Marco Bertorello via Getty Images
In March, as Vadim Gladyshev shifted through the reams of data detailing the kinds of people who were more likely to fall victim to Covid-19, the Harvard biochemist started to wonder if we were thinking about the viral infection in the wrong way.
In Europe, 95 per cent of those killed by the disease were aged 60 or over. According to the UN, the fatality rate for those over 80 is five times the global average. Although many infectious diseases impact older people disproportionately, with Covid-19 the skew towards older people is devastating. Given all this, Gladyshev wondered, why aren’t we treating Covid-19 as a disease of ageing?
As he watched the global arms race to try and find a treatment which either neutralised the SARS-CoV-2 virus or dampen the overactive immune response which leads to many of the deaths, Gladyshev – one of the world’s leading experts on the causes of ageing – could not help but ponder if academics and pharmaceutical companies across the world were heading down the wrong path. “If Covid-19 has the greatest impact on the elderly, rather than targeting the virus, should we not be focusing more on strengthening the host?” he says.
Since the 1930s, scientists have sought clues on how to turn back the ageing process in humans by first trying to extend lifespan in rodents, with two drugs – rapamycin and metformin – showing signs of promise. While it is doubtful that these drugs would be useful in severe cases of Covid-19 where patients are already on ventilator support, Gladyshev’s idea was simple. Could prescribing these drugs to the elderly as preventative measures could give the most vulnerable a better chance of fighting off Covid-19, and prevent them getting to that stage?
Since April, his idea has been taken up by a series of scientists across the US ranging from pharmacologists at Thomas Jefferson University to the Boston-based biotech company resTORbio, who are now testing forms of rapamycin in a series of clinical trials over the coming months.
While rapamycin and metformin are typically known for their clinical uses in cancer and diabetes respectively, the reason why Gladyshev and other longevity scientists think that these drugs could protect the elderly from covid-19 is linked to theories regarding biological age. We typically measure age chronologically based on the number of years a person has been alive, but there is a school of thought that biological age – determined by biomarkers varying from DNA expression to the length of telomeres, the tips of chromosomes – can vary depending on factors ranging from lifestyle to genetics.
Nir Barzilai, founder of the Institute of Ageing Research at the Einstein College of Medicine in New York, argues that the reason some people are less prone to age-related diseases such as cardiovascular disease, dementia, cancer and infections, is because their biological age is much younger. “By the age of 65, half of people in Europe have two diseases or more, but half have less,” says Barzilai. “For me, this is due to their differing biological ages.”
Most of the evidence that drugs might be able to reverse some of the hallmarks of ageing, and thus make an elderly person more resilient to viral infections, comes from studies either in human cells or rodents. This data suggests that rapamycin has the potential to revitalise the body’s natural defence mechanisms within the lungs, stimulating cells such as macrophages – which are designed to seek out and remove viruses – to work more efficiently.
But there have also been further findings in humans which has given longevity researchers increased confidence that they are on the right lines. Back in March, doctors in Wuhan published a study showing that diabetics taking metformin were much less likely to die of Covid-19 than diabetics not on the drug, an interesting finding which backed up previous epidemiological data showing that it can improve lifespan in diabetics. An earlier clinical trial conducted by resTORbio, using a formulation of rapamycin called RTB101, reported that it could reduce rates of respiratory viral infections in healthy people over 65.
Nevertheless when the Covid-19 pandemic began, few specialists outside of longevity research were aware of the anti-ageing properties of these drugs. At the start of April, Edwin Lam – a pharmacology researcher at Thomas Jefferson University – was looking at a study from molecular biologists across the US which used computer models to predict which drugs performed best when it came to helping the body remove the virus. To his surprise, rapamycin and metformin ranked top, ahead of many highly touted alternatives such as hydroxychloroquine.
“Initially I thought this seemed far-fetched,” says Lam. “But then I looked further and found that some scientists had previously used a form of rapamycin called Sirolimus to treat people with severe cases of H1N1 bird flu. They saw a reduction in the viral load and better clinical outcomes. It had also shown antiviral activity in a preclinical model of Middle East Respiratory Syndrome. I presented this to my colleagues and we became really intrigued.”
