In a series of experiments, scientists at Beth Israel Deaconess Medical Center (BIDMC), found that gene usage in the brains of patients with COVID-19 is similar to those observed in aging brains.
Using a molecular profiling technique called RNA sequencing to measure the levels of every gene expressed in a particular tissue sample, the scientists assessed changes in gene expression profiles in the brains of COVID-19 patients and compared them to those changes observed in the brains of uninfected individuals.
“Ours is the first study to show that COVID-19 is associated with the molecular signatures of brain aging,” said co-first and co-corresponding author Maria Mavrikaki, PhD, an instructor of pathology at BIDMC and Harvard Medical School. “We found striking similarities between the brains of patients with COVID-19 and aged individuals.”
Mavrikaki and colleagues analyzed a total of 54 postmortem human frontal cortex tissue samples from adults 22 to 85 years old. Of these, 21 samples were from severe COVID-19 patients and one from an asymptomatic COVID-19 patient who died. These samples were age- and sex-matched to uninfected controls with no history of neurological or psychiatric disease.
The scientists also included an age-and sex- matched uninfected Alzheimer’s disease case for analysis as a control to a COVID-19 case which had co-morbid Alzheimer’s disease, as well as an additional independent control group of uninfected individuals with a history of intensive care or ventilator treatment.
“We observed that gene expression in the brain tissue of patients who died of COVID-19 closely resembled that of uninfected individuals 71 years old or older,” said co-first author Jonathan Lee, PhD, a postdoctoral research fellow at BIDMC and Harvard Medical School.
“Genes that were upregulated in aging were upregulated in the context of severe COVID-19; likewise, genes downregulated in aging were also downregulated in severe COVID-19.
“While we did not find evidence that the SARS-CoV-2 virus was present in the brain tissue at the time of death, we discovered inflammatory patterns associated with COVID-19. This suggests that this inflammation may contribute to the aging-like effects observed in the brains of patients with COVID-19 and long COVID.”
“We also emphasize the potential clinical value in modifying the factors associated with the risk of dementia — such as controlling weight and reducing excessive alcohol consumption — to reduce the risk or delay the development of aging-related neurological pathologies and cognitive decline.”
Better understanding of the molecular mechanisms underlying brain aging and cognitive decline in COVID-19 could lead to the development of novel therapeutics to address cognitive decline observed in COVID-19 patients. The team is now trying to understand what drives the aging-like effects in the brains of COVID-19 patients.
In this study, we took advantage of prior indication that epigenetic age could be altered in the presence of viral infections 17,20,38 and from the fact that shorter telomeres have been associated with the risk of developing COVID-19 with worse outcomes 32.
We used five epigenetic clocks and one telomere length estimator to determine the epigenetic age of the whole blood in COVID-19 patients and healthy individuals. We observed strong correlation of the epigenetic clocks with the chronological age and increasing acceleration of epigenetic aging in the blood samples of healthy individuals and COVID-19 patients.
Our epigenetic study with consistent findings from different epigenetic clocks provides evidence for the association of accelerated epigenetic aging with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, we found a reversible influence of COVID-19 syndrome on epigenetic aging in some COVID-19 patients with the longitudinal DNA methylation profiling analysis.
Overall, these findings suggest that COVID-19 may perturb the epigenetic clock and telomere length. Although the epigenetic clocks and telomere length are known as independent28,29, DNAm aging was parallelled by a telomere shortening in all the observations.
DNA methylation-based estimator of telomere length was shown to have a relatively weak correlation with PCR-based telomere length that is recognized as an accurate quantification36. Therefore, PCR assays are needed to validate the correlation between telomere length and COVID-19.
Mongelli et al. applied PCR assay to quantify telomere length and found a telomere shortening in the post-COVID-19 survivors 39. Although some of our findings could be supported by Mongelli, the association of telomere attrition with severe COVID-19 and dynamic change of telomere length across disease phases need to be confirmed in a longitudinal cohort with PCR assays.
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Telomeres, the specific DNA–protein structures found at both ends of each chromosome, protect genome from nucleolytic degradation, unnecessary recombination, repair, and interchromosomal fusion.
Telomeres therefore play a vital role in preserving the information in our genome. As a normal cellular process, a small portion of telomeric DNA is lost with each cell division.
When telomere length reaches a critical limit, the cell undergoes senescence and/or apoptosis. Telomere length may therefore serve as a biological clock to determine the lifespan of a cell and an organism. Certain agents associated with specific lifestyles may expedite telomere shortening by inducing damage to DNA in general or more specifically at telomeres and may therefore affect health and lifespan of an individual. In this review we highlight the lifestyle factors that may adversely affect health and lifespan of an individual by accelerating telomere shortening and also those that can potentially protect telomeres and health of an individual.
Structure and function of telomeres
Telomeres, the DNA–protein complexes at chromosome ends (Fig. 1), protect genome from degradation and interchromosomal fusion. Telomeric DNA is associated with telomere-binding proteins and a loop structure mediated by TRF2 protects the ends of human chromosomes against exonucleolytic degradation [1], and may also prime telomeric DNA synthesis by a mechanism similar to ‘gap filling’ in homologous recombination [2].
As shown in Fig. 2, telomere shortening occurs at each DNA replication, and if continued leads to chromosomal degradation and cell death [3]. Telomerase activity, the ability to extend telomeres, is present in germline and certain hematopoietic cells, whereas somatic cells have low or undetectable levels of this activity and their telomeres undergo a progressive shortening with replication (Fig. 2).
Telomerases are reactivated in most cancers and immortalized cells. However, a subset of cancer/immortalized cells lack telomerase activity and maintain telomere length by alternative mechanisms, probably involving genetic (homologous) recombination [4], which is elevated in most immortal/cancer cell lines [5].
