Will pharmacists one day be advising on medicines to prevent ageing? Ingrid Torjesen reports on recent research on slowing down the ageing process.
While life expectancy is increasing across the globe due to better management of chronic conditions and medical care that reduces mortality, the length of time that people spend living with ill health at the end of their lives is also growing.1 The search is on, therefore, for medical interventions that can delay, slow or stop the processes that are associated with ageing and age-related diseases, including Alzheimer’s disease and cancer.
Traditionally, medicine has looked at disease in a compartmentalised way, but now some processes are increasingly being implicated in several conditions. For example, people with untreated diabetes are predisposed to conditions that include dementia, cardiovascular disease, blindness and peripheral neuropathy. But, Steven N. Austad, scientific director of the American Federation for Aging Research, says: “The traditional medical community is having a hard time grappling with this new kind of thinking about medicine which is that if you can treat the underlying process of ageing you can basically address many of the diseases and disabilities at the same time.”
The first randomised placebo-controlled trial to look at whether a drug could potentially do this and prolong the human lifespan is about to begin in the USA. The Targeting Aging with Metformin (TAME) study will include over 3,000 people aged 65 to 79 years, and assess whether metformin can delay the onset of age-related diseases, including cancer, cardiovascular disease and Alzheimer’s, over six years. Type 2 diabetes is associated with older age, obesity and physical inactivity, and raises the risk of early death, so when researchers at the University of Cardiff in Wales found that diabetic patients treated with metformin had a lower mortality rate than not only patients treated with sulfonylureas but also matched non-diabetic patients, they suggested that the drug might be a potential life-prolonging candidate.2 Animal studies had already shown that worms given metformin had a third longer lifespan3 and that mice given the drug in middle age had a longer life span, and were healthier.4
Even more promise?
Metformin is not the drug that shows the most promise in animal studies, but it was chosen because it has been used by millions of people safely for 60 years and there is a fair amount of observational data that patients with diabetes taking metformin have less cancer, less dementia and less cardiovascular disease than those who do not, says Professor Austad.
He was involved in getting the trial off the ground, and says that previously no one had thought it possible to do a clinical trial for drugs that treat underlying causes of ageing because it was assumed it would take 50 years to see the outcomes. Mouse studies, however, suggest that these drugs can be effective at preventing adverse health events, even if started late in life. Professor Austad originally favoured testing another drug that had shown more promise in mouse studies, but his view changed: “This is the first trial, so why not look at something that is explicitly safe,” he says, and because metformin is off patent and therefore cheap, “people don’t think we’re just doing it just to make a bunch of money.”
The most promising drug in mouse studies has been sirolimus, which is normally used as part of an immunosuppressant cocktail after kidney transplant and in some cancer chemotherapy, Professor Austad says. Dozens of studies have shown that mice treated with sirolimus live longer, with preserved cognition, muscle strength and balance, have a boosted immune system, and that the drug reduces Alzheimer’s disease and cancer.
One study showed that mice given sirolimus were much better protected when exposed to the influenza virus,5 and because the elderly respond less well to flu vaccination than younger people, one of the first potential uses for sirolimus being looked at is boosting their response to the vaccine, says Professor Austad. Elderly volunteers in Australia given sirolimus before the flu vaccine have already been shown to have a heightened antibody response.6
In its usual clinical use sirolimus is associated with side effects such mouth sores and lung inflammation, but Professor Austad points out that these patients are very sick and that the dose required for anti-ageing might be much lower. He predicts that sirolimus will be the next drug tested in a human anti-ageing trial, and says that there are at least six other potential drug candidates, but their health impact in mice needs first to be defined.
Senolytic drugs
Researchers are also looking into communities in which people are long-lived to try to identify genetic or environmental factors that might be significant. Others are trying to understand why some types of animal live much longer lives than humans. However, another research avenue that is close to human trials, because it has shown promise in mouse studies, is the use of senolytic drugs to eliminate senescent cells.
Senescence is a cell state, like proliferation or differentiation, but it is when cells lose their ability to divide. Although senescent cells can occur at any phase in life, they are resistant to apoptosis and tend to accumulate with increasing age. Senescence used to be considered something that happened only to cells that divide, and that the cells were prevented from dividing because of DNA damage or because their telomeres became too short after replicating too many times. It is now apparent that virtually any cell can acquire a senescent state, explains one of the leading researchers in the area, James Kirkland, director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic, Rochester, Minnesota, and Noaber Foundation Professor of Aging Research. Several dozen factors, including potentially cancerous mutations, metabolic stress, surrounding tissue damage or even high glucose, can induce a cell to become senescent.
