Can COVID-19 accelerate brain aging?

COVID-19 is an acute respiratory illness that is caused by the SARS-CoV-2 virus, but it can also cause long-term symptoms that last long after the viral infection has passed, often referred to as “long COVID”. These symptoms sometimes involve the brain, such as trouble focusing, memory loss, and brain fog. We previously discussed in our blog a study showing that people who have recovered from severe COVID-19 experienced significant cognitive deficits. Are cognitive symptoms experienced after COVID similar to cognitive decline seen with aging? A recent study reported that people who had severe COVID-19 had gene expression patterns in the brain that resembled those of older people.

These findings come from postmortem analyses of brains from 21 people who experienced severe COVID-19, one patient who had asymptomatic COVID-19, 22 age- and sex-matched people uninfected with COVID-19 with no history of neurological disorders, and another group of nine people uninfected with COVID-19 but who had a history of intensive care unit (ICU) or ventilator treatment [1]. Gene expression patterns were examined in the frontal cortex, a brain region critical for cognitive function.

Researchers discovered that gene expression patterns in the brain were significantly different between people with severe COVID-19 versus age-/sex-matched uninfected people—and people with severe COVID-19 had gene expression patterns that were similar to those of old people. In other words, genes that were upregulated in aging were also upregulated in severe COVID-19, and genes that were downregulated with aging were also downregulated in severe COVID-19. More specifically, in severe COVID-19 and in old people, genes involved in immune responses (e.g., inflammation) had increased expression, while genes involved in cognition and memory pathways had decreased expression. Severe COVID-19 was also associated with downregulation of genes involved in synaptic transmission (communication between brain cells), mitochondrial ? function, and insulin secretion, and upregulation of genes involved in DNA damage, oxidative stress, stress response, and cell death. Together, these findings suggest that many of the same biological changes that occur with brain aging are also seen in the brains of severe COVID-19.

In an effort to quantify the effects of severe COVID-19 on brain aging, researchers derived an aging index that comprised gene expression data. They discovered that severe COVID-19 was associated with a significantly higher “predicted aging index” compared to corresponding uninfected age-/sex-matched controls as well as those who were uninfected with COVID-19 but who had a history of ICU or ventilator treatment. Thus, the link with brain aging appears pronounced with severe COVID-19 and is not a commonality across other diseases requiring ICU and/or ventilator treatment.

Are the signs of aging seen in severe COVID caused by the infiltration of SARS-CoV-2 virus into the brain? Consistent with previous studies, SARS-CoV-2 virus was not detected in the brains of those who experienced severe COVID-19. Instead, inflammation markers (e.g., tumor necrosis factor and others) were increased in the frontal cortex of COVID-19 patients, suggesting that increased inflammation in the body leads to harmful effects in the brain in the absence of direct invasion of the SARS-CoV-2 virus. Inflammation markers are often increased in the aging brain and implicated in age-related cognitive decline [2; 3].

Although the link between severe COVID-19 and brain aging is alarming, there are many unanswered questions. Are these signatures of aging seen in severe COVID-19 permanent? Do similar changes occur in people with mild COVID-19 but to a lesser extent? What about in asymptomatic COVID-19? Also, with new variants of SARS-CoV-2 emerging, we currently don’t know whether there are any differences in gene expression across the different variants.

The scientific community is ramping up their efforts to determine the mechanisms behind cognitive symptoms associated with long COVID and to discover treatments and cures. In the meantime, the best way to protect yourself from COVID-19 and any subsequent cognitive symptoms is to prevent COVID-19 illness by receiving one of the approved vaccines/boosters for COVID-19. The additional benefit of receiving a COVID-19 vaccine/booster is that even if you do get COVID-19, it may partly reduce the risk of long COVID, including brain fog and other symptoms [4].

1. Mavrikaki M, Lee, J.D., Solomon, I.H., Slack, F.J. (2022) Severe COVID-19 is associated with molecular signatures of aging in the human brain. Nature Aging.
2. Fu P, Peng F, Alzheimer's Disease Neuroimaging I (2022) CSF TNF alpha levels were associated with conversion from mild cognitive impairment to dementia. PloS one  17, e0274503.
3. Hu WT, Howell JC, Ozturk T et al. (2019) CSF Cytokines in Aging, Multiple Sclerosis, and Dementia. Frontiers in immunology  10, 480.
4. Al-Aly Z, Bowe B, Xie Y (2022) Long COVID after breakthrough SARS-CoV-2 infection. Nature medicine  28, 1461-1467.

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