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Biological Age Increases With Stress and Is Reversed With Recovery, Study Suggests

A collection of old analog clocks.
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A new study in both mice and humans has found that biological age is dynamic, and that some increases in biological age caused by stress can be reversed with recovery. The research is published in Cell Metabolism.

How can we measure age?

Our biological age is not completely linked to our chronological age. While chronological age is a measure of the amount of time you have been alive, biological age indicates how much aging has occurred to your cells over your lifetime.


Biological age results from a combination of factors such as disease, lifestyle, genetics, drug treatments and environmental exposures. This means that a person’s biological age can be younger or older than their chronological age.


There are various ways to measure biological age, the most common being so-called epigenetic clocks. These measure the levels of chemical groups added to DNA – namely DNA methylation (DNAm) – across different locations in the genome that predictably change with chronological age.


“Despite the widespread acknowledgment that biological age is at least somewhat malleable, the extent to which biological age undergoes reversible changes throughout life and the events that trigger such changes remain unknown,” said Professor Vadim Gladyshev, co-senior author of the study and director of redox medicine at Brigham and Women’s Hospital.

Reversing the epigenetic clock

Researchers in the current study aimed to investigate this unknown by measuring the ticking of epigenetic clocks in both humans and mice.

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They showed that the biological of young mice (3 months old) could be increased when they were surgically attached to an older mouse (20 months old) using a procedure called heterochronic parabiosis. These upticks in biological age across multiple levels also showed that this measure is dynamic, as the mice’s biological ages were restored after separation. In other words, short periods of stress increased biological age, which was then restored with recovery.


“An increase in biological age upon exposure to aged blood is consistent with previous reports of detrimental age-related changes upon heterochronic blood-exchange procedures,” said Dr. Jesse Poganik, lead author of the study and research fellow at Harvard Medical School. “However, reversibility of such changes, as we observed, has not yet been reported. From this initial insight, we hypothesized that other naturally occurring situations might also trigger reversible changes in biological age.”


Using data from human studies, the researchers found that temporary changes in biological age can also occur during major surgery, pregnancy or severe COVID-19 infections. For example, they observed that trauma patients undergoing emergency surgery experience rapid rises in biological age, which subsequently decreases back to normal in the days after surgery. Additionally, pregnant subjects recovered biological age at varying rates after delivery, and an immunosuppressive drug helped recovering COVID-19 patients recover biological age.


The researchers also analyzed the readouts provided by different epigenetic clocks. They found that first-generation clocks (designed to predict chronological age) generally lack the sensitivity required to measure brief changes in biological age, whereas second-generation clocks (which reflect more physiological age-related conditions) provided consistent outputs.


“Whatever the underlying reason, these data highlight the critical importance of judicious selection of DNA methylation clocks appropriate to the analysis at hand, especially in light of the many clocks continuously coming to the fore,” added Gladyshev.

Studying aging over a lifespan

The authors note some important limitations to the study. Though multiple levels of aging were analyzed in the mouse models – such as gene expression (transcriptomics) and metabolism (metabolomics) – the researchers relied on the DNAm clocks for the human studies, which are currently the most powerful tool available to infer human age. In addition, the findings are limited in their ability to distinguish between short-term fluctuations and lifelong biological aging – for example, not all pregnant subjects recovered biological age at the same rate or extent.


“Our study uncovers a new layer of aging dynamics that should be considered in future studies,” said Dr. James White, co-senior author and assistant professor at Duke University School of Medicine. “A key area for further investigation is understanding how transient elevations in biological age or successful recovery from such increases may contribute to accelerated aging over the life course.”


Reference: Poganik JR, Zhang B, Baht GS, et al. Biological age is increased by stress and restored upon recovery. Cell Metab. 2023. doi: 10.1016/j.cmet.2023.03.015


This article is a rework of a press release issued by Cell Press. Material has been edited for length and content.