Growing up Scientists Seeking to Reverse Or Stall the Effects of Ageing Are Trying to Make the Leap from Laboratory Research to Human Trials

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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

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 neurodegenerative 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. The US National cific disease to treat if they want funding to test resistant, which lets them live longer2. Academy of Medicine is developing a Grand a drug. Researchers hope that by tackling one Although Kaeberlein hasn’t yet received Challenge for Healthy Longevity, which will aim age-related disease at a time while focusing on any funding for his dog study, he did run a to encourage research by providing monetary the underlying mechanisms, they can eventu- trial funded by the US National Institutes of prizes. Academics are not the only ones inter- ally build up the case that ageing itself is some- Health on 24 dogs. The work, published ear- ested in this field of research. In 2013, Google thing that can — and should — be modified. lier this year3, showed an improvement in the founded Calico, a company it said would focus “If you started to get old at 60 or 70 and eve- animals’ cardiac function after just ten weeks on health and wellness; the company put biolo- ryone around you lived to 200, your condi- of rapamycin treatment. Kaeberlein and his gist Cynthia Kenyon, who discovered that a tion would be given a name and people would team had already seen the same effect in mice, genetic mutation could double the lifespan donate money to try and help your family,” demonstrating that it works in more than one of the roundworm Caenorhabditis elegans, in says Sinclair. “It’s just how common it is that species4. He says that Mannick’s Novartis trial charge of ageing research. biases us to think that ageing is a natural — was the first to show that the results could be In addition to Novartis, UK drug firm Glaxo- and therefore acceptable — way of life, just like translated to humans using a measure affected SmithKline (GSK) has shown interest in ageing

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ANTI-AGEING RESEARCH SPOTLIGHT ISTOCK/GETTY

Red sea urchins have telomeres that do not shorten with age, so are of interest to researchers.

research. In 2008, it paid US$720 million for nanobots. British gerontologist Aubrey de Grey, Sirtris Pharmaceuticals, a US company that for instance, thinks that humans could live for Sinclair founded. Although the initial drug 1,000 years or more, and futurist Ray Kurzweil candidate, resveratrol, didn’t work out and thinks that we will merge with machines in the GSK absorbed Sirtris in 2013, the UK firm has next 30 years and become practically immortal. continued to develop new molecules to activate Mannick thinks that longer health is the a gene encoding the protein sirtuin, which has important focus. “I don’t think about ‘are we been shown to slow ageing in worms, fruit flies extending lifespan?’ because we don’t know if and yeast. James Ellis, who leads GSK’s sirtuin that is possible in humans, and many people research, says that the company is doing pre- don’t want to live longer unless they remain clinical testing on these new molecules for a healthy. I think an easier goal — and a very variety of inflammatory conditions. “Our com- important goal — is to just keep elderly people pounds are being targeted to specific disease free from the burden of disease,” she says. indications and not to ageing itself,” Ellis says. Sinclair is more optimistic. “Eventually, Drugs are not the only intervention that there’s no biological reason why we couldn’t might slow or reverse ageing. “We know that live to 150,” he says. “Many species on the exercise interventions can slow cellular ageing planet do already. I think extending healthy in many ways we can see,” says Epel. Diet, exer- lifespan by ten years is a goal that we will cise and social interaction can help people to achieve in our lifetimes.” live longer, healthier lives6. Epel aims to tie that Just keeping people healthier for longer will to molecular measures of ageing, such as the be beneficial, says Kaeberlein, not only for length of telomeres. A telomere is an area at the the quality of life of individuals, but also for end of a chromosome where DNA sequences the economy, which will have to devote fewer repeat, protecting the chromosome from dete- resources to caring for ill people. “If we could rioration. The sequences get shorter with age keep people healthy an extra two decades, that as cells divide, and people with disorders that would be more than has been accomplished in shorten their telomeres age faster. Some studies biomedicine over the past 50 years,” Kaeberlein show that telomere shortening can be slowed, says. “We don’t need to have people talking and that telomeres might even get longer under about immortality — and that’s counterpro- the right conditions7. ductive in my mind — when the reality of Research is needed to see what, if any, effect what’s possible and maybe not that far off is exercise, diet and stress reduction have on the really exciting and really important.” ■ molecular mechanisms that underlie ageing, Epel says. “We know just observationally that Neil Savage is a freelance science and longer telomeres predict less early disease and technology writer in Lowell, Massachusetts. in some cases — not all — longer lifespan,” she 1. Mannick, J. B. et al. Sci. Transl Med. 6, 268ra179 says. “But no one has ever shown that if you (2014). lengthen telomeres you then live with a longer 2. Laplante, M. & Sabatini, D. M. Cell 149, 274–293 healthspan. That is a gap.” (2012). 3. Urfer, S. R. et al. GeroScience 39, 117–127 (2017). 4. Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. A HUNDRED YEARS OR MORE? Nature 493, 338–345 (2013). So how much longer could people live if some 5. Barzilai, N., Crandall, J. P., Kritchevsky, S. B. & of this research pays off? Some people talk Espeland, M. A. Cell Metab. 23, 1060–1065 (2016). 6. Anderson, B. J., Greenwood, S. J. & McCloskey, D. about adding decades or centuries to life, per- Front. Aging Neurosci. 2, 30 (2010). haps by building new organs using stem cells 7. Shammas, M. A. Curr. Opin. Clin. Nutr. Metab. Care and 3D printing, or by repairing cells using 14, 28–34 (2011).

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ANTI AGING MEDICINE COMES OF AGE Japanese medical doctors and researchers endeavour to promote people’s healthy aging through ACTIVE INTERDISCIPLINARY RESEARCH and social outreach

In the era of longevity, anti- lives,” says Shigeo Horie, about the latest medical investigating a range of areas, aging medicine is important president of the Japanese breakthroughs. such as longevity-linked sirtuin not only for individuals but for Society of Anti-Aging Medicine “Medical research needs genes, bacterial fl ora in the society as a whole. Extending and professor and chairman of to move out of silos,” says intestine, and coenzymes people’s healthy lifespan and the Department of Urology at Horie. “Nowadays, much involved in metabolism, reducing medical expenses Juntendo University’s Graduate medical research has become gathered at the 2017 annual while maintaining the labour School of Medicine. excessively specialized. But meeting to discuss the force is a top priority in countries anti-aging medicine is so mechanisms of aging. such as Japan with a rapidly INTERDISCIPLINARY complex it’s important to In 2015, the society launched aging and shrinking population. RESEARCH exploit elements of many an open access journal called Thanks to recent advances The society and its a liated advanced research fi elds at npj Aging and Mechanisms in the biological sciences, organization — the Japan the same time.” The society of Disease, which covers all researchers are now able to Anti-Aging Foundation — have consists of 9,000 practitioners relevant disciplines of aging intervene in aging processes at an unconventionally open and researchers with a variety research. Two of the world’s the molecular and cellular levels. modus operandi, which is of disciplinary backgrounds leading researchers in the fi eld “It’s time to use the scientifi c characterized by a focus on and provides opportunities — David Sinclair from Harvard insights we have gained to interdisciplinary research and for them to learn from each Medical School and James directly enrich people’s daily educating the general public other. For example, researchers Kirkland from the Mayo Clinic,

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The society’s 18th annual meeting will be held in May 2018

Ryuichi Morishita, vice president of the Japan Anti-Aging Foundation (second from left), and Katsunobu Kato, minister for the MHLW (second from right), at the second Anti-Ageing Japan fair held in Tokyo in collaboration Shigeo Horie, president of with Fuji Television. the Japanese Society of Anti-Aging Medicine

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