How Stress Alters DNA Methylation to Accelerate Biological Age — and How Oxytocin May Modulate This Epigenetic Pathway

Introduction

While chronological age (the number of years since birth) is easy to measure, it tells us very little about an individual’s true physiological condition. In contrast to chronological age (years of age since birth), biological age represents an individual's functional “age” at the cellular level. In other words, at 65 years of age, you are aging slowly if your biological age is only 50, whereas a biological age of 70 indicates that you are aging more rapidly. Additionally, the individual with a younger biological age is likely to have a greater healthspan (number of years free from disease and disability), even if these two individuals live the same length of time. 

The preferred method of assessing biological age involves epigenetic clocks that are based on predictable, age-dependent changes to DNA methylation (DNAm), chemical tags on DNA that influence gene activity without altering the underlying code. These predictable changes are referred to as DNAmAge. Numerous environmental, behavioral, and genetic factors can elicit changes to DNAm that occur at a slower or faster rate than predicted for chronological age. An “acceleration of DNAmAge progression” occurs when DNAm profiles change faster than predicted and is associated with adverse health outcomes that can shorten both healthspan and longevity. 

Among the most potent and pervasive drivers of biological age acceleration is stress. In this review, we will detail a 2023 article published in Cell Metabolism describing the transient impact of three types of stress – surgical trauma, pregnancy, and severe infectious disease – on the acceleration of DNAmAge. A common theme of these studies is that the biological aging process is rapidly accelerated in response to stress but is reversible once the stressor has subsided.

Results from this study demonstrate how stress-induced changes to biological age contribute to the aging process over the total lifespan and highlight the importance of stress-mitigating strategies to help increase your resiliency at the cellular level. In this article, we will discuss how stress gets under our skin and impacts the biological aging process. In addition, we will detail emerging pharmacological and behavioral strategies to increase stress resiliency with the aim of arming you with methods to slow, and potentially reverse your biological age. 

A Brief Framework for Stress-Induced Biological Aging

Stress is a pervasive experience that is fully integrated into lives and has long been known to negatively impact the biological aging process. The direct impact of stress on overall health and aging is only beginning to be revealed, and the cumulative effects of stress play an important role in determining both healthspan and longevity. 

Although the mechanisms by which stress alters DNAm profiles to accelerate biological aging have yet to be elucidated, at least a fourth of all CpG sites are located in areas of DNA responsible for responding to glucocorticoids. Glucocorticoids are hormones released during stress, with cortisol being the most well-known; these hormones influence which genes are turned on or off in our cells, including those tied to aging.[14]. 

In addition, dexamethasone, an activator of the glucocorticoid receptor utilized by cortisol, induces significant changes to DNAm profiles, suggesting that dysregulated cortisol concentrations in response to stress play a role in regulating the biological aging process. 

The manifestation of stress primarily results from physical and psychological occurrences that perturb the functions of nearly every system within our body. Although the general “fight-or-flight” stress response is predictable and well characterized in humans, each stressful experience is unique, and the consequence of physical and psychological stress varies widely across each individual. 

It is likely that each of us experience numerous acute, short-lived stressors that occur simultaneously against the backdrop of chronic, more persistent stressors across each phase of our life. Over decades of time, the cumulative interaction of short term and persistent stress gradually alters the biological aging process. This is especially true when stressful situations present themselves unpredictably, uncontrolled, or as life threatening [15]. 

Many individuals remain resilient to stress. For example, perceiving a stressor as a challenge and not a burden, maintaining increased social support, and improving our coping abilities all can help mitigate the negative consequences of stress and help maintain or potentially improve our body’s response and overall health outcome by slowing the biological aging process [15,16,17]. This cellular “give-and-take” between stress exposure and resiliency is vital to managing the molecular, genomic, and cellular changes that accumulate, cause cellular damage, and modify our physiology in a way that contributes to the development and progression of age-related diseases [16,18]. 

The roles of stress on the biological aging process were recently detailed in a 2023 article published in Cell Metabolism. Poganik and colleagues utilized the current generation of DNAm clocks to examine the impact of stress on CpG methylation patterns to measure transient changes to biological age in response to three types of physiological stressors: surgical trauma, pregnancy, and severe infectious disease [3]. 

A common theme across each study is that biological aging is accelerated in response to stress, and reversible once the stressor has subsided [3]. Although the reversal of the aging process appears to occur at different rates across subjects, these results reveal necessary insight into the clinical outcomes following stressful events and support the incredible plasticity of the biological cellular aging process. 

