ANTI-AGEING RESEARCH SPOTLIGHT ILLUSTRATION BY MICHELLE THOMPSON; PHOTOS: GETTY MICHELLE THOMPSON; PHOTOS: BY ILLUSTRATION Growing up Scientists seeking to reverse or stall the effects of ageing are trying to make the leap from laboratory research to human trials. BY NEIL SAVAGE nyone who’s ever owned a pet dog mechanisms involved in ageing that should to life. “The real question to me is not ‘can we knows that the relationship will end enable them to intervene in, slow or even reverse push the average lifespan up so it’s closer to 100 too soon. After 10 or 15 years, Fido’s the process. Researchers have already shown instead of 70-something?’ but rather ‘can we Afur is grey, his hips are out of joint and he’s that they can extend lifespans in yeast, round- have a healthier healthspan?’” says Elissa Epel, unsteady on his feet. It’s like watching a family worms and mice, so why not in dogs or people? a psychiatrist who directs the Aging, Metabo- member get old, but it happens much faster Human lifespan has increased markedly lism, and Emotions Lab at the University of than with a spouse or parent. And therein over the past century, in large part owing to California, San Francisco. “Who cares if you might lie an opportunity for scientists seeking improvements in nutrition and sanitation, and live to 100 if you are not able to do stuff?” to delay ageing in humans. through the use of vaccines and antibiotics. In Kaeberlein is hoping to treat 500 dogs over a “We all accept that dogs age about seven times 1900, according to the World Health Organiza- 5-year period with rapamycin, a drug that has faster than people do,” says Matt Kaeberlein, a tion, the global average life expectancy was just been shown to lengthen life in mice by 30–40%. biologist who directs the Healthy Aging and 31 years; even in the wealthiest countries it was Because of the rate at which dogs age — their Longevity Research Institute at the University under 50. By 2015, the average was 72, and it average lifespan is around 11 years — 5 years of Washington, Seattle. “What’s different about was as high as 84 in Japan. should be long enough to show whether rapam- a dog and a person? It’s just our DNA.” Most anti-ageing researchers are not seek- ycin can extend the life of a middle-aged dog sig- DNA studies have identified genes that ing immortality. They’re hoping to extend nificantly, and to hint at whether the same might affect ageing and longevity in a wide array of the ‘healthspan’, the period in which people be possible for humans. The trial would be run species, including humans. Over the past two remain disease-free and vigorous, shortening in parallel with a larger longitudinal study look- decades, scientists have uncovered molecular old age and perhaps adding a decade or two ing at the genetic and environmental factors ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. A14ll ri gDECEMBERhts reserved. 2017 | VOL 552 | NATURE | S57 SPOTLIGHT ANTI-AGEING RESEARCH that are linked to longer life and better health cancer was 100 years ago.” by age — in this case, immune function. in 10,000 dogs across the United States. Kaeber- Some people also question whether trying to One way that rapamycin might help to slow lein likens that study to the Baltimore Longitu- treat ageing makes sense from a humanitarian ageing is by tackling the problem of cellular dinal Study of Aging, a project that has followed standpoint. Brian Patrick Green, an ethicist at senescence. Damaged cells can either undergo more than 3,000 human volunteers since 1958. Santa Clara University in California, says that apoptosis, a form of cellular suicide, or they “Except that in a dog, you can follow them from although there’s nothing intrinsically wrong can become senescent, shutting down cellular birth to death in a decade.” with extending human life, it does carry some division and sending out signals that lead to Kaeberlein sees his dog study as one of a risks. He worries, for instance, that people an immune response. That’s beneficial for, say, series of steps that will ultimately lead towards in rich countries will benefit while those in dealing with a wound, but as people age, the translating laboratory findings into human developing nations continue to die young. mechanisms that clear away the senescent cells medicine. On one level, his aim is concep- People living longer could also consume more become less effective and the cells build up. That tual. “A big challenge we have in this field is resources, leading to social and environmental can lead to long-term inflammation of a variety convincing non-scientists that ageing is just a catastrophes, he says. of tissues, a risk factor in conditions