Does stress increase biological age?

In a recent study published in Cell Metabolism, researchers used deoxyribonucleic acid methylation (DNAm) clocks from different generations to evaluate stress-induced biological age (BA) changes among mice and humans.

Study: Biological age is increased by stress and restored upon recovery. Image Credit: VectorMine/Shutterstock.comStudy: Biological age is increased by stress and restored upon recovery. Image Credit: VectorMine/


It is thought that BA gradually increases over an individual's lifespan; however, it has been established that BA is not completely associated with the chronological-type age of individuals. One could be biologically younger or older than implied by the chronological-type age.

Animal and human studies indicate that BA could be affected by several factors, including disease, medications, environmental exposure, and lifestyle, indicative of age reversal possibilities.

Despite the reported BA malleability, the degree of reversible alterations in BA and triggering events have not been well-characterized.

About the study

In the present study, researchers investigated whether BA could be increased or reduced by stress using DNAm clocks and various stressful stimuli.

The team examined probable BA fluctuations using a murine heterochronic parabiosis model. Young mice were exposed to the aged circulation and surgically joined heterochronic pairs of murine animals aged three months and 20 months. After three months of parabiosis, the team separated the murine pairs and allowed for recovery over two months.

Subsequently, the murine tissues were examined using DNA methylation clocks, adjusted for the chronological-type age. DNA methylation in the brain, liver, kidney, adipose, and heart tissues was analyzed using the HorvathM clock.

Additionally, murine hepatic samples from the parabiosis animals were subjected to reduced representation bisulfate sequencing (RRBS), and several epigenetic clocks trained using RRBS data were applied. The effects were analyzed at the metabolomic and transcriptomic levels.

Further, the team examined DNA methylation in serum samples from older individuals undergoing major surgeries using human DNA methylation clocks of the second generation (DunedinPACE, DNAmGrimAge, and DNAmPhenoAge). The samples were obtained immediately before surgery, on the morning following surgery, and after four to seven days before hospital discharge.

In addition, the effects of pregnancy on the BA were evaluated using C57BL/6 murine animals, from whom sera were obtained in the initial and late stages of pregnancy, following parturition, and during the recovery period. In addition, DNAm datasets from 54 expecting women were analyzed.

Furthermore, the team examined BA changes in severe infections using a model of severe coronavirus disease 2019 (COVID-19). Drugs such as tocilizumab, remdesivir, and hydroxychloroquine were investigated for their possible anti-aging actions.


BA was found to be dynamic, undergoing rapid fluctuations in both directions in murine animals and humans. Severe stress transiently increased BA, as read out by multiple advanced biomarkers of aging, which reversed upon recovery from stress.

Heterochronic parabiosis, trauma surgery, pregnancy, and SARS-CoV-2 infections temporarily increase BA in humans and/or mice. Good agreement was noted between the DNAm and RRBS clocks for hepatic tissues, consistent with other murine tissues. Heterochronic parabiosis perturbed BA at metabolomic and transcriptomic levels.

The functional analysis findings showed positive correlations between heterochronic parabionts and aging signatures, with significant inverse associations upon recovery. The team observed significant increases in BA markers in older individuals undergoing emergency surgical repair of traumatic hip fractures within 24 hours, and BA returned to baseline within four to seven days of surgery.

In addition, significant fluctuations in the counts of natural killer (NK) cells, monocytes, and plasmablasts were observed in the patients.

BA recovery rate may predict gerotherapeutics. Second-generation human DNAm clocks gave consistent results, whereas first-generation human DNAm clocks (Hannum clock, Horvath clock, and blood and skin DNAm age) were not as sensitive to detect short-term alterations in BA.

The trends observed using the original DNAm clocks agreed with the results obtained using principal component (PC) clocks.

Murine blood assessed by the BA clocks showed an elevation in BA post-pregnancy that resolved following parturition. Similar results were obtained for pregnant women, with BA peaking around delivery and reducing postpartum. However, there were no significant changes in the blood composition of pregnant women.

The DNAmPhenoAge clock findings indicated that severe infections such as COVID-19 can reversibly increase the BA of intensive care unit (ICU)-admitted female patients, followed by a decrease post-hospital discharge; however, the results seemed to be clock- and sex-specific.

The reversal of increased BA could be used to develop anti-aging interventions. Notably, tocilizumab recipients demonstrated a greater reversal in BA than non-recipients.


Overall, the study findings highlighted the increase in BA caused by stress and age reversal upon recovery from stressful events.

Heterochronic-type parabiosis among young mice increased the BA at the metabolomic, transcriptomic, and epigenetic levels, especially in the liver, and reversed following recovery. Traumatic hip fractures, pregnancy, and severe acute respiratory coronavirus (SARS-CoV-2) infection among humans increased BA.

The findings indicated a rapid but transient elevation in BA under various stressful stimuli followed by a reversal after stress recovery, providing valuable insights into the dynamics of aging. The stress-induced increase in BA could be targeted to develop anti-aging therapies.

Particularly, tocilizumab and other interleukin-6-targeting monoclonal antibodies must be investigated further as age-reversal drugs.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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