Stress leads to an increase in biological age, which can be reversed upon recovery

A recent study found that biological age, which refers to how old our bodies appear based on various biological markers, can increase temporarily in response to stress but then return to its baseline level after the stress is relieved. The researchers observed this pattern in both mice and humans at the epigenetic, transcriptomic, and metabolomic levels. The findings have been published in the journal Cell Metabolism.

The concept of biological age is based on the understanding that individuals of the same chronological age can have different rates of aging and varying levels of health and vitality. Some individuals may exhibit signs of accelerated aging, characterized by increased risk of age-related diseases and diminished physiological function, while others may maintain a more youthful and healthier state.

While it has been widely believed that biological age steadily increases throughout life, recent evidence suggests that it is not a unidirectional process and can be influenced by various factors. This study aimed to explore whether biological age changes in response to stress and if these changes are reversible.

“My lab studies mechanisms of aging across different tissues and how anti-aging approaches work to slow these processes. The divergence between chronological and biology aging is very interesting, since it shows the pace of aging can be accelerated or slowed down, despite the constant push from Father Time,” explained study author James White, an assistant professor at the Duke Aging Center at the Duke School of Medicine.

“In the current study, we were able to observe the acceleration in biological age, or more precisely epigenetic age, when young mice are exposed to old blood and in humans with surgical, pregnancy or illness-related stressors. The fascinating results from our study were the observations that, upon recovery from these stressors, both mouse and human cohorts showed the ability to reverse their biological age back with recovery from these stressors.”

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Biological age is determined by assessing specific biomarkers, such as epigenetic modifications (changes in gene expression patterns), DNA methylation patterns, telomere length (the protective caps at the ends of chromosomes), gene expression profiles, and metabolic markers. These biomarkers provide insights into the functional and structural changes that occur within cells and tissues as an individual ages.

For their study, the researchers focused on DNA methylation clocks, which are tools that assess biological age based on predictable changes in DNA methylation patterns over chronological age. They measured changes in biological age in humans and mice in response to different stressful stimuli. The researchers also used transcriptomic and metabolomic biomarkers to support their findings.

In the mouse experiments, C57Bl/6 mice were obtained and acclimated before subjecting them to various manipulations or conditions. For example, parabiosis experiments involved surgically attaching pairs of mice for a specific period and then separating them to observe the recovery phase. In pregnancy experiments, female mice were mated, and blood samples were collected at different time points to track changes in biological age throughout the pregnancy and postpartum period.

For the COVID-19 study, a cohort of patients with confirmed COVID-19 was selected from intensive care units, and their clinical blood samples were obtained. The DNA from these samples was used for methylation profiling to assess the changes in biological age associated with the disease.

The study utilized existing datasets from other studies to compare and validate their findings. The researchers analyzed methylation data from various sources, including surgical patients and pregnancy cohorts, to expand the scope of their investigation.

The researchers discovered that exposure to stress, such as major surgery or trauma, caused a temporary increase in biological age. However, they also found that this increase was reversible, and the biological age could be restored to its original level once the stress was alleviated.

For example, elderly patients who underwent emergency surgery showed a rapid increase in biological age, but it returned to baseline within a few days following the surgery. Similar reversible changes in biological age were observed in response to pregnancy and COVID-19 infection.

“Mental and physical stress is well known in the clinic and research field to accelerate biological age and impair quality of life,” White told PsyPost. “The results from our study highlight the capacity to reverse the rate of aging and return biological age back with successful recovery from stress.”

The study challenges the traditional notion that biological age only increases in a unidirectional manner as we get older. Instead, it reveals that biological age can fluctuate and be malleable over relatively short periods of time. The findings suggest that stress-induced increases in biological age may contribute to mortality, and reducing biological age could potentially decrease mortality and improve the ability to recover from stress.

“The cumulative trend to reverse biological aging upon recovery from rather diverse stressors was exciting and supports the idea of a common mechanism for biological age reversal after recovery from stress,” White said.

The researchers also noted that second-generation DNA methylation clocks, which are advanced aging biomarkers, provided more sensitive and consistent results compared to first-generation clocks. This highlights the importance of selecting appropriate biomarkers for assessing biological age and understanding its fluctuations accurately.

However, the study has some limitations. While the researchers used DNA methylation clocks to estimate biological age in humans, there is a need for further exploration of the connections between short-term changes in biological age and long-term aging processes.

“What this study does not answer is: 1. what the specific ‘drivers’ are that accelerate aging and are they related to the mental or physical stress and 2. we measure biological aging with epigenetic clocks, which estimate biological age based on DNA methylation patterns. Although the epigenetic clocks are sensitive to detect age-related patterns, they are only one indices of biological aging,” White noted.

The study, “Biological age is increased by stress and restored upon recovery“, was authored by Jesse R. Poganik, Bohan Zhang, Gurpreet S. Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T. Lu, Amin Haghani, Tong Gong, Anna M. Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B. Clish, Steve Horvath, James P. White, and Vadim N. Gladyshev.