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

Summary

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.
- Immunosenescence:
  - Hampers pathogen recognition, alert signaling and clearance.
  - Defects in both the innate and adaptive immune systems.
  - Innate: ineffective recognition and macrophage activation, ineffective natural killer cells.
  - Adaptive: thymic atrophy (see: “Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections”
- Inflammaging:
  - Overactive, yet ineffective alert system.
  - Drives chronic systemic inflammation.
- Driven by pathogenic, genetic, and lifestyle factors.
  - All of these affect the cell’s epigenetic status and the diversity of immune cells.

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.

Summaries