Near everyone who dies from the SARS-Cov-2 virus responsible for the COVID-19 pandemic is old. The old are vulnerable firstly because their immune systems are much diminished in effectiveness, and secondly because the state of chronic inflammation characteristic of old age makes the cytokine storm that causes much of the SARS-Cov-2 mortality more likely and more severe.
Members of the medical research community focused on intervention in the aging process – a way to treat all age-related conditions by addressing their underlying causes – are attempting to use the attention given to COVID-19 to educate the public and policy makers. Any number of influenza seasons, in which the vast majority of the dead are elderly, seems to have failed to get the point across: that the age-related decline of the immune system causes great harm, and that harm might be significantly reduced in the future given a focus on research and development for immune rejuvenation. But perhaps this pandemic will cause people to listen. Hope springs eternal.
Understanding how drugs can delay aging and related diseases is part of a larger scientific endeavor supported by the National Institute on Aging and others called geroscience. This approach aims to understand and ultimately modify the basic biology of aging and in so doing, develop new paradigms to treat multiple age-related chronic diseases at the same time. Geroscientists have long hypothesized that by targeting the biology of aging, all diseases of aging can be delayed. Hallmarks of aging have been established and shown that they are all interconnected, thus targeting any single hallmark results in improvements in others. In animal preclinical studies, health span and life span have been dramatically increased by targeting those hallmarks, using genetic tools and drugs, demonstrating that aging is a modifiable condition.
Older people are at such risk in part because the vigor of our immune response flags as we age. Of particular importance are the hallmarks of immune dysfunction underlying the vulnerability of older adults to infections and the inflammation which accounts for the response to those infections. In addition to age, many of us are also weakened by coexisting age-related conditions that diminish our resilience further.
Interventions with existing drugs with established safety profiles that target the biology of aging, immune mechanisms and resiliency (i.e. “geroprotectors” or “gerotherapeutics”), should be explored. While many geroprotectors have been successfully tested in pre-clinical settings, to date none of them has been approved as geroprotectors for use in humans. Consequently, self-medication with any of these compounds is highly discouraged.
One such drug is metformin which has been shown to target multiple hallmarks of aging and increase health span and life span in animals. Metformin has already indicated protective capacity against COVID-19. In a retrospective analysis of 283 type 2 diabetes patients from Wuhan, China, with confirmed COVID-19, investigators found no difference in the length of stay in hospital, but persons taking metformin had significantly lower in-hospital mortality (3 of 104, 2.9%) than those not taking metformin (22 of 179, 12.3%).
A second line of drugs are mTOR inhibitors, which have been shown to increase healthspan and lifespan in almost all animals tested, from yeast to rodents. The mTOR inhibitor rapamycin reverses age-related declines in influenza vaccine response in mice and two Phase 2 clinical trials completed by resTORbio showed that the rapamycin derivative everolimus could enhance influenza vaccine response in healthy elderly people. A phase 3 clinical trial failed.
Given the current public health crisis that is disproportionately affecting our aging population, it is imperative that we start discussing pragmatic approaches to rapidly implement the testing of such drugs in the face of the COVID-19 pandemic and an aging global population. At this stage, broad clinical trials of potential geroprotective therapies are needed, to enable extensive data collection and analysis of their potential benefits and indications.