We have found that telomerase physically interacts with recombinase family of proteins and inhibitors of homologous recombination reducing telomere length in telomerase positive Barrett’s adenocarcinoma cells (unpublished data from our laboratory). This suggests that recombinational repair is closely connected to telomere maintenance.
Figure 1
Telomeres, the DNA–protein structures which protect chromosomes
Our chromosomes end with repeats of conserved ‘TTAGGG’ sequence. These sequences interact with specific proteins and attain a looped conformation which protects chromosomal DNA from degradation. The length of telomeric DNA shortens with each cell division and when it reaches below a critical limit, the cell undergoes replicative senescence or apoptotic cell death. The length of telomeric DNA determines the lifespan of a cell in culture.
Length of telomeric DNA is important for lifespan of a cell
(a) Telomere length can be prevented from shortening by an enzyme Telomerase. Telomerase has a protein subunit (hTERT) and an RNA subunit (hTR). This enzyme is active in germline and stem cells and maintains their telomere length by adding ‘TTAGGG’ repeats to the ends of chromosomes. Therefore, telomeres do not shorten in these types of cells. (b) Telomerase is inactive in normal somatic cells. These cells, therefore, lose telomeres over time and when telomere length reaches below a critical limit, cells either senesce or die. (c) In the absence of appropriate signals for senescence or apoptotic death, continued cell division leads to severe telomere shortening and genomic instability. Although rare, but cells which survive this crisis, activate a telomere maintenance mechanism (either telomerase or homologous recombination-based ALT) and may become oncogenic. Therefore, most cancer cells have very short but stable telomeres. TA, telomere attrition; TL, telomere length.
reference link:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/
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Epigenetic changes have been reported to be associated with the SARS-CoV-2 infection and unfavorable COVID-19 outcomes, including the methylation regulation of Angiotensin Converting Enzyme 2 (ACE2)40, interferon-related pathways23, and immune response genes 23,41.
Considering the DNA methylation changes in SARS-CoV-2 infection that may affect the expression of metabolic process and epigenetic aging of COVID-19 41, a further question could be whether the accelerated epigenetic aging exists before the first viral contact, worsening progressively up or coming back to normal during the convalescence phases and post-COVID-19 period.
Our analysis of epigenetic clocks and telomere shortening indicates an increasing age acceleration at the initial phases of COVID-19 and this could be partly reversed at later phases. We speculated that COVID-19 syndrome might accelerate epigenetic aging in SARS-CoV-2-infected patients based on these findings.
Our longitudinal DNA methylation profiling analysis indicates that the influence of COVID-19 syndrome on epigenetic aging in peripheral blood could be reversed in some patients. However, additional experiments are necessary to validate these findings and elucidate the underlying mechanism.
In the current study, we found accelerated epigenetic aging could serve as a predicting biomarker for severe COVID-19 that requires hospitalization with increased mortality. However, a recent study found that the association of accelerated epigenetic aging with severe COVID-19 varied among different epigenetic clocks and datasets 42, which might be attributed to the small sample size in some datasets, unspecified severity of COVID-19 cases, and the different estimation method of age acceleration.
Interestingly, the difference between severe COVID-19 patients and other individuals in the GrimAge clock was most significant among the five epigenetic clocks in our cohort. The strong stratification in the severity of COVID-19 may come from the correlation between GrimAge clock and smoking-associated changes that were shown to be a prognostic factor for severe illness and mortality in COVID-19 patients43,44,45.
Of note, there is a lack of molecular biomarkers potentially valuable in monitoring post-COVID-19 syndrome that will require long-term assistance among the millions of COVID-19 survivors46. Based on our findings, we speculate that the accumulation of epigenetic aging and telomere attrition after SARS-CoV-2 infection might contribute to the post-COVID-19 syndrome, and irreversible epigenetic aging might be served as a biomarker for the risk of developing post-COVID-19 syndrome.
It is noteworthy that this study has some limitations. First, our longitudinal analysis indicates the recovery of accelerated epigenetic aging occurred in some patients, though none of the post-COVID-19 survivors with post-COVID-19 syndrome was included in our study. In addition, the limited cases were included in the longitudinal analysis, and the findings require validation in a larger and more diverse longitudinal cohort.
Next, the causal relationship between COVID-19 and accelerated epigenetic aging remains unanswered in the current study. A longitudinal cohort with sustaining follow-up from the time point before SARS-CoV-2 infection to post-COVID-19 phase would be helpful to address this question, though it would be challenging to conduct a study with this design.
A long-term follow-up of crowdsourced populations 47,48 may facilitate the longitudinal research and provide valuable evidence. Furthermore, we cannot rule out the potential confounding effects of chronic inflammation, oxidative stress in respiratory failure and prior medication use.
Finally, the application of epigenetic aging markers in predicting COVID-19 outcomes is limited by the cost and accessibility of methylation arrays. However, representative age-related CpG methylations could be applied by using qPCR-based assays and pyrosequencing39,49,50. We anticipate that epigenetic aging-related markers would be useful to predict disease progression in COVID-19 with other laboratory assays8,51.
In conclusion, our results indicate that accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, COVID-19 could exert influence on the epigenetic clock and telomere attrition and accelerate the epigenetic aging, which may contribute to the post-COVID-19 syndrome.
However, this influence is reversible in some patients. Together with other laboratory assays and clinical characteristics, it would be helpful to identify the patients with high risk of developing severe COVID-19 and post-COVID-19 syndrome.
reference link :https://www.nature.com/articles/s41467-022-29801-8#Sec7
Original Research: Closed access.
“Severe COVID-19 is associated with molecular signatures of aging in the human brain” by Jonathan Lee et al. Nature Aging
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