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A mouse study running for decades has found promising compounds for extending life—and ruled out many others
Later this year, 240 mice will begin nibbling food laced with sildenafil citrate, the active ingredient in Viagra. An equal number will start dining on chow that includes the antihypertension drug captopril. The mice don’t suffer from erectile dysfunction or high blood pressure. They are the latest rodent recruits in the Interventions Testing Program (ITP), a 22-year-old project funded and run by the National Institute on Aging (NIA) that gauges whether compounds extend longevity in mice—with the hope that they will also do so in people.
So far, the ITP has evaluated more than 60 drugs, dietary components, hormones, supplement ingredients, and other molecules, alone and in combinations. Sildenafil citrate and captopril are among the eight new candidates announced in late August, a couple of months after NIA announced it would re-up the program’s funding—more than $5 million annually—for another 5 years.
Researchers say the ITP has been worth the money. They laud its transparency, meticulous methods, and commitment to replication—each compound is tested at three sites. “It’s important to have this robust validation” of proposed life-extending drugs, says bioinformatician Mahdi Moqri of Harvard Medical School, who is not involved in the project but is investigating biomarkers of aging.
The ITP “has tipped us off to some interesting drugs,” says biogerontologist Steve Austad of the University of Alabama at Birmingham, who has served on the project’s steering committee. Twelve compounds and two combinations prolonged the rodents’ lives in ITP studies. These positive findings haven’t yet produced a treatment to slow human aging. But the project performs another valuable service, Austad notes. “It has also debunked some overhyped drugs.”
The idea that treatments might delay human aging may be mainstream now. But when the ITP launched in 2002, “many people thought you couldn’t do anything about aging,” says gerontologist Richard Miller of the University of Michigan (UM), one of its three principal investigators. “The only goal of research in this area was to make old people comfortable.”
Some research had suggested certain compounds stretch mouse survival, but the studies were usually small and their results rarely replicated. “You didn’t know what to believe,” says molecular biologist Joseph Baur of the University of Pennsylvania Perelman School of Medicine.
To provide credible evidence, the ITP has followed roughly the same procedure for more than 20 years. Each spring, outside researchers nominate candidates that provide health benefits in mice or humans, boost longevity in other organisms, or trigger other positive effects. A committee then selects the six to eight most promising, which are evaluated at UM, the University of Texas Health Science Center, and the Jackson Laboratory.
Researchers test each intervention in 240 mice—80 at each site—while another 160 serve as controls. The scientists track the mice through the rest of their life spans, which can be more than 2 years. (A companion study, the CITP, assesses possible pro-longevity molecules in nematodes to probe their effects and delve deeper into aging mechanisms.)
The three institutions try to ensure uniformity, using the same food and bedding suppliers and housing the mice under identical conditions. Precise replication is a challenge, says molecular neurogeneticist Monica Driscoll of Rutgers University, one of the CITP’s principal investigators. “It took us a year to sort out variation among the labs.”
Another virtue of the ITP, scientists say, is the mice themselves. Studies often rely on inbred mice, whose genetic idiosyncrasies can lead researchers astray. The ITP’s rodents, in contrast, come from crosses between two hybrid strains, making them more genetically diverse—and thus more similar to people.
The program publishes all of its results, even negative ones. That openness was a feature of the program from the beginning, Miller says, and it contrasts with the reticence of many companies in the field. “There are a lot of startup companies that want to develop antiaging drugs, but we don’t have a clue about what they are doing.”
Among the compounds the project has discredited are the big-selling supplements L-leucine and MitoQ, fish oil, and curcumin, an ingredient in turmeric. The vaunted grape extract resveratrol also fell flat in three rounds of studies. “They did resveratrol to death” but couldn’t find any evidence that mice consuming it squeak out any extra time, Austad says.
Still, contrary to most scientists’ initial expectations, the ITP did identify molecules that lengthen the mice’s lives by weeks or months—evidence, Miller says, that “aging is malleable.” Its biggest find so far is the drug rapamycin, normally used to prevent transplant rejection, which increased longevity even when mice started on it late in life.
The drug’s positive effects were surprising, Baur says, because rapamycin inhibits the immune system. But follow-up studies by other teams have shown that it and closely related molecules can counteract some effects of aging in people. A 2014 study, for instance, found that one rapamycin derivative improved elderly patients’ responses to influenza vaccines. Other clinical trials are testing whether the drug or its relatives are beneficial for Alzheimer’s disease, muscle weakness, gum disease, and other age-related conditions. Austad says the project has uncovered other dark horse molecules that appear to be beneficial, including the diabetes treatment canagliflozin and 17alpha-estradiol, a form of estrogen.
The ITP “increases the chances that we will have at least one antiaging intervention that has an effect in humans,” says Jennifer Fox, project scientist for the effort. But turning its insights into treatments is difficult. The U.S. Food and Drug Administration (FDA) doesn’t consider aging a disease and won’t accept signs of delayed aging as an endpoint for clinical trials. Miller notes that one proposed trial, headed by geneticist Nir Barzilai of the Albert Einstein College of Medicine, did receive FDA permission to use indicators such as the occurrence of age-related conditions, including cancer and dementia. However, researchers haven’t been able to raise the $50 million needed to launch the trial, which would track 3000 older people taking the diabetes drug metformin for 6 years.
The mice used to test possible life-extending drugs are genetically diverse, like people.RICHARD MILLER
Miller says the ITP data suggest a way to increase the odds of success in human studies. Last year, he and his colleagues analyzed results from long-lived mice to identify what they called aging rate indicators—measures of how fast individuals are aging, including the number of immune cells called macrophages in fat and hormone levels in the blood. Miller and colleagues are seeking funding to test whether these indicators start to change after mice consume compounds for only a short time. If they do, he says, researchers could watch for similar alterations in human samples and perhaps identify molecules more likely to work in clinical trials.
For now, Driscoll says, “We are still looking for blockbuster drugs, but we are realizing it’s complicated.” Still, the program isn’t showing its age. In the past 2 years, the ITP received 25 and 29 proposals for molecules to test, twice as many as just a few years ago. “There is still a need for this gold-standard approach,” Baur says.
