key: cord-0692764-oi0bzx7l
authors: Cox, Lynne S; Bellantuono, Ilaria; Lord, Janet M; Sapey, Elizabeth; Mannick, Joan B; Partridge, Linda; Gordon, Adam L; Steves, Claire J; Witham, Miles D
title: Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults
date: 2020-11-09
journal: Lancet Healthy Longev
DOI: 10.1016/s2666-7568(20)30011-8
sha: 057cf70552e904a29fb76cc4e41b91d18e2dea5a
doc_id: 692764
cord_uid: oi0bzx7l

nan

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 vaccines 1 -one of our most powerful tools for preventing infectionswith 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 proinflammatory 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.

FDA-approved indication Effect on senescence or immunosenescence mTOR inhibitors: first generation (allosteric, non-competitive)-sirolimus and everolimus; second generation (active site inhibitors, competitive with ATP)-RTB101 and AZD8055

First generation inhibitors target mTORC1, decrease translation, increase autophagy and alter metabolism; second generation inhibitors target mTORC1 and possibly mTORC2, as above and also affect cytoskeleton Cancer; immunosuppressant in kidney transplant rejection and some autoimmune conditions (NB doses for these indications are far higher than those that provide geroprotection) Improve outcomes in many age-related diseases; 4 improve response to flu vaccination 5 (ACTRN12613001351707); decrease incidence and severity of respiratory tract infections in older adults; 6 sirolimus in trials (NCT04341675) for COVID-19 pneumonia; RTB101 in trials for COVID-19 prophylaxis in older people in the community (NCT04584710) or in nursing homes (NCT04409327), geroprotective at 1/120th maximum tolerated dose, well tolerated in older adults (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 Given such promise, what needs to happen now to make progress towards widespread clinical use of geroprotectors? The majority of current experimental drug trials-both for COVID-19 and for non-COVID infections-do not include older adults with multimorbidity. This exclusion of older people from trials must change if we are to understand the efficacy of new drugs in this population group who are at the highest risk. Additionally, randomised controlled trials of geroprotectors are needed, both as adjuvant therapy to enhance vaccine responses and to improve immunity in older people at risk of contracting COVID-19 and other infections. Care home residents, too often neglected during the COVID-19 pandemic, have much to gain from such an approach and should be prioritised for involvement in geroprotective trials. Candidate medications are already widely used in the clinic and have good safety profiles, especially at the low doses needed for geroprotection. Notably, shortterm treatment can give long-term protection, as seen with drugs that remove senescent cells (senolytics) 9 that have a hit-and-run activity requiring only infrequent administration thus maximising benefit while minimising side-effects. Finally, we need regulatory bodies to support applications for appropriate clinical testing of geroprotectors, and to provide appropriate frameworks for their marketing authorisation and regulatory approval. The promise of geroprotective drugs will, if realised, extend far beyond the COVID-19 pandemic to improve overall health resilience in our ageing populations. Now is the time to test them. , during the conduct of the study; reports personal fees, non-financial support and other support from resTORbio, outside the submitted work; is employed by resTORbio; and has 14 patent families, which have been filed by Novartis or resTORbio related to RTB101, pending. LP reports grants from The Wellcome Trust and Alzheimer's Research UK, outside the submitted work; reports other support from The Max Planck Society, outside the submitted work; and is the Director of the Max Planck Institute for Biology of Ageing, Cologne. ALG reports grants from NIHR Applied Research Collaboration East Midlands, Dunhill Medical Trust, British Geriatrics Society, Abbeyfield Foundation, the Academy of Medical Sciences, the Newton Fund, and The Wellcome Trust, outside the submitted work. CJS reports grants from The Wellcome Trust and The Chronic Disease Research Foundation, outside the submitted work; and is the clinical and scientific lead on the COVID Symptom Study. MDW reports grants from NIHR Newcastle Biomedical Research Centre, NIHR, British Heart Foundation, Chief Scientist Office of the Scottish Government, British Geriatrics Society, outside the submitted work; and is the National Speciality Lead for Ageing for the NIHR's Clinical Research Network. All authors have jointly submitted a clinical trials bid for COVID-19 prophylaxis to NIHR and continue to work towards establishing clinical trials for improving immunity, COVID vaccine responses, and the overall health of older people.

TORC1 inhibition enhances immune function and reduces infections in the elderly

TORC1 inhibition with RTB101 as a potential pan-antiviral immunotherapy to decrease the incidence of respiratory tract infections due to multiple respiratory viruses in older adults

Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial

In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19

Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study

Observational study of metformin and risk of mortality in patients hospitalized with Covid-19

LP); Institute of Healthy Ageing and GEE

University Hospitals of Derby and Burton NHS Foundation Trust

Hospital, London, UK (CJS); Department of Twin Research and Genetic Epidemiology

Hospitals NHS Foundation Trust

The effect of ageing of the immune system on vaccination responses

Find drugs that delay many diseases of old age

The quest to slow ageing through drug discovery

mTORC inhibitors as broad-spectrum therapeutics for age-related diseases