such as heart biological process, and because it’s a biologi- disease. “Senescence is something that is good cal process it can be modified, genetically or PROMISING PATHWAYS for the organism, but eventually it can become a pharmacologically,” he says. In her former position as a researcher at problem,” says Manuel Serrano, a cancer biolo- The study is also a way to test a potential Novartis, Mannick led a study that focused gist at the Institute for Research in Biomedicine anti-ageing drug in conditions that are similar on immunosenescence, the decline of the at the University of Barcelona, Spain. to those of humans. Dogs live in our houses, immune system’s function with age. The study Rapamycin can stimulate autophagy, the breathe second-hand smoke, drink tap water showed that a rapamycin derivative, RAD001, clearance mechanism for senescent cells. That and sometimes even sleep in our beds. “It’s helped to restore immune function in older could prove useful in diseases, such as Alzhei- hard to imagine an animal that shares the people, such that their subsequent response mer’s and Parkinson’s, in which plaques build human environment more than dogs,” Kaeber- to an influenza vaccine was more effective1. up in the brain. “All sorts of ageing-related lein says. “It’s a huge step forward — closer to ResTORbio is now following that up with a neuro degenerative diseases might benefit from the human condition than laboratory studies.” small-scale study of whether the same drug can mTOR inhibition,” Mannick says. help older people to ward off lung infections. Rapamycin is not the only drug being PIECE BY PIECE Mannick expects to get the results of that trial explored to treat ageing. Another promis- For researchers who want to investigate drugs in the second half of next year. ing candidate is metformin, an oral medicine that might slow ageing in humans, one approach taken by people with diabetes. Metformin is to test them not on ageing itself, but on condi- inhibits mTOR and has other effects related tions that become more common as people age to cellular ageing: it improves autophagy and — from arterial hardening, arthritis and heart reduces tissue inflammation and DNA dam- disease to cancer, diabetes and Alzheimer’s. AGEING age. Nir Barzilai, a geneticist who directs the “We’re breaking ageing into pieces that we can IS JUST A Institute for Aging Research at Albert Einstein tackle one piece at a time,” says Joan Mannick, a College of Medicine in New York City, has been clinician who serves as chief medical officer at BIOLOGICAL trying to get funding for a metformin trial for resTORbio in Boston, Massachusetts, a spin-off ageing. His plan is to give the drug to people of the Swiss pharmaceutical company Novartis. who already have one age-related disease — “We’re tackling a common pathway that may be PROCESS. cancer, heart disease or Alzheimer’s — and see underlying multiple ageing-related conditions whether the treatment reduces their likelihood and looking at one condition at a time to see if of developing one of the others. Researchers we can have clinical benefit.” Rapamycin is usually used to suppress the have already found that people with diabetes That approach is needed because the conven- immune response, not to boost it — the drug taking metformin have lower rates of heart dis- tional view is that ageing is just to be expected, is given to recipients of organ transplants to ease and cancer than a control group of people whereas an illness such as liver cancer is seen prevent rejection. It inhibits a protein known without diabetes; they also have less cognitive as something that went wrong. “The medical as mechanistic target of rapamycin (mTOR), impairment and live longer overall5. “When and scientific community have thought of age- which is part of a signalling pathway that you fix ageing on the cellular level, you fix a lot ing as something different from disease,” says affects ageing in organisms from yeast and fruit of other things,” Barzilai says. David Sinclair, a geneticist at Harvard Medical flies to mice. The protein senses environmental Both Barzilai and Sinclair are supported by School in Boston and co-director of Harvard’s cues, such as whether a cell is getting sufficient the Glenn Foundation for Medical Research, Paul F. Glenn Center for the Biology of Aging. nutrition. In good conditions, it signals cells to which seeks to find ways to prolong healthy Because ageing isn’t viewed as an illness, Sin- grow and reproduce; in times of stress, it shuts lifespan, and which funds ageing-research clair says, researchers are forced to find a spe- down reproduction and makes cells stress- centres at 11 US universities.