The search for a treatment for ageing OVERVIEW • Geroscience research is exploring and some are already being tested in human interventions that delay biological ageing and clinical trials. reduce the risk of age-related diseases and • Many uncertainties remain about the effects conditions. that treatments for ageing would have • Strong market demand is driving investment on human health span and lifespan, the in geroscience research, particularly in economy, models of care, health inequalities, the US. Investment in this area has been personal identity, and how people work and highlighted as a key opportunity for the UK in live later in life. the future. • There are calls for an ethical framework • Animal research has led to the discovery for geroscience research to help guide of several potential interventions for ageing researchers, policy makers and consumers. INTRODUCTION In most countries, people are living longer and number of older people is predicted to increase healthier lives than ever, but are still spending markedly over the next 25 years,2 addressing a significant number of years in poor health age-related health conditions is a pressing towards the end of their lives.1 Common societal challenge. Healthy ageing is a priority conditions experienced by older people include policy area for the World Health Organization and cardiovascular disease, cancer, dementia, governments around the globe. arthritis, and general frailty. Given that the Geroscience, also called biogerontology, is a we are healthy – than tackling each condition field of research that is exploring the biological individually. This briefing note summarises processes that underlie ageing. Researchers the main scientific developments to date, and working in this field believe that intervening in the potential ethical and social issues that the these processes could be a more efficient way discovery of a treatment for ageing might raise. of increasing health span – the number of years BIOLOGICAL AGEING Biological ageing is a progressive decline in Hundreds of genes also have been found to bodily function and an increasing susceptibility be involved in ageing.4 Recent advances in the to disease and death as we get older. There tools of research, such as genome sequencing, is no consensus about the precise processes computer modelling, data science, and the that cause biological ageing, although it is clear collection of long-term data from specific that no single mechanism is responsible. Cell groups of people, are likely to accelerate our damage and errors in DNA accumulate over our understanding of ageing processes in the near lives, eventually leading to cellular dysfunction.3 future.5 INVESTMENT IN AGEING RESEARCH Large amounts of public and private funding lead longer and healthier lives”.6 Anti-ageing are being directed towards research on biotech has been described as: “risky and most ageing, driven by strong market demand. likely to fail, but if one company is successful the The US is the world leader in geroscience, outcomes would be monumental”.7 Geroscience with several government-funded research research groups and companies also exist in programmes on ageing, such as the US almost every other developed country in the National Institute on Aging, and a number of world, with particularly active centres in Germany, biotechnology companies exploring potential Spain, Australia, and the UK. However, a recent ageing interventions, many backed by wealthy Government strategy for the life sciences entrepreneurs. Google founders Sergey Brin suggests that the UK has been underperforming and Larry Page, for example, have launched in the field of ageing research, and investment in biotechnology company Calico, which is seeking this field is highlighted as a key opportunity for to “devise interventions that enable people to the UK in the future.8 POTENTIAL AGEING TREATMENTS Although questions remain about the underlying responsiveness of this enzyme has been found causes of ageing, animal studies have shown that to decline with ageing, suggesting that metformin it is possible to intervene in ageing processes. may have beneficial effects on the ageing The main scientific developments in the search process.10 The Targeting Aging with Metformin for ageing interventions are summarised below.9 (TAME) clinical trial in the US, expected to start in 2018, will explore the effects of metformin on METFORMIN ageing in 3,000 men and women aged 60 or over who have no existing serious illnesses.11 This Metformin has been used as an effective is the first trial to study the effects of a drug on diabetes drug for over 50 years. It works partly biological ageing, which could pave the way by enhancing the activity of an enzyme involved to ageing being recognised by regulators as a in metabolic processes essential for health. The disease and to further drug trials in this area. Nuffield Council on Bioethics 2 HORMESIS, DIETARY RESTRICTION AND age, and injecting stem cells into animals has RAPAMYCIN been shown to enhance the repair of age-related damage in organs