Does COVID-19 "accelerate aging"?
Does COVID-19 "accelerate aging"?
A review of the evidence
You may have seen the media claiming that COVID-19 “accelerates aging.” Researchers like David Sinclair, who works in the field of longevity, have also made such claims:
Do we, in fact, have “good evidence” that COVID advances biological age? Are we shortening our lifespans every time we get a bout of COVID-19?
It turns out that this is not straightforward to answer.
How is aging measured?
In order to answer this, we first have to determine how “aging” is typically measured. By “aging” here we don’t mean chronological age, which is just the number of years a person has lived since birth, but “biological age,” which takes into account physical changes that have occurred in a body.
Researchers use different proxies to try to measure biological age. One commonly used approach is to look at epigenetic changes in DNA, which are reversible modifications to DNA that regulate which genes are turned on or off.
One type of epigenetic modification is DNA methylation, where methyl groups are added to select portions of DNA. A “methyl group” is just a carbon bonded to three hydrogen atoms, and has the chemical formula CH3.
DNA methylation patterns are thought to change with age; they are therefore used to construct “epigenetic clocks” that are used to estimate an individual's biological age.
Other methods include assessing telomere length. Telomeres are the protective caps at the ends of chromosomes that shorten over time, eventually leading to cellular senescence or cell death. Telomere length is sometimes used as a marker of biological aging because it is thought to reflect the cumulative damage and replication history of cells.
Other types of data like blood pressure, lung-function data, and blood markers are also sometimes used to make models that predict aging.
It’s important to note that none of these proxies are perfect, and in fact their methodologies may be highly flawed. We’ll return to this point later, but for now let’s take these proxies at face value to see what the research on COVID-19 and aging shows.
The research is mixed
There are several studies that purport to “measure aging” as a result of COVID-19. They’re not of equal quality though, and they don’t all agree with each other.
Study 1
Let’s first look this study: Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors
They reported that COVID-19 survivors had telomere shortening and accelerated age compared to COVID-19-free people, based on how DNA from their blood was methylated.
However, the COVID-19 survivors were people who “came to the attention of our physicians.” That presumably means that these people had enough symptoms to see a doctor, so these are not like your average person. They were compared against volunteers that were age and sex-matched with some risk factors partially overlapping the COVID-19 patients, but arguably these are not great controls for the COVID-19 survivors who, again, got sick enough from COVID-19 to seek a physician and may have had “accelerated aging” (as compared to their chronological age), to begin with.
Study 2
What would be even better would be a longitudinal study looking at markers of aging both before and after COVID-19 in the same people. Fortunately we have that: Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination
They observed “large bidirectional fluctuations in epigenetic age” that “did not seem to be related to COVID-19 infection.” This “appeared to be attributable to widespread technical noise” in DNA methylation measurement, “as previous studies have found that repeated measurements of the same sample to deviate up to 9 years.”
To mitigate the impacts of “these unreliable epigenetic clock estimates” they applied some techniques to attempt to improve model predictions. They then looked at how different epigenetic clocks predicted aging as a result of COVID-19.
Four of the epigenetic clocks1 showed “no significant differences in epigenetic age” while two of the epigenetic clocks observed increased aging for those over 50 years of age, but either no significant increase or even a decrease in aging for those under 50 years of age, following COVID-19.
Study 3
Accelerated biological aging in COVID-19 patients
They looked at DNA methylation and telomere lengths in blood samples from healthy people, non-severe, and severe COVID-19 patients and found an “increasing acceleration of epigenetic aging at the initial phases of COVID-19,” but this age acceleration could be partly reversed at later phases.
Study 4
Shorter telomere lengths in patients with severe COVID-19 disease
This looked at blood samples from patients that had been hospitalized with COVID-19.
We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.
However, this wasn’t compared with any non-COVID controls, so it doesn’t say anything about whether COVID-19 caused the shortening of telomeres. As with Study 1, these patients, who had been hospitalized with COVID-19, may have had “accelerated aging” to begin with.
Study 5
Epigenetic Clocks Are Not Accelerated in COVID-19 Patients
They found that “COVID-19 samples did not consistently reveal accelerated epigenetic age as compared to chronological age” and “there was overall no evidence for significant telomere attrition in COVID-19 patients.”
Taken together, our results do not provide evidence that severe outcome of COVID-19 is associated with accelerated epigenetic age or significantly shortened telomere length.
Study 6
Strangely, this study found that there was a negative causal relationship between COVID-19 severity and epigenetic age. That is, “people with very severe respiratory symptoms of COVID-19 infection can delay the acceleration of epigenetic age” when using an epigenetic clock called “GrimAge.”
Study 7
COVID-19 subgroups may slow down biological age acceleration
This one also, strangely, found that “hospitalized COVID-19 may slow down GrimAge acceleration and PhenoAge acceleration.” GrimAge and PhenoAge are two different epigenetic clocks.