Heterochronic parabiosis induces a reversible increase in biological age

In the first experiment examining biological age in response to physiological stressors, researchers used a procedure called heterochronic parabiosis, a process that exposes the circulatory system of young mice to the circulatory system of aged mice [3]. Although the exposure of aged mice to the blood of young mice has been shown to be rejuvenating across multiple tissues and extends lifespan in aged mice [19], the reverse is deleterious to young mice [20, 21]. In other words, while old mice benefit from young blood, young mice exposed to old blood tend to suffer negative effects, including signs of accelerated aging.

Utilizing this procedure as a form of physical stress, researchers surgically joined the circulatory systems of young mice to either other young mice (isochronic parabiosis) or to older mice (heterochronic parabiosis) for three months [3]. After 3 months, young mice were separated and provided 2 months to recover. The liver, heart, brain, kidney, and adipose (fat) tissue were then collected and analyzed using DNA methylation (DNAm) clocks to assess their biological age relative to chronological age. Specifically, acceleration of DNAmAge progression was calculated as an unbiased way of comparing differences between mice paired with other young (same age) or older mice throughout the 3-month intervention period.

The biological age of each tissue increased after 3 months in young mice joined with older mice compared to those joined with age-matched young mice. However, after being separated and provided 2 months to recovery, the biological age of each tissue returned to levels observed prior to being surgically joined. These findings suggest that the biological aging process was fully reversed across all tissues analyzed in young mice. 

In the liver specifically, researchers focused on changes to gene expression and metabolite levels among mice surgically joined to older mice [3]. As expected, young mice joined with older mice for 3 months experienced age-related changes to gene expression and metabolite levels, supporting the age-related changes to DNAm profiles. However, these profiles were also reversed in the 2-month recovery period following their separation, indicating that transient increases and subsequent reversals in biological age are observed at the DNAm, transcriptional (gene expression), and metabolic levels.

In short, not only did the DNA aging markers return to normal, but the gene activity and chemical processes in the liver did too, demonstrating that these systems are flexible and can rebound after stress.

Trauma surgery reversibly increases the biological age of elderly patients

In humans, the process of parabiosis is not a translatable procedure. However, physical and psychological stress associated with traumatic events are woven into the fabric of our lives. In one such example, researchers focused on elderly patients undergoing an emergency surgery on their hip and compared the biological aging process in their blood to other patients undergoing either an elective hip operation or a routine health procedure (a colonoscopy) [3]. 

Blood samples from each group were retrospectively assessed immediately prior to and on the day after surgery, as well as between 4-7 days following the surgery. In elderly patients undergoing emergency hip surgery, human DNAm clocks revealed that biological age increased the day after surgery and returned to pre-surgery levels within 4-7 days. Interestingly, patients undergoing an elective hip replacement or routine colonoscopy experienced no change to their biological age relative to their baseline values. Differences in the biological aging process between these three procedural scenarios supports a mental preparedness or an ability to foster a certain level of stress resiliency may mitigate the negative consequences associated with a traumatic experience [22].

Biological age of mice and humans reversibly increases during pregnancy

Pregnancy represents another physiologically stressful event with increased physical and metabolic demands required to develop a fetus throughout the gestational period. In fact, a 2020 publication posited pregnancy as a model for aging [23]. To investigate the role of pregnancy on biological age in mice, researchers measured DNAm across 4 separate time points of the study: day 1, day 14, day 28, and day 42 [3]. 

In mice, the gestational period is about 3 weeks. Under the conditions of this experiment, day 14 represented an early period of pregnancy and day 28 represented a late stage of pregnancy, and 42 represented a period shortly after birth. Compared to baseline at day 1, biological age increased early and throughout pregnancy (days 14 and 28) but decreased back to baseline after delivery of the litter (day 42). To the contrary, control mice that were not pregnant during the study displayed no change in biological age throughout the 42-day period.

In humans, researchers next examined changes in biological age across several cohorts of pregnant women [3]. It is important to note that this was a retrospective study and results were examined using a variety of methodologies. Nonetheless, a progressive increase in biological age was observed in all three cohorts from the first blood samples, typically measured early in the first trimester, to the follow-up measures assessed late into pregnancy.

In addition, blood samples in one cohort were available about 6 weeks following the end of their pregnancy. Consistent with results observed in the mouse study, the biological age of humans reversed back towards baseline following completion of pregnancy. Similar to surgical trauma, the biological aging process is accelerated throughout pregnancy, then is quickly reversed following completion of the gestational period. 

Severe COVID-19 causes a reversible increase in biological age

In a third study, researchers obtained blood samples from COVID-19 patients who were admitted to an intensive care unit for treatment [3]. Their aim was to investigate the potential consequence of severe infectious disease on changes to the biological aging process. Blood samples were only obtained among survivors with multiple blood samples collected throughout their hospitalization.

