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Aging-US: Why does COVID-19 disproportionately affect older people?


Here is a link to a video interview with Dr. David A. Sinclair about their research on the Aging-US YouTube Channel

Here is a link to a free Altmetric Report on this Research Output

Aging-US published "Why does COVID-19 disproportionately affect older people?" which reported that the severity and outcome of coronavirus disease 2019 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.

The authors 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, they 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.

Dr. David A. Sinclair, Professor of Pathology and Co-Director of the Glenn Laboratories for Aging Research at Harvard Medical School as well as Co-Editor-in-Chief of Aging-US and Dr. Amber L. Mueller, also from Glenn Center for Biology of Aging Research, Blavatnik Institute, Harvard Medical School, said, "Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the worldwide pandemic of coronavirus disease (COVID-19) originated in Wuhan, China, in late 2019."

COVID-19 has (at the time of this study) killed more than 350,000 people, with the majority of deaths occurring in people over the age of 65.

For example, simple explanations for the impact of age that are based solely on co-morbidities or on a general lack of resilience in aging, for example, fail to explain why the immune system often reacts uncontrollably.

Particularly in older people, severe cases of the disease are characterized by acute lung injury and ARDS, the latter of which is typically treated by positive airway pressure with oxygen and pronation or invasive ventilation.

In this perspective, the authors offer potential mechanistic explanations as to why COVID-19 advances in some people and not others, and especially in older patients, including differences in the immune system, glycation, the epigenome, inflammasome activity, and biological age.

Figure 3. Age-related changes that increase COVID-19 susceptibility. The aging immune system undergoes immunosenescence, T-cell diversity alterations and chronic activation of the innate immune system, known as inflammaging. These hallmarks of the aging immune system cripple the body’s ability to clear the SARS-CoV-2 virus, initiate and sustain cytokine storms, than cause acute organ injury, DIC and multi-organ failure. An age-associated decline in NAD+ results in derepression of NLRP3 and inflammasome in older people, further exacerbating the cytokine storm. Coronaviruses also possess an ADP-ribosylhydrolase that further depletes already-low NAD+ levels in older people. Leveling of the epigenetic landscape during aging results in changes in immune cell composition and function that decrease the immune system’s ability to mount a response to infection. Epigenetic dysregulation of ACE2 may also impact increased viral loads in older people. Dysregulation of the RAS during aging and in the context of age-associated disease, such as cardiovascular disease, hypertension, COPD and obesity, contributes to severity of COVID-19 infection. The glycome which controls a variety of immune signaling pathways changes during aging and in the context of metabolic diseases. For example, decreases in IgG galactosylation contribute to chronic inflammation. Biological clocks that measure different biomarkers of biological age may explain increased COVID-19 susceptibility more accurately than advanced chronological age. Created with BioRender.

They also discuss therapies that may improve immunity against viral infection while enhancing the ability of older people to recover from severe COVID-19.

The Sinclair/Mueller Research Team conclude in their Aging-US Research Output that besides understanding the basis of the cytokine storms and coagulopathy, it is not known why SARS-CoV-2 so easily damages such a broad array of tissues in older people but rarely in the young.

Nor is it clear whether older people develop stronger or weaker functional immunity during seroconversion, or how long their protection will last compared to younger people.

Therefore, in designing vaccines against SARS-CoV-2, it will be important to consider that older people may not respond as well to vaccines as young people.

Studies that follow the long-term consequences of SARS-CoV-2 infection in older people will also be critical to understand the long-term health consequences of COVID-19 pathology, such as fibrosis and scarring of the lungs, micro-ischemic events, cardiopulmonary dysfunction, and neuropsychological disability.

These could significantly reduce viral resistance and lifespan in older and middle-aged people who recover from severe cases of COVID-19. The most exciting and potentially impactful technologies to combat COVID-19 and other viral pandemics are those that activate the body’s defenses against aging.

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Correspondence to: Amber L. Mueller email: and David A. Sinclair email:

Keywords: aging, cytokine storm, COVID-19, epigenetic clock, immunity

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

To learn more about Aging-US, please visit or connect with @AgingJrnl

Aging-US is published by Impact Journals, LLC please visit or connect with @ImpactJrnls

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