The Best Way to Fight COVID May Be to Fight Ageing Itself

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. Eventually, with advances in the field, it may even be possible to reverse the age of cells and tissues so that high-risk older individuals can respond to viral infections as though they were young.

At the onset of the pandemic, we quickly learned that COVID-19 is a disease that primarily affects the elderly. Around 80% of hospitalisations and 74% of deaths due to Covid are of people over the age of 65. This is partly because conditions like diabetes and heart disease (which are risk factors for fatal Covid) are more common with age. However, this does not fully explain the increased risk among older people: there is some fundamental biological factor that makes them more susceptible.

In this article, longevity researcher David Sinclair and colleagues present some of the possible molecular differences in older people and whether these can explain why COVID-19 is a mild illness in some, and a fatal one in others:

• Cells of the innate immune system, such as macrophages and dendritic cells, are less able to detect and alert the immune system to the presence of viruses. As these cells are the first line of defence against a virus, this is likely to accelerate the early stages of infection.
• The immune system becomes more inflammatory (inflammageing), which results in greater tissue damage during the later stages of a serious Covid infection.
• The adaptive immune system, the body’s most powerful and precise weapon against pathogens, becomes less competent with age. This makes it harder for the immune system to eliminate the virus, and makes it more likely that a patient will progress to severe COVID-19.
• Older individuals are more likely to suffer from a cytokine storm, in which the immune system becomes hyperactivated. This leads to widespread and uncontrolled inflammation and tissue damage that is often fatal.

• As we age, our cells accumulate epigenetic changes: alterations to the DNA’s packaging proteins that affect which genes are expressed. Some of these changes may make an individual more susceptible to Covid. One theory, for example, is that epigenetic changes could affect the expression of the ACE 2 receptor, which Sars-CoV-2 uses to gain access to human cells. However, ACE 2 receptor expression doesn’t appear to change with age in humans, nor does its expression seem to affect Covid suscetibility.
• With age, levels of a molecule called NAD+ decline. The primary role of NAD+ is to transport electrons within the mitochondria, where the cell’s main energy source – ATP – is made. Sirtuins are a family of molecules with antiviral and anti-inflammatory properties, but their activity requres NAD+. A reduction in sirtuin activity due to declining NAD+ may therefore contribute to increased risk from COVID-19 with age.

These age-related changes occur at different rates in different individuals. It may therefore be possible to assess a person’s risk from COVID-19 using metrics of biological age. Multiple such metrics, referred to as clocks, have been developed over the last decade. Biological clocks measuring inflammation, gene expression and protein levels can predict longevity more accurately than chronological age. The most widely used clocks currently are DNA methylation clocks, which measure changes to the way DNA is packaged. More recently, a clock based on the immune system called IMM-AGE was developed, and appears to be even better than methylation clocks at predicting mortality. Many other types of clock exist and should all be able to predict COVID-19 susceptibility.

With age being the largest risk factor for fatal COVID-19, many researchers have speculated that geroprotectors – molecules that target ageing itself – could provide an effective means to fight the virus. Several drugs such as metformin and rapamycin control pathways linked to ageing and immune function. Various supplements may also be able to reverse some aspects of immune system decline, for example by reducing chronic inflammation or boosting NAD+.

Age is the strongest predictor of all-cause mortality. The most effective way to reduce mortality from all infectious and chronic diseases is to find ways to make an old body behave like a younger one.