Some senescent cells develop a senescence-associated secretory phenotype (SASP) which means they kill cells and damage tissue around them. Senescent cells tend to accumulate at the sites of age-related changes and disease stimuli, like fat tissue in diabetes, plaques in arthrosclerosis and the brain in Alzheimer’s disease, Professor Kirkland says, which raised the question: Is it possible to selectively eliminate senescent cells and perhaps delay, prevent or alleviate multiple age-related chronic diseases?
Researchers hypothesised that senescent cells have mechanisms to defend themselves against the destructive products that they produce and identified at least six pathways by which they do this. They then used RNA interference studies to show that if they disabled key regulators on those pathways, senescent cells died but normal cells were unharmed. Existing drugs and natural products were screened to identify those which target these particular proteins and could be senolytic. Around 15 agents have been described in the literature, including the chemotherapy drugs dasatinib and navitoclax, and the plant flavanol quercetin, and potentially hundreds more have been identified by pharmaceutical companies.
Many mouse studies have been conducted and these show that senolytic drugs reduce frailty and improve logic function in rapidly aged mice.7 In two-year-old mice (equivalent to an 80-year-old human) such drugs have been shown to enhance cardiac ejection fraction and to reduce age-related vascular stiffness and calcification, for which there is no treatment. This condition, called calcific medical sclerosis, is distinct from atherosclerosis, and is the main driver of systolic hypertension and therefore strokes and atrial fibrillation, but for which there is no treatment. Senolytic drugs have also been shown to alleviate hepatic steatosis, which is caused by fat accumulation in the liver and is now the leading cause of cirrhosis in the developed world, by reducing senescent cell abundance.
Osteocytes, the non-dividing cells within bone, can become senescent-like and accumulate in bone marrow and Professor Kirkland’s group found that targeting these with senolytic drugs can increase the number of functional osteoblast cells that make new bone. “We found that we were able to get regeneration of trabecular bone in the spine and both cortical and trabecular bone in the femur, which increased bone strength in the context of age-related osteoporosis in mice,” he says.
Senolytic drugs have also be shown to improve pulmonary function and reduce pulmonary fibrosis in mice with bleomycin-induced lung damage, a model of idiopathic pulmonary fibrosis, for which there are only two minimally effective drugs and for which the only real treatment is lung transplantation. It is in this serious condition that the first trials to see whether senolytic drugs clear senescence cells in humans will soon be conducted, and the results should be evident within months, says Professor Kirkland.
Because it takes two to four weeks for new senescent cells to form and senolytic drugs have an elimination half-life of under 12 hours, a “hit-and-run approach” will be used, he says. “These drugs do not have to be continuously present to work. In fact, we found that they were more effective and safer in mouse models if given once every two weeks or once a month.” Because the senescent cells cannot divide, development of proliferation-dependent drug resistance is not anticipated, he adds.
It is possible that one of the drugs being studied in proof-ofconcept trials right now might be able to extend healthy lifespan by 10 to 20 years, Professor Austad says, but the real question will be whether it also extends the period of ill-health at the end of life or compresses it. “That’s just starting to be looked at in the experimental animal work and the results are different depending on the kind of intervention,” he says. The oldest intervention, which is dietary restriction in mice, not only seems to prolong health but also to shorten the period of disability at the end of life, whereas in some genetic models mice live longer, but the period of ill health is prolonged.
S. Jay Olshansky, professor at the School of Public Health, University of Illinois at Chicago, and research associate at the Centre on Aging at the University of Chicago and the London School of Hygiene and Tropical Medicine, says there are two potential futures for medicine. In the first, we continue to treat diseases such as heart disease, cancer and Alzheimer’s as if they are independent of each other. “If we continue to succeed in any way in any of these diseases we expose the same population to an elevated risk of everything else that is not influenced by whatever we succeed against,” he explains. The second way is to try to slow down the underlying processes of ageing associated with such diseases. “The goal here is to extend the period of healthy life, so what we would like to do is put pharmacists and doctors out of business. But that’s not going to happen,” says Professor Olshansky. “What realistically is going to happen, we hope, is that, if we succeed in extending the period of healthy life, there will be much less to do until you get very old — into your 80s or 90s. Then you have to treat the inevitable consequences of changes that occur to the body with time. These are the Achilles heels of the human body, we can’t stop these processes, but we might eventually be able to slow them down.”