The COVID-19 pandemic highlighted the high-risk older people face from infections due to weaker immune systems and existing health conditions. Care home residents are especially vulnerable. The effectiveness of vaccines, like the flu shot, is lower in older adults, and COVID-19 vaccines may also be less effective for them. Researchers are looking for ways to improve older people’s immune responses. One approach is using drugs called geroprotectors, which can counteract age-related immune decline. These drugs, like mTOR inhibitors and statins, have shown promise in improving vaccine responses and fighting infections. Ongoing trials are testing their effectiveness against COVID-19.

Abstract

The COVID-19 pandemic serves as a potent reminder that older people are at very high risk of adverse outcomes from infectious disease because of comorbidities associated with ageing and decreased immunological competence (immunosenescence). Care home residents are particularly at risk because physiological vulnerability is compounded by cohabitation with other frail adults, increasing exposure and risk of infection. Immunosenescence not only increases susceptibility to disease but also blunts the effectiveness of vaccines¹—one of our most powerful tools for preventing infections—with annual influenza vaccinations only 30–40% effective in the most at-risk older populations. In the race for creating a vaccine against COVID-19, immunosenescence is most likely to present a disincentive to the inclusion of older people in trials, and vaccine formulations effective in younger people (<65 years) might not engender immunity in older populations. Finding ways to alleviate immunosenescence is a priority to improve the health of ageing populations, but to do so requires a robust understanding of the underlying causes of age-related decline and immunosenescence.

Biological ageing results in loss of physiological reserve—the capacity of a cell, tissue, or organ system to function beyond its basal level in response to increases in physiological demands. This loss of reserve is now known to be underpinned by a discrete set of biological mechanisms that can be therapeutically targeted. One such mechanism is cellular senescence, leading to the accumulation of dysfunctional cells that secrete tissue-degrading proteases plus pro-inflammatory cytokines and chemokines, causing local and systemic harm. Senescence of immune cells (eg, via proliferative exhaustion), combined with depletion of naive T cells through thymic atrophy, exacerbates age-related loss of immunity to novel pathogens and vaccines. Approaches aimed at restoring immune function and improving tissue and organ physiology are thus likely to be important in mitigating the catastrophic effect of infections on older people.

Geroprotectors are drugs that target core biological mechanisms underlying ageing^2,3 and are able to counteract the loss of function occurring with age in multiple organ systems, including the immune system. These drugs might offer unique opportunities to protect vulnerable older people from infectious pathogens and might help to mitigate the consequences of acute infections and chronic multimorbidity, for example by acting to alleviate detrimental effects of senescent cells. Several drugs have shown geroprotective efficacy in preclinical testing, with several agents repurposed (often at very low doses) from existing alternative clinical indications (table). Of particular note for reversal of immunosenescence is that short-term treatment with geroprotective mTOR inhibitors (everolimus and BEZ235–RTB101 [Basel, Switzerland]) was found to improve responses to influenza vaccination in older adults, with benefits possibly persisting for a year after treatment.⁵ Such drugs suppress excess senescence-associated inflammation while also improving innate immunity. RTB101 has been shown to upregulate interferon-induced antiviral gene expression in older adults,⁶ which is the first line of immune defence against viral infections such as COVID-19. Trials of RTB101 and other mTOR inhibitors to prevent and treat COVID-19 are ongoing (table). Similarly, statins can act as geroprotectors to support immunity, positively affecting innate and adaptive immune responses to improve pneumonia outcomes in older adults.⁷ Statins are also now being tested for benefit in COVID-19 (table).⁸

Authors: Lynne S Cox , Ilaria Bellantuono , Janet M Lord  Elizabeth Sapey , Joan B Mannick , Linda Partridge , Adam L Gordon , Claire J Steves , Miles D Witham