As a caveat, the researchers acknowledged that the first blood sample, obtained upon admission for treatment, may have already represented a slight increase in biological age compared to a sample obtained in the weeks prior. Likewise, analysis was separated for males and females due to the sex disparities observed among COVID-19 patients: males tend to experience poorer outcomes compared to females [24].

As a result, DNAm analysis indicated that the biological age of females either increased or remained the same throughout the hospitalization periods (depending on the method of DNAm assessment), then decreased at the time of their discharge from the hospital. To the contrary, no changes were observed among males. Interestingly, patients treated with the tocilizumab showed the greatest recovery in biological age. Tocilizumab is a monoclonal antibody that targets the receptor of the inflammatory molecule interleukin-6. As such, researchers suggest that tocilizumab may serve as a candidate for additional research into its potential as an anti-aging treatment. 

Stress-Induced Biological Aging is Reversible

The manifestation of stress primarily results from physical and psychological occurrences that perturb the functions of nearly every system within our body. Our bodies are well-equipped to maintain and reestablish our internal “set-points”, such as heart rates, blood pressure, plasma glucose concentrations, and other vital functions [25]. Each of these functions operate within a broad range, termed allostasis, that functions as a protective buffer to a stressful experience.

Persistent and unregulated stress can push the boundaries of these vital functions beyond their normal operating levels. This inability to maintain allostasis forces our body to reestablish new set-points that extend beyond the desired ranges. This condition is termed allostatic load [26], a maladaptive state that accelerates the aging process and increases our risk of premature death [27]. In fact, early life exposure to traumatic stress at a young age is associated with the acceleration of biological age later in life [28], suggesting that certain stressors leave a lasting impact on healthspan and longevity. Nonetheless, the culmination of chronic stress and the cumulative impact of stress-induced allostatic load manifest at the cellular level to provide insight into the biological aging process [14, 30]. 

Poganik and colleagues further suggest that exposure to intense, yet short-term stress – surgical trauma, pregnancy, and severe illness – also accelerates biological aging in as short as a few days [3]. However, the novelty of this paper is heightened by the apparent reversibility of the biological aging process once the stressful situation has subsided. Likewise, the partial or full reversal in biological age occurred across the lifespan, even in the elderly (mean age of surgical trauma subjects = 77.9 years), indicating that the biological aging process remains flexible across the lifespan.

Strategies to Prevent or Reverse Stress-Induced Biological Aging

From a practical standpoint, the types of stressors detailed by Poganik and colleagues are isolated events that occur with low frequency throughout our lives. Although these can accumulate and have a lasting impact throughout our lives [28], assessments that aim to measure how we perceive stress daily may provide a more relevant framework to examine the potential consequences of stress on biological age. For example, a 14-question Perceived Stress Scale developed in the 1980’s has been utilized as a gold standard assessment of our baseline level of stress that we experience [29] and is highly correlated with current and the progression of biological age determined from DNAm patterns [30]. 

The use of DNAm technologies to examine the impact of biological age is still new and research is increasingly being published to better understand their interactions. Nonetheless, several characteristics have been shown to impact the biological aging process, including age-related declines in physical function (walking capacity and overall strength) [31]. Indeed, a new DNAm calculation called DNAmFitAge based on the influence of physical activity on DNAm profiles predicts increased cardiorespiratory fitness (VO_2max), hand grip strength, and vertical jumping ability in a large cohort of 33–88-year-old individuals [32]. Although stress was not assessed in the DNAmFitAge study, physical activity is well known to mitigate the negative consequences of stress and research has shown that a 24-week physical activity intervention (4-5 moderate-intensity exercise sessions per week lasting ~30 minutes each session) lowers perceived daily stress and reverses the cellular aging process compared to non-exercisers [33] 

Like physical activity, 10-20 minutes of meditation, breathing exercises, and relaxation training techniques all reduce indices of baseline stress and reactivity to stressful situations [36, 37]. Similarly, relaxation training involving 20-minutes of breathing exercise performed twice per day has been shown to reverse DNAmAge between 1.93 and 4.67 years after about 8 weeks when performed along and in combination with dietary, endurance exercise (150 minutes of moderate-to-high intensity), and sleep (at least 7 hours per night) intervention in healthy adults [34, 35]. Although the research has yet to fully elucidate the interactions of these interventions on stress-induced biological age, early evidence suggests that the implementation of such techniques may translate into better stress resilience and improved biological aging profiles.

