COVID-19 Review Volume 12, Issue 10 pp 9959—9981

Why does COVID-19 disproportionately affect older people?

Amber L. Mueller1, , Maeve S. McNamara1, , David A. Sinclair1, ,

  • 1 Glenn Center for Biology of Aging Research, Blavatnik Institute, Harvard Medical School, Boston, MA 20115, USA

Received: April 29, 2020       Accepted: May 18, 2020       Published: May 29, 2020
How to Cite

Copyright © 2020 Mueller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection and effectively regulate immune responses.


SARS-CoV-1: severe acute respiratory syndrome coronavirus identified in 2003; SARS-CoV-2: severe acute respiratory syndrome coronavirus identified in 2019; MERS-CoV: middle east respiratory syndrome coronavirus; COVID-19: coronavirus disease 2019; ARDS: acute respiratory distress syndrome; TLR: Toll-like receptor; TCR: T cell receptor; DIC: disseminated intervascular coagulation; IL: interleukin; ACE: angiotensin-converting enzyme; ACE2: angiotensin-converting enzyme 2; RAS: renin-angiotensin system; SIRT1-7: sirtuin 1-7; AGE: advanced glycan end product; NLRP3: NOD-, LRR- and pyrin domain-containing protein 3; IMM-AGE: immune age; PARP: poly (ADP-ribose) polymerase; NAD+: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; SARS-CoV-1 ORF3a: SARS-CoV-1 open reading frame 3a; NK cell: natural killer cell; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PD-1: programmed cell death protein 1; IgG: immunoglobulin G; IgE: immunoglobulin E; AM: alveolar macrophages; CRP: C-reactive protein; CMV: cytomegalovirus; GCSF: granulocyte-colony stimulating factor; IP-10: interferon gamma-induced protein 10; MCP-1: monocyte chemoattractant protein-1; MIP-1α: macrophage inflammatory protein 1 alpha; TNF-α: tumor necrosis factor alpha; mTOR: mammalian target of rapamycin; mTORC1: mammalian target of rapamycin 1; AMPK: 5' AMP-activated protein kinase; TAME: targeting aging with metformin; HDAC: histone deacetylases; CCR1: C-C Motif Chemokine Receptor 1; CXCR2: CXC chemokine receptor 2; ICAM-1: intercellular adhesion molecule 1; HMGB1: high mobility group box 1.