Study 8
Virus-induced senescence is a driver and therapeutic target in COVID-19
They found that SARS-CoV-2, like other viruses, evokes “cellular senescence” as a primary stress response in infected cells. Senescence is a process by which a cell ages and stops dividing but does not die.2 Patients with COVID-19 displayed markers of senescence in their airway mucosa.
Summary of the studies
This will be a very crude summary of all these studies, but just so you can easily see how mixed these results are:
Study 1:
Reported telomere shortening and accelerated aging based on DNA methylation but was not a longitudinal study.
Study 2:
Longitudinal study reported that four different epigenetic clocks showed no significant difference in aging while two epigenetic clocks showed increased aging in those over 50 years but no significant increase or even a decrease in aging for those under 50, as a result of COVID-19.
Study 3
Found increased acceleration of aging initially during COVID-19 but this could be partly reversed in later phases.
Study 4
Found shorter telomeres were associated with increased severity of COVID-19. However, this wasn’t compared to COVID-free people so we can’t say COVID caused the telomere shortening.
Study 5
Did not find that COVID-19 led to accelerated aging as measured by epigenetic clocks.
Study 6
Found that COVID-19 seemed to lead to a slow down of epigenetic age.
Study 7
Found that COVID-19 seemed to lead to a slow down of epigenetic age.
Study 8
SARS-CoV-2 evoked cellular senescence in the airways.
Why are the results so mixed? Well, for one, some of these studies may not have used the best controls. Also, the studies did not all use the same epigenetic clocks. Some will be better than others, or some will be better for particular tissues or situations. Also, COVID-19 leads to changes in the composition of white blood cells, and this can affect DNA methylation signatures.
As this cautionary note says:
The systematic evaluation of DNA methylation signature of COVID-19 in relation to the biological age is currently a new scientific inquiry.
Based on this, can we really say that we have “good evidence” that COVID-19 accelerates aging?
Can “biological age,” as predicted by epigenetic clocks, reverse?
Suppose we accepted that COVID-19 accelerated biological age. Even so, there’s evidence that this “aging” can be reversed: Biological age is increased by stress and restored upon recovery
This study looked at COVID-19 patients that were admitted to the ICU and had provided multiple blood samples during the course of their pregnancy. They found a significant reversal of biological age in females following discharge from the ICU, but no significant change in males. Males exhibited much more heterogeneity in the trajectories of their biological age over the disease course.
The last time point for the study was “≥7 days post-ICU discharge” so it’s conceivable that we would have seen a reversal in the males too, if the study had gone on for longer.
Does comparable “aging” happen with other stresses? Or other common viruses?
By the way, the study above also found that stresses, like trauma surgery, and even pregnancy, caused a reversible increase in biological age.
That should make us wonder: how special is this “accelerated aging” that we (maybe) see with COVID-19? If comparable “aging” is seen even for things like pregnancy, and if it’s reversible, does it even make sense to call this “aging” at all? Do these stresses even shorten life?
It’s also relevant to know whether we see comparable “aging” effects from other viruses. There’s evidence that respiratory syncytial virus (RSV) infection leads to signs of aging like DNA damage and an accumulation of senescent cells for example:
Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus
The damage observed is associated with the accumulation of senescent cells, displaying all the hallmarks of the senescence phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging… at different times post-infection.
However, there do not appear to be any studies looking at whether flu or common cold viruses can lead to similar “aging” effects as SARS-CoV-2. This doesn’t mean that those viruses can’t cause similar effects; it just means that no one has bothered to look.
Meanwhile, when it comes to COVID-19, we’ve had near-constant fear-mongering for years, which has probably led to researchers hyper-focusing on COVID-19, at the expense of other topics.
This can give us a false sense that SARS-CoV-2 is especially dangerous and special. Maybe it is special, or maybe it’s only special for people who get long COVID; after all, it’s conceivable that these people, who can suffer symptoms for long periods of time, do “age” meaningfully, though we don’t know how irreparable or reversible that “aging” is.
But what we certainly don’t have, is evidence that people who get mild or typical or even severe bouts of COVID-19 will “age” in a way that meaningfully shortens their lives.
How reliable are current measures for aging?
We haven’t even gone into all the caveats associated with the current “measures” for aging.
How should we interpret telomere or epigenetic clock predictions? Do their predictions of “accelerated aging” actually mean that one’s life is shortened?
We’ll explore these questions more in a future article. Stay tuned.
Specifically the PCHorvath1, PCHorvath2, PCHannum, and epiTOC epigenetic clocks did not show a difference.
When a cell gets infected by a virus, it triggers the activation of stress-response pathways that try to control virus replication. Sometimes this leads to the infected cell going into a “zombie-like” state called “senescence.” This is when the cell no longer replicates, but stays viable and metabolically active. Cellular senescence is actually a stress response that protects cells against malignant transformation, facilitates tissue repair and development, and prevents virus replication.
Covid mandates certainly accelerate ageing!
Excellent summary. Thank you.