Even as the COVID-19 pandemic continues to spread across much of the world, scientists are increasingly finding the underlying reasons for the apparent link between older age and worse outcomes following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A new study published on the preprint server medRxiv* in August 2020 shows that genetic factors, chronic disease, and biological aging define the relationship between aging and the severity of COVID-19.
Transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. Virus particles are shown emerging from the surface of cells cultured in the lab. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Image captured and colorized at NIAID's Rocky Mountain Laboratories (RML) in Hamilton, Montana. Credit: NIAI
As people age biologically, the immune system becomes less effective at countering pathogens, which is termed immunosenescence. This includes an impaired response to novel antigens, inadequate memory responses, higher autoimmunity, and excessively long periods of inflammation. However, people who live healthy lives upward of a century have been reported to have circulating immune cells that have unique immune responses. Again, their children also show lower inflammatory responses. This suggests that genetically heritable factors are involved in determining longevity.
Severity of COVID-19 Increases with Aging
Prior research has shown that anywhere from 70% upward of people with COVID-19 above the age of 70 years become symptomatic, compared to 20% in the age group 10-19 years. Mortality is also exponentially higher with increasing age. Thus, many drugs to reverse cell senescence and biological aging are being trialed to protect older individuals from this disease. However, crucial evidence between the susceptibility to COVID-19 and lifespan is still wanting.
Using MR to Understand Why
The current study uses an approach called Mendelian randomization (MR), which looks at genetic variants strongly linked to a particular exposure phenotype to discover the causal role of the exposure under study. The explanation for the validity of this principle is the random location of the gene variants at the time of conception, independent of environmental influences or reverse causation effects. This means that MR can pick up exposure-related effects that are due only to these genetic factors as causes of the outcome. This technique is, therefore, analogous to the randomized controlled trial (RCT), which is a gold standard method in detecting actual relationships.
The researchers say, “MR can provide valuable insights into causality when it is infeasible to perform an RCT or before an RCT is performed.”
Exposures vs. COVID-19 Outcome
In the current study, the researchers analyzed multiple single nucleotide polymorphisms (SNPs) to disentangle the relationship between aging and COVID-19, focusing on the following as exposures: four traits linked to lifespan (parental lifespan, healthspan, longevity and the combination of these traits); and four genetic risk factors known to be linked to earlier death in humans (Alzheimer disease (AD), cardiovascular disease (CVD), type 2 diabetes (T2D) and smoking; and four measures of epigenetic age acceleration. They also estimated the biological age acceleration (BAA) in COVID-19 patients taken from the UK Biobank cohort.
Longevity and Lifespan are Protective
The research showed that humans with a long lifespan were protected against COVID-19, at 32% lower odds, which means that the risk of being infected decreases by about 68% per additional decade of life. Defining longevity as survival to the 90th percentile of age, the odds were 68%. Taking into account the cohort’s known bias towards severe COVID-19, this could also mean that these factors are related to severity and death odds following infection, rather than infection risk per se.
This protective effect was not observed in patients with severe respiratory illness or respiratory failure – perhaps because there were too few cases.
Again, the four measures of epigenetic age were found to be related to aging in one case, namely, GrimmAge. An annual increase in this parameter was related to a 25% higher risk of COVID-19 per year. Significantly, this is the only one of the four, which focuses on mortality and is the most accurate at predicting lifespan.
Protective Effect of Longevity is Via Slower Aging
Healthspan is a term that denotes the lifespan free of age-related chronic disease, mainly myocardial infarction, congestive cardiac failure, chronic obstructive pulmonary disease, dementia, diabetes, stroke, and cancer. In the current study, there was no link between the healthspan and COVID-19. This is unexpected since there was a high number of significant SNPs in genome-wide association study (GWAS) healthspan. The investigators concluded that longevity was protective against the infection not by delaying the appearance of these disease conditions, but by slowing down the biological aging process and thus extending the lifespan.
Accelerated Biological Age
To test this, they used other measures for parallel assessment of biological age prediction based on risk factors such as the biochemical results, complete blood counts, and physical activity. The BAA derived from all these were found to be linked to the COVID-19 incidence. The odds of infection were raised by 28% and 31% for each additional decade of biological age measured by the Phenotypic Age and DOSI tools, which rely on blood biochemistry and complete blood counts, respectively. These were also found to affect the risk of COVID-19 incidence and case fatality rate even after excluding the BAA association with chronic disease, that is, in non-frail cohorts.
Biological age was also increased in cohorts of those who died of COVID-19 relative to those tested and probably infected. The same applies to those tested vs. those free of the disease.
Disease and COVID-19
Lifespan genetic variance was found to depend most on the loci for AD, CVD, T2D, cancer, and smoking. The study was therefore extended to MR analysis of these exposures in particular. The research indicates that the only exposure associated with a higher risk of COVID-19 is late-onset AD, which increases the odds by 13%.
BAA and Acute Diseases
Prior research shows that, as confirmed in the current study, the use of biological age predictors based on risk factors is clearly linked with chronic disease and unhealthy lifestyles, as well as with the future odds of chronic disease developing in healthy subjects.
The current study, however, shows that BAA is also associated with a higher risk of acute diseases, including COVID-19, as well as death due to such diseases. Acute disease risk was significantly linked to BAA predicted by biochemical blood markers, complete blood count, and mean steps per day recorded over a week.
Exercise and COVID-10 Risk
Mean steps per day are a predictor of BAA, which is, in turn, linked to the risk of acute infection. Following lockdown, research indicates reduced mean physical activity by about 28%, or over 1,400 steps a day, over 30 days. The current study suggests that taking 1,500 steps a day, on average, is linked to a lower chance of disease by over 10%. Lower mobility reacts in a feedback loop to further increase BAA measures, and this requires more advanced studies to predict the resulting increase in risk.
The researchers concluded that the aging clocks, which are the phenotypes that indicate the occurrence of ongoing aging, are linked to COVID-19 risk and fatality. Thus, it would appear that drugs that extend lifespan do have a role to play in preventing COVID-19 in the elderly. People who have a longer lifespan may have a more effective immune response, which is probably responsible for the decreased odds of infection.
The current study also uses BAA predictors from pre-pandemic days, thus avoiding the charge of reverse causation. Moreover, causality is likely in the absence of other confounding factors.
The study concludes: “In our MR study, we established a causal link between aging and COVID-19 infection, thus supporting the idea that lifespan-extending or biological age-reversing drugs, as a category, should be considered as a preventive measure in the elderly and prioritized in clinical trials.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.