Lam has now designed a placebo-controlled clinical trial to see whether rapamycin can reduce the viral load in 20 patients with mild to moderate cases of Covid-19. A similar study is also taking place at the University of Cincinnati. ResTORbio are now looking at whether giving 550 nursing home residents an oral capsule of RTB101 each day over a period of one month, could protect them from becoming severely infected with the virus, and needing hospitalisation.
“Nursing home residents have a very high risk of dying from Covid-19,” says Joan Mannick, co-founder and chief medical officer of resTORbio. “This elevated mortality has made the public acutely aware of the dysfunction of the aging immune system. I think the pandemic has the potential to catalyse interest in therapeutics that target aging biology as a new way to improve the function of aging organ systems.”
But other scientists looking at ways to protect the elderly from Covid-19 caution that while they will be monitoring the results of the trials with interest, the evidence regarding the effectiveness of anti-ageing drugs remains limited. “It’s an interesting approach, but the data will have to speak for itself,” says Ofer Levy, who heads the Precision Vaccines Program at Boston Children’s Hospital. “It’s all about safety and efficacy. Is it safe, how long can they be on it, and then is it effective? But it’s something to consider.”
Levy points to another potentially promising approach for protecting the elderly from Covid-19, vaccines which are specifically designed for older people. These typically contain additional chemicals known as adjuvants to try and kick-start the ageing immune system. It’s an approach which was successfully used by British pharma company GlaxoSmithKline to create the Shingrix vaccine in the past five years. This has shown to be highly effective in preventing shingles in people over 50, and Levy is looking to apply this strategy to a Covid-19 vaccine.
One of the ironies of vaccine development is that while over 65s stand to benefit most from immunisation, research has often shown that vaccines against influenza and other infections are at their least effective in the very old. This is thought to be due to changes in the blood which affect the immune response. “As we age, the blood plasma changes and we tend to develop a low level of inflammation in our bloodstream,” Levy says. “Because of this, when you try to immunise someone, you often get an incomplete response to the vaccine.
Instead, Levy’s group is designing a vaccine which is specifically modelled on older immune systems. “Our approach is to take blood donations from elderly volunteers, and then we isolate the immune cells in a dish,” he says. “We then screen lots of small molecules until we find ones which are like rocket fuel to the immune system, we add them to the vaccine and select the formulations which seem to work best against the coronavirus. This is completely different to normal vaccine development as we’re actually designing it with the ageing immune system in mind.”
He hopes that such a vaccine could be in clinical trials by autumn 2021. Barzilai points out that in the meantime there is some evidence to suggest that supplementary treatment with rapamycin could enhance the effectiveness of the first wave of vaccines when they become available, with Japanese company AnGes hoping to make their Covid-19 vaccine available at the start of next year. Rapamycin has previously been shown to enhance the effectiveness of the influenza vaccine. “I’m sure that the initial vaccines will not be effective in the elderly, because their designs ignore their immune deficiencies,” Barzilai says. “But rapamycin could make a difference.”
With the increased interest in rapamycin, longevity scientists predict that Covid-19 could prove to be a major boon for the field of anti-ageing research, a sector which has already been benefiting from injections of funding in recent years. Last year Barzilai received $75 million (£60.5m) to conduct the TAME clinical trial, looking at whether giving metformin to elderly people over a period of four to five years can give them more years of good health. Gladyshev says that the three Covid-19 clinical trials involving rapamycin could provide a whole host of information regarding its ability to reduce biological age.
However, Barzilai is still frustrated that many within the medical community appear to be unaware of the potential of these drugs. He points to the Wuhan study in March, saying that while similar findings have been observed in Italy and Spain, no one has conducted a clinical trial looking at whether administering metformin to the elderly population in general, can offer protective benefits against Covid-19.
“The major problem is that our health organisations are in silo and so ageing is often overlooked as a risk factor in these diseases,” he says. “For me, the question is why are we not using these two drugs on a wider scale to try and protect the vulnerable, when we already have information that they can offer benefit? Metformin has been used clinically for 60 years, it’s already known to be safe. If we just focus on stopping the disease in older people, the whole mortality issue would be different, the lockdowns wouldn’t need to happen, and the economic impacts would be less as well.”
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