The Science Of Senolytics: The End Of Ageing

The science of extending life is a subject of morbid fascination, conjuring the image of old billionaires being cryogenically frozen. But imagine if, instead of a pill you could take to live forever, there was a pill that could push back the ageing process – a medicine that could stave off the fragility, osteoarthritis, memory loss, macular degeneration and cancers that plague old age. It could happen, with the science of senolytics: an emerging – and highly anticipated – an area of anti-ageing medicine. Many of the world’s top gerontologists have already demonstrated the possibilities in animals and are now beginning human clinical trials, with promising results. If the studies continue to be as successful as hoped, those who are currently middle-aged could become the first generation of oldies who are youthful for longer – with a little medical help. Most scientists studying longevity are more concerned with prolonging what they call “health-span” than they are lifespan: that is to say, helping people to age with less pain and illness, with a better quality of life. Not only would this be good for old people, but in these times of booming elderly populations worldwide, it would be great for economies.

In England and Wales, life expectancy has risen by almost 25 years in the past century; the Office for National Statistics predicts that the UK’s population of over-65-year-olds will grow by 8.6 million (about the population of London) over the coming 50 years. This will be expensive: the NHS spends more than twice as much on 65-year-olds as it does on 30-year-olds; 85-year-olds cost more than five times as much. “Healthy ageing is a huge project – it can come with a lot of benefits, both for governments and older patients themselves,” says Ming Xu, an assistant professor at the University of Connecticut’s Centre on Ageing. Ageing, as Xu notes, is the biggest risk factor for most chronic diseases; the goal of his lab is to unearth novel interventions to slow down the ageing process and simultaneously prevent the diseases.

Xu is at work on senolytics, a branch of medicine that targets senescent cells; the various faulty cells that have been identified as instrumental in our eventual demise. These so-called “zombie” cells linger and proliferate as we age, emitting substances that cause inflammation and turn other healthy cells senescent, ultimately leading to tissue damage throughout the body. Xu was part of a team at the Mayo Clinic, an academic medical centre in Minnesota, that showed in 2011 that “using a genetic trick to get rid of these senescent cells can significantly improve health and lifespan” in prematurely aged mice. In 2016, the same group achieved similar results in naturally aged mice, releasing an arresting image of two elderly rodents born of the same litter. The one cleared of its senolytic cells seems spry and glossy, while its sibling is shrunken, greying and looks its age. The picture alone helped bring in millions from investors including Jeff Bezos and PayPal co-founder Peter Thiel, who saw the promise of replicating the same results in humans. Kevin Perrott, president of the Washington DC-based Global Healthspan Policy Institute, said in 2018 that the response showed that Silicon Valley tended to view ageing as a problem that could be solved “with enough time and enough steps”: “The size of the return is huge. If you’re able to bring anything like that to the market, you have something that’s universally needed.”

However, the “genetic trick” used to destroy senescent cells in the mouse studies was not viable as a safe treatment for people, so a new company, called Unity Biotech, was formed to raise funds to develop a medicine that could safely clear zombie cells from the human body. The first hurdle – for them, and the other scientists investigating the unknown intricacies of senolytics – was identifying what, exactly, they were trying to treat. In order for a drug to be approved, it has to be shown to be effective in treating a disease; but ageing is a natural built-in process, and, far from a localised problem, it involves complex systemic degradation. Trials in senolytics are initially targeting specific conditions such as age-related macular degeneration, glaucoma and chronic obstructive pulmonary disease (which includes emphysema). Most are in the fledgeling stages, working on rodents or human tissue in Petri dishes, although in February a small early human trial showed an improvement in the distance patients were able to walk. Also this year, a pre-clinical pilot trial for injecting a senolytic drug into the knees of people with osteoarthritis showed promising, if mixed results. In the first part of the study, where patients received varying doses of the drug, significant improvements in pain and function were observed, whereas the second experiment, in which patients received the maximum dose, didn’t see significant benefits. It is hoped that, eventually, there will be a number of senolytic drugs that could potentially target different senescent cell types, but currently much of the research has involved a combination of a leukaemia drug called dasatinib and quercetin, a polyphenol common in plants.

This is an extremely new field of research. “That’s why there’s so much interest,” says Sebastian Grönke at the Max-Planck Institute for Biology of Ageing in Cologne. Senolytics are particularly exciting, he says, because “they seem to still work very late in life” … “So it will be possible to study more quickly whether they actually work in humans, and they are applicable to people already at the end of their lives.” Xu says that in theory at least, it should prove impossible to build up a resistance to the drugs, “because senescent cells cannot proliferate.” Even more importantly, he says, there is significant data to show “that you don’t have to treat these patients every single day. You just treat them once a week or once a month … intermittent treatment is more than enough to have huge benefits.” Senolytic drugs may also be able to play a part in other conditions. Xu has found that obesity can cause senescent cells to develop prematurely. “We also found that clearing senescent cells improves insulin sensitivity. So senolytic drugs not only work on ageing but also on obesity … Senescence is a connection between these two very common conditions.” While treating obese mice with senolytics, Xu observed that their anxiety levels reduced, too.

These aren’t the only potential added benefits. Grönke says that senescent cells “play a big role after cancer treatment,” developing as a result of chemotherapy and radiation therapy. “If senolytics can be used to help eliminate the damaged cells before they can spread, a detrimental side-effect of cancer treatment could be alleviated.” Xu usually administers senolytics to mice at their equivalent of 70 to 80 years old in humans. “You don’t want to take it when you’re young, which would have zero effect or harmful effects – but you don’t want to leave it too late. When to start giving the drug is a huge project and a huge question for us to answer over the next several decades.” He expects the ideal treatment age will differ from person to person, and that ultimately scientists will develop a blood or urine test that can assess the level of senescence present. “Some people age very fast, and some age very slow, so it could vary a lot,” he says.

So what can anyone determined to hold off the debilitating effects of age do while we await the wonder drugs? Intermittent fasting may have senescent effects. Grönke says caloric restriction, whereby “people eat less in general,” has been linked to healthy ageing and longevity. Mouse trials have shown that they can live 30 to 50% longer than control animals able to eat as much as they want. “It’s also well known that these animals have less senescent cells at comparable ages.” There is also a diet, developed by the gerontologist Valter Longo at the University of Southern California, that mimics the effects of fasting for those too frail to skip meals. Of course, the risks of disease that increase with ageing are heightened by sedentary living, alcoholism and bad diet. Grönke recommends, along with a healthy diet, “reducing the amount of animal protein you consume – you can eat meat but ideally maybe once per week, maximum.” He says an association between low protein intake and longevity is well established in humans. “Ideally the protein should come from vegetables and not from meat.” Just as obesity has been shown to increase the burden of senescent cells in the tissue, exercise can reduce it, says Xu. But the effects were recorded in obese mice that had undergone a lot of vigorous exercises: “I don’t think the aged population is able to take intense exercise like that.” So some signs are promising, and the potential is huge, but much still remains unknown about senolytics for ageing. There are clinical trials in the pipeline, with drugs for osteoarthritis leading the way, but an effective pill accessible to all is certainly not imminent. Xu puts it at five to 12 years away: “Theoretically I’m confident.” Those looking to live forever might be wise to book that cryogenics appointment, just in case.

Credit: Amy Fleming for The Guardian, 2 September 2019.