Other factors known to reduce the stress-induced acceleration of biological age are increased emotional regulation, self-control, and increased social support [30, 38]. Although each of these measures is subjective and determined by individual questionnaires, individuals who score higher on each of these three psychological traits exhibit lower stress reactivity and improved indices of biological age. Importantly, these are not necessarily inherent traits, but can be improved with deliberate practice and by focusing on nurturing interpersonal relationships.

Oxytocin: A Potential Pharmacological Tool for Addressing Stress-Induced Aging

While lifestyle interventions like exercise, meditation, and sleep optimization are foundational for stress resilience, recent research has turned attention toward pharmacological agents that may further support the reversal of stress-induced biological aging. One promising candidate is oxytocin, a neuropeptide hormone best known for its role in childbirth and social bonding, but increasingly recognized for its broader physiological effects, including modulation of the stress response, inflammation, and cellular aging.

Oxytocin is synthesized in the hypothalamus and released both into the bloodstream and locally within the brain. Beyond its reproductive functions, oxytocin plays a key role in attenuating the hypothalamic-pituitary-adrenal (HPA) axis, the central stress response system that controls cortisol release.  By inhibiting excessive cortisol secretion, oxytocin may help reduce the allostatic load, the cumulative wear and tear on the body that accelerates biological aging. [39]

Recent studies support oxytocin’s role in counteracting the physiological damage caused by chronic stress. In preclinical models, oxytocin administration has been shown to reduce markers of oxidative stress and inflammation in the hippocampus and prefrontal cortex (brain regions highly susceptible to stress-induced damage). These anti-inflammatory effects may be central to oxytocin’s role in slowing or reversing biological aging, as inflammation is a major driver of epigenetic aging and immune system dysfunction. [40]

Emerging research also suggests that oxytocin may exert epigenetic effects of its own. In rodent models, chronic stress leads to hypermethylation of the oxytocin receptor gene (OXTR), reducing oxytocin sensitivity and impairing stress resilience. However, repeated oxytocin exposure has been shown to reverse stress-induced methylation changes, enhancing receptor expression and restoring behavioral and physiological balance. While these findings are preliminary, they point toward a potential role for oxytocin in directly modulating the epigenetic landscape that governs biological aging. [41]

In humans, studies have begun to link oxytocin signaling to improved cardiovascular, immune, and metabolic function, all of which are key determinants of healthy aging. For example, intranasal oxytocin has been shown to improve heart rate variability, a marker of parasympathetic nervous system activation and stress resilience. [39] Other trials suggest oxytocin may enhance glucose homeostasis, reduce blood pressure, and promote wound healing, all of which may contribute to improved physiological reserve and slower biological aging. [42]

Notably, oxytocin has also been shown to enhance social connectedness and emotional regulation, traits previously identified as protective against stress-induced biological aging. In randomized controlled trials, oxytocin administration improved emotional reactivity and trust in social situations, while also reducing amygdala activity in response to social threat. These effects may explain, in part, the hormone’s restorative properties on stress-related aging by amplifying resilience through both biological and behavioral pathways. [39]

Although more research is needed, early findings support oxytocin’s therapeutic potential as a stress-buffering agent that operates at multiple levels: neurological, hormonal, and epigenetic. Given the reversibility observed in studies on biological age following stressful events, oxytocin may represent a novel tool for accelerating recovery, dampening inflammation, and restoring biological youth in individuals under chronic or acute stress.

Future studies are warranted to examine oxytocin’s impact on DNA methylation clocks directly. However, given its known ability to regulate cortisol, reduce inflammation, and promote recovery in both physical and emotional domains, oxytocin stands out as a promising intervention to be integrated alongside lifestyle approaches for preserving biological age and extending healthspan.

Conclusion

As discussed, the impact of severe, short-term stress on the biological aging process is not fixed but instead represents a dynamic and reversible phenomenon. The findings from Poganik and colleagues underscore that biological aging can accelerate rapidly in response to acute stress—such as trauma, infection, or pregnancy—but can also recede once the stressor has resolved. This reversibility suggests that biological age is not simply a marker of damage but a sensitive and responsive indicator of health status and resilience.

The authors propose that an individual’s capacity to recover from stress-induced biological aging may be a critical mechanism for extending both healthspan and longevity. In this context, tracking biological age provides a valuable framework to assess how well the body rebounds from adversity and adapts over time. While more research is needed to determine how repeated or cumulative stress-related changes influence long-term aging trajectories, these findings highlight the potential for targeted interventions (both behavioral and pharmacological) to support recovery and slow cellular aging.

These insights reinforce the importance of stress mitigation as a cornerstone of healthy aging. By improving stress resilience, through physical activity, emotional regulation, social support, or emerging therapeutics, we may be able to beneficially shift the trajectory of biological aging and enhance our ability to maintain health and function throughout the lifespan.