Why does COVID-19 disproportionately affect the elderly?

By: Amber L. Mueller, Maeve S. McNamara, David A. Sinclair

Glenn Center for Biology of Aging Research, Blavatnik Institute, Harvard Medical School

Preprint, 30 April 2020 – not peer reviewed.


  • Severity and outcome of COVID-19 largely depends on a patient’s age.
    • > 65 years old: over 80% of hospitalizations.
    • > 65 years old: 23-fold greater risk of death.
  • Co-morbidities and a lack of resilience fail to explain inability to clear the virus.
    • Co-morbidities increase the chances of fatal disease.
      • Cardiovascular disease, diabetes, obesity and hypertension.
    • But co-morbidities alone do not explain variability in COVID-19 symptoms.
  • Molecular differences across age categories may determine whether COVID-19 is a mild or life-threatening illness.
    • Identify the mechanisms of the disease and individuals most at risk.
    • Treatments that could increase survival in the elderly (restoring ability to clear the virus).
  • Viable hypotheses for different impact across ages include:
    • Age-related changes in immune cell repertoire, epigenome, NAD+ levels, inflammasome activity and biological clocks.
  • Technologies that activate the body’s defenses against aging may help prevent COVID-19 severity.

Human coronaviruses have been known to impact elderly people disproportionately.

  • Typical disease trajectory in the elderly.
    • Virus spreads to the lungs -> pneumonia, ARDS.
    • Virus spreads to other organs (through epi- and endothelial cells) -> widespread inflammation, immune reaction, blood clotting, organ damage (death…).
  • Role of the immune system in suppression.
    • Recognize.
    • Alert.
    • Destroy.
    • Clear.
  • Unclear which part of immune system is compromised in the elderly.
  • Aging and the (deteriorating) immune system.

Innate immune system

  • Body’s first line of defense.
    • Sentinel cells (macrophages) recognize viral proteins.
    • When detected, pro-inflammatory state is triggered, attracting immune cells to the site of infection.
  • Deterioration with aging:
    • Initial stage: slow to recognize infection and trigger pro-inflammatory state -> fast spread of virus.
    • Advanced stage: prolonged activation of pro-inflammatory stage -> excessive inflammatory damage.

Adaptive immune system

  • Thymus:
    • Primary lymphoid organ.
    • Site of T cell development.
    • One of the first tissues to experience aging.
    • Thymic atrophy with age -> reduction in naïve T cells.
  • Other common effects with age: loss of T cell diversity, weaker T cell activation.
  • T cell depletion:
    • Exhaustion of the immune system.
    • Driven by repeated exposures to viruses over one’s lifetime.

Citokyne storm

  • One in two fatal cases of COVID-19 experience a cytokine storm.
    • 82% > 60 years old.
  • Hyper-activation of the immune system.
    • Rapid and uncontrolled inflammatory signaling cascade.
    • Triggers inflammation in major tissues such as the lungs, kidneys, heart, liver and brain.
    • Likely involves the immune system’s detection of a large quantity of viral antigens released by dying cells.
  • Hyper-coagulation in small blood vessels (blood-clotting).
    • High levels of IL-6 cause vascular endothelial cells to secrete fibrin.
    • Fibrin causes small clots to form in the microvasculature of the body.
      • In COVID-19, in the lung, this may underlie the hypoxemia seen in patients with seemingly functional lungs.
    • If left untreated, clots leach additional clotting factors from the bloodstream.
    • Increases the risk of bleeding and multi-organ failure.
  • Cytokine storm: triggering sequence.
    • Inflammaging.
      • Higher basal circulating levels of pro-inflammatory cytokines.
      • Obesity, poor diets and oral health, and sedentary lifestyles.
    • Increase in NLRP3 activity.
      • Major protein component of the inflammasome.
        • Steady age-related increase in the abundance and activity of NLRP3 in immune cells.
      • SIRT2 (see “NAD”) controls NLRP3.
        • No NAD+ -> no SIRT2  -> too much NLRP3 -> cytokine storm.
        • Also:  no SIRT2 -> no DNA repair -> inflammaging.
    • Virus, stressor, challenge.
      • For instance: SARS-CoV-2 antigen-mediated hyperactivation.
  • COVID-19 pathway to cytokine storm:
    • Coronavirus proteins cause a decline in NAD+ and increase in NLRP3.
    • Decline in NAD+: disrupt cell signaling, DNA repair, gene regulation and apoptosis.
    • Increase in NLRP3: hyper-activity of the inflammasome.
  • Components of this pathway also play a dominant role in many chronic diseases.
    • Chronic disease also triggers hyper-active inflammasome.
    • Explains positive correlation of co-morbidities, cytokine storm and COVID-19.
      • Diabetes, obesity, etc.

Epigenetic changes with age

  • Dysregulation of epigenome during aging.
    • Lifetime accumulation of epigenetic changes.
    • Results in changes in gene expression.
    • A biomarker of chronic diseases and aging.
    • Potentially the underlying cause of chronic diseases and aging.
  • Effects:
    • Compromises immune cell composition and function.
    • Negatively impacts viral defenses.
      • Including adaptive immune memory during infection.
  • COVID-19 perhaps accelerates epigenetic changes.
    • By altering DNA methylation.
    • For instance by deregulating the ACE2 system.

Impact of decline in sirtuins

  • During aging and particularly during the course of COVID-19, levels of NAD+ decline.
  • Changes to the levels of NAD+ affect immunity and coagulation.
  • NAD boosters, such as the NAD+ precursors NMN and NR [110], have been suggested as first-line treatments against COVID-19, especially aged patients.

Biological clocks

  • Biological clocks predict human health and longevity better than chronological clocks.
    • An individual with a biological age greater than their chronological age is thought to be undergoing accelerated aging.
    • May increase the risk of COVID-19 fatality.
  • Measured by:
    • DNA methylation patterns.
    • Inflammaging.
    • Gene expression patterns.
    • Frailty (see “Interventions for Human Frailty“).
    • Serum proteins.
    • IgG glycosylation.
  • Clocks based on DNA methylation patterns.
    • Or “epigenetic age”.
    • Affected by various factors:
      • Lifestyle factors such as calorie intake and smoking.
      • Chronic diseases.
    • Clocks based on IgG glycosylation.
      • Enzymatic process by which carbohydrates called glycans are attached to proteins or lipids.
      • Typically on the cell surface or in the bloodstream.
      • IgG glycosylation affects pro- and anti-inflammatory properties.
    • Clocks based on immune system.
      • Immune system heterogeneity between individuals increases during aging.
      • May prove to be the most accurate in identifying COVID-19 susceptible individuals.

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