Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults
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
Journal: The Lancet Healthy Longevity (2020)

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 vaccines1Lord JM The effect of ageing of the immune system on vaccination responses.Hum Vaccin Immunother. 2013; 9: 1364-1367Crossref Scopus (87) Google Scholar—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 ageing2Bellantuono I Find drugs that delay many diseases of old age.Nature. 2018; 554: 293-295Crossref Scopus (49) Google Scholar, 3Partridge L Fuentealba M Kennedy BK The quest to slow ageing through drug discovery.Nat Rev Drug Discov. 2020; 19: 513-532Crossref Scopus (198) Google Scholar 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.5Mannick JB Morris M Hockey HP et al.TORC1 inhibition enhances immune function and reduces infections in the elderly.Sci Transl Med. 2018; 10eaaq1564Crossref PubMed Scopus (258) Google Scholar 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,6Mannick J Tomlinson A Shergill S Teo G Klickstein L LB2. 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.Open Forum Infect Dis. 2019; 6: S993-S994Crossref Google Scholar 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.7Sapey E Patel JM Greenwood H et al.Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial.Am J Respir Crit Care Med. 2019; 200: 1282-1293Crossref PubMed Scopus (66) Google Scholar Statins are also now being tested for benefit in COVID-19 (table).8Zhang XJ Qin JJ Cheng X et al.In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.Cell Metab. 2020; 32: 176-187Summary Full Text Full Text PDF PubMed Scopus (337) Google ScholarTableExamples of geroprotective agentsMolecular targetFDA-approved indicationEffect on senescence or immunosenescencemTOR inhibitors: first generation (allosteric, non-competitive)—sirolimus and everolimus; second generation (active site inhibitors, competitive with ATP)—RTB101 and AZD8055First generation inhibitors target mTORC1, decrease translation, increase autophagy and alter metabolism; second generation inhibitors target mTORC1 and possibly mTORC2, as above and also affect cytoskeletonCancer; 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;4Walters HE Cox LS mTORC inhibitors as broad-spectrum therapeutics for age-related diseases.Int J Mol Sci. 2018; 192325Crossref PubMed Scopus (59) Google Scholar improve response to flu vaccination5Mannick JB Morris M Hockey HP et al.TORC1 inhibition enhances immune function and reduces infections in the elderly.Sci Transl Med. 2018; 10eaaq1564Crossref PubMed Scopus (258) Google Scholar (ACTRN12613001351707); decrease incidence and severity of respiratory tract infections in older adults;6Mannick J Tomlinson A Shergill S Teo G Klickstein L LB2. 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.Open Forum Infect Dis. 2019; 6: S993-S994Crossref Google Scholar 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 adultsStatinsPleiotropic: main target is the HMG-CoA reductase pathway; might also target small G protein Rho, affecting the actin cytoskeleton and cell motilityReduction of low density lipoprotein cholesterolIncrease neutrophil cytokinesis and NETosis; decrease sepsis, organ failure and death in older adults hospitalised with community acquired pneumonia7Sapey E Patel JM Greenwood H et al.Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial.Am J Respir Crit Care Med. 2019; 200: 1282-1293Crossref PubMed Scopus (66) Google Scholar (EudraCT 2012-00343-29); currently in many trials for COVID-19 (NCT04407273, NCT04390074, NCT04348695, NCT04426084, NCT04333407, NCT04380402, and NCT04343001) and reported to COVID-19 deaths8Zhang XJ Qin JJ Cheng X et al.In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.Cell Metab. 2020; 32: 176-187Summary Full Text Full Text PDF PubMed Scopus (337) Google ScholarDasatinib (in combination with plant flavonoid quercetin)src-family tyrosine kinase inhibitor (also inhibits BCR-ABL kinase)CancerSenolytic—ie, selectively kill senescent cells; improve physiological function in idiopathic pulmonary fibrosis;9Justice JN Nambiar AM Tchkonia T et al.Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study.EBioMedicine. 2019; 40: 554-563Summary Full Text Full Text PDF PubMed Scopus (588) Google Scholar in phase 2 trials in chronic kidney disease (NCT02848131)MetforminPleiotropic: main target is mitochondrial complex I, inhibition of which leads to activation of AMPK, and inhibition of acetyl CoA carboxylase; increases GLP-1 in gutType 2 diabetesImmunomodulatory especially through T helper cell balance, leading to reduced autoantibodies, cytokines, and neutrophil NETosis; retrospective analysis suggests might improve outcomes for female patients with obesity and diabetes who have COVID-1910Bramante C Ingraham N Murray T et al.Observational study of metformin and risk of mortality in patients hospitalized with Covid-19.medRxiv. 2020; (published online Jun 28.) (preprint)https://doi.org/10.1101/2020.06.19.20135095Google Scholar Open table in a new tab 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, short-term treatment can give long-term protection, as seen with drugs that remove senescent cells (senolytics)9Justice JN Nambiar AM Tchkonia T et al.Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study.EBioMedicine. 2019; 40: 554-563Summary Full Text Full Text PDF PubMed Scopus (588) Google Scholar 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. LSC reports grants from Public Health England, Research England (UK SPINE), Elysium Health, Diabetes UK (under the BIRAX programme), the Mellon Longevity Science Programme, and Access Business Group, outside the submitted work; reports personal fees from a Geroscience Masterclass, outside the submitted work; and is an advisor to the All Party Parliamentary Group for Longevity (UK Parliament). IB reports grants from the Biotechnology and Biological Sciences Research Council, Medical Research Council (MRC), Arthritis Research UK, Horizon2020, Cancer Research UK, and the National Centre for the Replacement, Refinement, and Reduction of Animals in Research, outside the submitted work; and reports other support from Novartis, outside the submitted work. JML reports grants from MRC, Versus Arthritis, National Institute for Health Research (NIHR), Scar Free Foundation, Foundation for Research in Rheumatology, Research England (UK SPINE), outside the submitted work; is the Director of the Institute of Inflammation and Ageing, University of Birmingham; and is a special advisor to the House of Lords Science and Technology select committee on Ageing Science, Technology, and Healthy Living. ES reports grants from Health Data Research UK, The Wellcome Trust, MRC, Alpha-1 Foundation, NIHR, British Lung Foundation, outside the submitted work; is the Director of PIONEER, the Health Data Hub in Acute Care at Health Data Research UK; and is the Managing Director of NIHR Clinical Research Facility Birmingham. JBM reports grants from National Institutes of Health (R01AG064802), 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.