The Telegraph
While most scientists look at Covid-19 as a viral respiratory illness, Nir Barzilai takes a slightly different perspective. Instead Barzilai, founder of the Institute of Ageing Research at the Albert Einstein College of Medicine in New York, sees it as a disease of ageing. The grim statistics show that he has a point. In Europe, people over 60 have accounted for 90% of fatalities since the start of August. While the impact of Covid-19 has been universal, older people have been disproportionally affected. “This virus has no eyes, but it could see immediately who is old and more vulnerable,” says Barzilai. For Barzilai and other geroscientists – scientists who study the biology of ageing – this represents an opportunity. They have long argued that we need a different perspective for tackling many chronic diseases, from cancer to Alzheimer’s. As all of these illnesses become more common with age, geroscientists have suggested that therapies attempting to reverse some of the cellular mechanisms of ageing, might make older individuals more resilient to a whole range of diseases. The premise of this approach is that while we typically measure age chronologically, the number of years we have been alive, your biological age says far more about your health. Biological age is indicated through various biomarkers ranging from the length of telomeres – the tips of chromosomes – to changes in DNA expression, and even your gut microbiome. Some 55-year-olds may be biologically equivalent to 45, making them more resilient to disease, while others may be far older, due to lifestyle or genetics. Since the 1930s, scientists have identified certain drugs which appear capable of reversing biological ageing in mice. Over the past nine months, the pandemic has provided increasing evidence they may be capable of doing the same in humans. “Covid has moved anti-ageing from hope to promise,” says Barzilai. “The promise is that ageing is flexible, and can be manipulated, is something we’ve shown again and again in animals.” The eight hallmarks of ageing Geroscientists have defined eight hallmarks of biological ageing, which when targeted can improve health and lifespan in animals. These hallmarks range from declining immune function, to a decrease in the quality and quantity of mitochondria – the energy factories of our cells – and an impaired ability of cells to perform garbage disposal and remove toxins or viruses. There are drugs which can target some hallmarks of ageing, including resveratrol - a compound found naturally in foods such as blueberries – but the impact of Covid-19 has sparked particular interest in a cheap, commonly available medication called metformin, which has been used to treat diabetes for over fifty years, due to its ability to lower glucose levels. But recently, epidemiologists have begun to notice people taking it for diabetes also appeared to have reduced rates of cardiovascular disease and cancer. When the pandemic began, an early study from a hospital in Wuhan sparked particular interest. It showed diabetics taking metformin were much less likely to die of Covid-19 than diabetics not on the drug. Geroscientists around the world took note. “Because of the number of people contracting Covid-19, we could gather data on metformin and its impact on reducing mortality, which would otherwise have taken years to collect,” says Vadim Gladyshev, a biochemist at Harvard Medical School. Soon, further studies yielded similar findings. Doctors at the University of Minnesota found metformin lowered mortality rates across more than 6,000 Covid-19 patients with diabetes, albeit only in women. Barzilai believes he understands why. In a paper published earlier this year, he showed that metformin targets all eight hallmarks of ageing at the same time. Now, this accumulation of evidence has helped convince investors to provide $75 million in funding for a landmark randomised control trial called TAME. Intended to begin in June 2021, it aims to see whether giving metformin to older people for four to five years, can give them more years of good health. If this proves successful, it could see metformin licensed by regulators as the world’s first clinically proven anti-ageing therapy. AI recommendations In April, Edwin Lam, a pharmacologist at Thomas Jefferson University, was looking at AI-based predictions of potential Covid-19 treatments and found a drug called rapamycin ranked higher than many highly touted alternatives. Rapamycin is currently used to prevent organ transplant rejection, but geroscientists have been interested in its effects on longevity for decades. It specifically targets a pathway called mTOR, a major driver of many of the cell degradation processes that occur with ageing. Because rapamycin inhibits mTOR, it can help reactivate different parts of the immune system, making them behave like a younger person. Boston-based biotech company resTORbio have previously shown that forms of rapamycin can reduce rates of respiratory infections in over 65s. They are now conducting a clinical trial in the US, looking at whether giving rapamycin to nursing home residents on a daily basis, could protect them from becoming severely infected with Covid-19. If successful, it could pave the way for rapamycin becoming a new treatment for protecting older people from seasonal infections, and future viral outbreaks. New hope for Alzheimer’s The renewed interest in biological ageing as a result of Covid-19, could also yield benefits for other diseases linked to the ageing process, in particular Alzheimer’s. For years, pharma companies have attempted to develop treatments which target the accumulation of amyloid proteins in the brain during the course of the disease. With Covid-19 increasing the spotlight on how ageing makes people more vulnerable to disease, Alzheimer’s scientists have begun to consider alternative approaches. “I think neurologists are becoming more open to the idea that we have been too insensitive to the ageing context in which Alzheimer’s occurs,” says Jeffrey Cummings, professor of neurology at UCLA. “Most patients have the onset of their disease in their 80s, where you get this accumulation of multiple adverse influences on cognitive function.” One particular clue about how to prevent this accumulation may lie in our DNA. As we age, telomeres become shorter, leading to a variety of cell changes. However, in 1984 biologists Elizabeth Blackburn and Carol Greider discovered an enzyme produced in cells called telomerase which naturally prevents telomere shortening, a finding which won them the 2009 Nobel Prize. Telomerase levels also decline with age, but in recent years pharma companies have begun to wonder whether artificially boosting telomerase through drugs, could prevent age-related diseases. Seoul-based pharma company GemVax have developed a product named GV1001 which boosts telomerase levels in cells, with the aim of seeing whether it can prevent decline in Alzheimer’s patients and prevent the onset of the disease altogether. In a recent Phase II clinical trial of moderate to severe Alzheimer’s patients, they reported promising results on an assessment tool called the severe impairment battery (SIB) scale. “The results exceeded our expectations,” said Jay Sangjae Kim, chairman of GemVax. With the major test – a Phase III trial which is set to get underway in 2021 – still to come, the results must be viewed cautiously, but the success of GV1001 has the potential to yield a new frontier of telomerase based drugs for age related diseases.
