Stiff Fibroblasts: Why Healthy Ageing Is Not Enough to Fight Covid-19
Imagine skin wrinkles; no amount of exercise of healthy eating could prevent that.
Age represents the number one risk factor for severe Covid-19. “Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65,” Harvard researchers stated in a published review in Aging.
The risk is independent; it remains even after adjusting for confounds, including medical comorbidities. It seems even healthy older adults are at risk for severe Covid-19. This is by no means surprising as ageing alone is an independent risk factor for many diseases like cancer, Alzheimer’s disease, and respiratory virus infections like influenza and SARS.
Ageing of the Immune System
The most common explanation for the direct causal link between ageing and diseases is that the immune system gradually becomes inefficient. The organ where cancer- and virus-fighting T-cells mature called thymus decrease in size as people age, for example. Other mechanisms include immunosenescence, inflammaging, epigenetic and glycome changes, many others, as the Harvard researchers pointed out.
But the immuno-ageing process can be attenuated with lifestyle factors to a certain extent. “Conversely, individuals who live healthy lifestyles and consume geroprotectors such as metformin, resveratrol and NAD+ boosters may have a decreased risk of fatality [of Covid-19],” the Harvard paper admits. Geroprotectors are anti-ageing substances.
Living a healthy lifestyle — marked by regular exercise, not smoking, not drinking alcohol, and maintaining a healthy weight — reduce the risk of being hospitalized for Covid-19 by 50% in a U.K. population study. And this protective effect is adjusted for age and other confounds. (I narrated this study here).
If a healthy lifestyle blunts immuno-ageing and lowers the risk of severe Covid-19 and chronic diseases such as obesity or diabetes, surely it can mitigate the effects of age in Covid-19 severity. But it doesn’t, at least not entirely. There must be something else besides immuno-ageing, lifestyle, or chronic diseases.
Stiff Fibroblast From Ageing
Fibroblasts synthesize protein fibres — such as collagen, reticular, and elastic fibres — that form the extracellular matrix (ECM). ECM holds cells together to maintain the structural integrity of tissues and organs.
Protein fibres that fibroblasts make, however, accumulate with age. They take up space and increases tissue stiffness. Scientists call this phenomenon the stiffening of fibroblasts. “We found that fibroblasts from old donors exhibited an increase in rigidity of ∼60% with respect to cells of the youngest donors,” said a 2010 experiment published in Biophysical Journal.
Stiff fibroblasts make tissues less elastic, which is an irreversible process like how the skin loses elasticity with age.
Likewise with lung tissues that became stiff, or less elastic, with age. “The respiratory system in ageing individuals is characterized by fibroblast dysfunction, which results in increased deposition of extracellular matrix (ECM) and in local differences in tissue stiffness,” Switzerland bioengineer professors wrote in Nature Reviews Molecular Cell Biology. “We hypothesize that coronaviruses can potentially take advantage of the altered mechanical state of cells in ageing hosts for their replication and propagation.”
The professors then cited a series of experiments showing that stiff and relaxed fibroblasts — or old vs young — have a distinct gene profile. Because as the mechanical state of the cell changes, so is its genetic expression and cell functions.
To illustrate this mechanical-gene-function concept, consider types of sponge that absorb water more readily due to different kinds of material used that results in different mechanical states. Or consider how less elastic skin (from ageing) bruise more easily as it loses its potency to blunt external forces.
The shape of stiff lung fibroblasts could make it more conducive to coronavirus infection.
Similarly, stiff and relaxed fibroblasts respond differently to the same stimulus (or the external environment) at the genetic level. And there is an “overlap between genes that are differentially regulated by coronavirus infection and the mechanical state of cells,” the professors noted. They proposed that the stiffness of lung fibroblasts — acquired via ageing — could shape lung tissues in such a way that is more conducive for coronavirus infection.
For more compelling and advanced reasonings, have a look at the professors’ paper: “Mechano-genomic regulation of coronaviruses and its interplay with ageing.”
What makes ageing the number one independent predictor for severe Covid-19? The current consensus is immuno-ageing. But lifestyle factors and chronic comorbidities — both of which are also independent risk factors — could explain some of its effects. The chances are that immuno-ageing is not the sole factor for the causal link between age and severe Covid-19.
Imagine skin wrinkles. No amount of exercise of healthy eating could prevent that.
Stiff fibroblast as a result of ageing could be another prominent factor. It doesn’t have to be just Covid-19, but other respiratory infections like influenza virus where age is also an independent predictor of poor disease outcomes. To blunt fibroblast stiffening would require much more than a healthy lifestyle, such as stem cell therapy or substances containing fibroblast growth factors. Imagine skin wrinkles brought about by less elastic and stiff dermal fibroblast, for example. No amount of exercise of healthy eating could prevent that.