Biological age increases with stress and is restored with recovery — ScienceDaily

“This finding of a fluid, fluctuating, and malleable age challenges the long-held conception of a unidirectional upward trajectory of biological age through the life course,” says study co-lead author James White, from the School of Medicine from Duke University. “Previous reports have hinted at the possibility of short-term fluctuations in biological age, but the question of whether such changes are reversible has, until now, remained unexplored. Critically, the triggers for such changes were also unknown.”

It is believed that the biological age of organisms increases constantly throughout the life course, but it is now clear that biological age is not indelibly linked to chronological age. Individuals may be biologically older or younger than their chronological age implies. In addition, growing evidence in animal and human models indicates that biological age can be influenced by diseases, drug treatments, lifestyle changes, and environmental exposures, among other factors.

“Despite widespread recognition that biological age is at least somewhat malleable, the extent to which biological age undergoes reversible changes throughout a lifetime and the events that trigger such changes are unknown,” says study co-lead author Vadim Gladyshev of Brigham and Women’s Hospital, Harvard Medical School.

To address this knowledge gap, the researchers harnessed the power of DNA methylation clocks, which were innovated based on the observation that methylation levels at various sites throughout the genome change in predictable ways over time. the chronological age. They measured changes in biological age in humans and mice in response to various stressful stimuli. In a series of experiments, the researchers surgically joined pairs of mice that were 3 months old and 20 months old in a procedure known as heterochronic parabiosis.

Results revealed that biological age can increase for relatively short periods of time in response to stress, but this increase is transient and tends to return to baseline after recovery from stress. At epigenetic, transcriptomic, and metabolomic levels, the biological age of young mice was increased by heterochronous parabiosis and restored after surgical detachment.

“An increase in biological age upon exposure to aged blood is consistent with previous reports of detrimental age-related changes in heterochronous blood exchange procedures,” says first author Jesse Poganik of Brigham and Women’s Hospital, Harvard Medical School. “However, the reversibility of such changes, as we observed, has not yet been reported. From this initial information, we hypothesized that other natural situations could also trigger reversible changes in biological age.”

As predicted, transient changes in biological age also occurred during major surgery, pregnancy, and severe COVID-19 in humans or mice. For example, trauma patients experienced a sharp and rapid increase in biological age after emergency surgery. However, this increase was reversed and the biological age was restored to baseline in the days after surgery. Similarly, pregnant women experienced postpartum recovery of biological age at different rates and magnitudes, and an immunosuppressive drug called tocilizumab enhanced the recovery of biological age in patients convalescent from COVID-19.

“The findings imply that severe stress increases mortality, at least in part, with increasing biological age,” says Gladyshev. “This notion immediately suggests that mortality may be decreased by lowering biological age and that the ability to recover from stress may be an important determinant of successful aging and longevity. Finally, biological age may be a useful parameter for assessing stress.” physiological and its relief.”

Additional findings showed that second-generation human DNA methylation clocks provide consistent results, while first-generation clocks generally lack the sensitivity to detect transient changes in biological age. “Whatever the underlying reason, these data highlight the critical importance of judicious selection of the appropriate DNA methylation clocks for the analysis at hand, especially in light of the many continually emerging clocks,” says Gladyshev.

While this study highlights a previously unappreciated aspect of the nature of biological aging, the researchers acknowledge some important limitations. Although they characterized the parabiosis model at multiple omic levels, they primarily relied on DNA methylation clocks to infer biological age in human studies because these tools are the most powerful aging biomarkers available today. Furthermore, the findings have limited ability to investigate connections between short-term fluctuations in biological age and life-span trajectories of biological aging.

“Our study uncovers a new layer of aging dynamics that needs to be taken into account in future studies,” says White. “A key area for further research is understanding how transient elevations in biological age or successful recovery from such increases may contribute to accelerated aging throughout the life course.”