Washington in Seattle. “There are reasons why these mutations that slow aging are generally not selected for in nature,” he says. “They have costs associated with them.” How hefty those costs might be and whether society will be willing to pay them remains a question for the ages.

Source:Nature

 

 

 

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