Biological Aging Fluctuates with Stress

Epigenetic age is not fixed in stone.


Chaotic clocksChaotic clocks

A preprint published in bioRxiv has demonstrated that the second-generation aging clocks PhenoAge, DunedinPACE, and GrimAge show increased but reversible age acceleration in mice and people exposed to significant stress.

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?

What clocks are for

As the researchers remind us, epigenetic clocks measure “how old you are” in a very specific context. Two of the clocks used to test the humans in this study, PhenoAge and GrimAge, are focused on mortality: that is, if someone has a GrimAge of 60, the clock is saying that this person is as likely to die from age-related causes as the average 60-year-old. DunedinPACE is similar, with a focus on age acceleration and the rate of aging. This particular clock was presented at last year’s Ending Age-Related Diseases conference.

in this paper, the researchers show that these biomarkers of increasing mortality rise with certain stresses but return to baseline once the stresses have passed.

Heterochronic parabiosis, revisited

It is well-known in the longevity field that heterochronic parabiosis, the joining of the circulatory systems of old and young animals, leads to the reversal of multiple aspects of aging in the older animal [1]. On the other hand, it also causes stress to the body of the younger animal.

The researchers joined three-month-old mice to 20-month-old mice for three months, with a control group of three-month-old mice joined together in the same way, and then allowed two months for recovery. The liver, which filters the blood, was chosen as the organ for this testing, and the researchers used six separate clocks, including pan-tissue clocks and clocks specifically geared to the liver.

Both groups suffered some epigenetic stress from the procedure itself, as shown by their recovery following the procedure; however, the heterochronic group substantially increased in biological age, which was then reverted after the recovery period. These results make it clear that the young mouse in this scenario is actually aged in a quantifiable, but reversible, way.

Humans age from some stresses, not others

The researchers tested the methylation of older people undergoing surgery at three time points: immediately before, the morning after, and four to seven days later before discharge from the hospital. An emergency hip surgery group had 9 people, an elective hip surgery group had 10, and an elective colorectal surgery group had 11.

In the emergency hip surgery group, biological aging was increased in nearly all the patients and then decreased after surgery, according to all three human clocks. There were outliers in this group; in particular, one person had much greater age acceleration than the others, which continued even after surgery. However, the results were still significant.

However, this did not occur in the elective hip surgery group, and colorectal surgery, which is much less physically traumatic than hip surgery, had no discernible effect on aging according to these clocks. Therefore, the researchers conclude that only large-scale physical trauma is enough for this stress to affect epigenetic clocks.

The researchers also tested two major, well-known sources of stress: COVID-19 infection and pregnancy. In the case of COVID-19, the patients’ age was already accelerated by the time they were admitted to the ICU; therefore, the researchers expected to see a decrease in aging according to multiple clocks.

The results were very interesting: females, but not males, showed a decrease in epigenetic age during recovery, particularly after discharge from the ICU. The researchers also analyzed the effects of three well-known interventions common at the time the study was conducted: hydroxychloroquine, remdesivir, and tocilizumab. While the first two were not significantly connected with a decrease in biological age, patients who took tocilizumab were reported as being younger after discharge, according to all three clocks.

The researchers also analyzed longitudinal data from multiple studies of human pregnancy among multiple demographics. While first-generation clocks did not show these results, these second-generation clocks reported that human mothers gradually increase in biological age during their pregnancies, with reversal after birth.


Probably the largest potential concern is what constitutes aging in the biological sense. If something can be, and is, reversed as the result of normal biological processes, is it truly aging? The researchers hold that biological aging, while it has a gradually upward trajectory, does naturally fluctuate in this way. Therefore, these clocks report biological changes that constitute real epigenetic aging, which has downstream biological consequences.

If this is the case, it may be possible to develop interventions that harness the inherent malleability of the short-term fluctuations in epigenetic aging, keeping them lower for longer periods of time and thus slowing or perhaps reversing multiple other aspects of aging.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

Restoring Heart Regeneration With a Metabolic Switch

In a recent article in Nature, researchers have restored cardiac regeneration to adult mice by disabling fatty acid oxidation, discovering...

Human Clinical Trials of NMN for Safety and Effectiveness

In a recent paper, researchers reviewed the literature for human clinical trials that address NMN's safety and anti-aging effects [1]....

Lifespan News – Elon Musk and the Living Forever Curse

On this episode of Lifespan News, Ryan O'Shea ruminates on Elon Musk's statement on living forever being a curse rather...

ARDD 2023: The Mother of All Longevity Conferences

Once a year, Copenhagen becomes a Mecca for the longevity community. Hundreds of people flock to the picturesque Danish capital...


[1] Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760-764.

Related Topics

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called β€œreal life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
No Comments
Write a comment:


Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.