such as the brain, and increase Inducing a mild stress response in cells, known lifespan.23 Until recently, there were significant as hormesis, can delay ageing in animals. barriers to the use of stem cells for therapeutic Exercise, heat, and radiation are all hormesis- purposes in humans. Stem cells can be derived inducing agents.12 However, the best studied from donated embryos, but are prone to immune agent is dietary restriction without malnutrition, rejection when transplanted. The use of embryos which can extend healthy lifespan in a range of is also ethically controversial. In 2006, it was animals. In humans, it has been shown to reduce discovered that stem cells could be generated risk factors for diabetes, cardiovascular disease, from adult cells, opening up a range of new and cancer, and to slow biological ageing, but possibilities in the field of regenerative medicine. dietary restriction is not desirable or realistic for The effects of stem cell therapy on age-related most people.13 Similar effects are seen when conditions such as frailty and Alzheimer’s disease the activity of metabolic pathways that detect are being explored in early-stage clinical trials nutrients are reduced by gene mutations or in the US.24 Unproven and unlicensed stem cell drugs.14 Rapamycin, for example, a drug used treatments for a range of ‘rejuvenation’ purposes to prevent organ transplant rejection, inhibits are also being offered by private clinics across the pathway involved in nutrient sensitivity and the world.25 extends lifespan in animals.15 Despite the risk of serious side-effects, the effects of rapamycin YOUNG BLOOD on frailty in people aged 60 and over with heart disease are being explored in a small clinical Research suggests that blood from young mice trial in the US.16 A similar drug, RAD001, has can have a rejuvenating effect in older mice. been shown in a small trial to boost the immune It was recently found that injecting one blood system of healthy people aged 65 years or over.17 protein in particular called GDF11 can regenerate animal organs including the heart and brain.26 RESVERATROL AND OTHER SIRTUIN This was hailed as a major breakthrough in INHIBITORS ageing research,27 but the findings have been disputed by companies developing drugs A group of enzymes called sirtuins have a role that inhibit, rather than stimulate, GDF11.28 in many cellular processes that affect ageing.18 Nevertheless, a number of commercial clinical Chemicals that interact with sirtuins have strong trials are exploring the effects of transfusions potential as ageing treatments. Resveratrol, for of young blood in humans. One US study is example, a naturally occurring chemical found in recruiting 600 people aged 35 and older who red wine, is known to affect sirtuin activity and will pay to receive a blood transfusion from a the ageing process in animals.19 The resveratrol donor aged 25 or younger.29 Critics suggest the anti-ageing supplement market is already big design of the study is dubious, both ethically and business globally, but only small amounts of scientifically.30 Another trial, also in the US, is resveratrol are absorbed into the body when studying the effects of young blood transfusion administered in humans and the long-term health in a small number of people with Alzheimer’s effects are unproven.20 Synthetically produced disease.31 sirtuin inhibitors show more promise, and some have been found to improve the health and TELOMERASE AND TA-65 extend the lifespan of mice.21 The pharmaceutical industry has invested heavily in the development The discovery in the 1980s that telomeres, of synthetic sirtuin inhibitors, but they have not the tips of chromosomes, are vital for cell yet been translated into drugs for human use.22 division and repair earned the researchers a Nobel prize.32 Telomere shortening occurs with STEM CELL THERAPY ageing and is associated with an increased incidence of disease and death.33 The enzyme Stem cells are unspecialised cells involved in telomerase lengthens telomeres and thus has repairing and replenishing other cells and tissues been suggested as a target for anti-ageing in the body. Stem cell function decreases with interventions. The plant-based supplement Bioethics briefing note: The search for a treatment for ageing 3 TA-65, said to increase telomerase activity, is working on developing drugs, collectively called available to buy worldwide as an anti-ageing aid. senolytics, that will selectively kill senescent cells. Industry studies suggest TA-65 has beneficial Several senolytics have been found to work in effects on the health span of mice and humans.34 mice and it is likely they will be tested in human The US-based manufacturer is now conducting trials in the near future.40,41 clinical trials on healthy adults.35 However, the reliability and independence of these studies HORMONES AND ANTIOXIDANTS have been questioned and there are concerns that stimulating telomerase activity could The anti-ageing effects of hormones have been increase the risk of cancer.36 Another way of studied for many years.