Life stressors, particularly those experienced during early developmental stages, significantly impact mitochondrial function. Early adverse experiences, such as maltreatment or neglect, have been linked to persistent oxidative stress and low-grade inflammation (Duchowny et al., 2024; Gumpp et al., 2020). Mitochondria are key organelles within cells, responsible for producing energy through oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. They contain electron transport chain (ETC) complexes I-IV and ATP synthase (complex V), which convert nutrients into adenosine triphosphate (ATP), the primary energy source for cellular activities. In this process, mitochondria also produce reactive oxygen species (ROS), which can function as signaling molecules but can also cause cellular damage if not adequately regulated. Therefore, maintaining redox balance is crucial for mitochondrial health and efficient energy production (Geldon et al., 2021).

Mitochondria play a key role in physiological responses to chronic psychological stress by influencing neuroendocrine, metabolic, and inflammatory pathways. Experimental deletion of mitochondrial genes alters HPA axis and SAM axis activity, catecholamine levels, and exaggerates the inflammatory response (Picard et al., 2015). Moreover, reduced expression of SIRT3 and PGC-1α, key regulators of mitochondrial bioenergetics and biogenesis, can further compromise mitochondrial activity and cellular energy metabolism (Scarpulla, 2011). Studies show that individuals with a history of early-life stress exhibit reduced ATP production and impaired mitochondrial respiratory capacity in immune cells and skeletal muscle (Duchowny et al., 2024; Gumpp et al., 2020). These mitochondrial impairments are observed not only in affected individuals but also in subsequent generations. Mitochondrial function may mediate the link between prenatal and postnatal stress exposures and neurodevelopmental outcomes in infants, with maternal mitochondrial bioenergetic profiles modulating early brain development and behavior (Zhao et al., 2022).

A primary mechanism by which chronic psychological stress impairs mitochondrial function is sustained ROS overproduction (Figure 2). Chronic stress reduces mitochondrial oxygen consumption rate (OCR) and disrupts ETC function, particularly at complex I, thereby promoting electron leakage and superoxide formation (Hunter et al., 2016; Nikolic et al., 2023; Yegorov et al., 2020). It also suppresses cellular antioxidant defenses. Clinical and preclinical studies have reported reduced activity of antioxidant enzymes, including SOD1, SOD2, and catalase (CAT), in depression (Herken et al., 2007; Qingfeng et al., 2019; Yıldız Miniksar and Göçmen, 2022). Consistent with this, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates antioxidant-response gene expression and is downregulated under chronic stress (Zuo et al., 2022). Glucocorticoids can suppress the Nrf2 pathway in vivo and in vitro (Chen et al., 2020; Kratschmar et al., 2012), and postmortem analyses show lower Nrf2 expression in the frontal cortex of individuals with major depressive disorder (Martín-Hernández et al., 2018). Conversely, upregulation of Nrf2 alleviates depression-like behaviors, underscoring its protective role against stress-induced oxidative damage (Bansal et al., 2022; Yao et al., 2021).

Mitochondrial DNA (mtDNA) is a particularly vulnerable target of stress-induced oxidative damage because of its proximity to the ETC, absence of protective histones, and limited repair capacity (King and Copeland, 2025; Xu et al., 2025). Accumulating oxidative lesions in mtDNA can create a feed-forward cycle in which dysfunctional mitochondria generate more ROS, thereby exacerbating mtDNA damage and mitochondrial impairment. Consistent with this, oxidative stress induction in human epithelial cells significantly increased mitochondrial 8-oxo-2′-deoxyguanosine (8-oxodG), a widely used marker of oxidative DNA damage (Scala et al., 2023). In vivo, chronic mild stress impaired mitochondrial ultrastructure and function and reduced mtDNA integrity (Qingfeng et al., 2019). Moreover, oxidative damage to cardiolipin (CL) and phosphatidylethanolamine in the inner mitochondrial membrane can trigger lipid peroxidation via the isoprostane pathway, generating toxic byproducts that further compromise mtDNA integrity (Panov and Dikalov, 2020).

In addition to oxidative damage, chronic psychological stress disrupts mitochondrial quality control mechanisms. Under normal conditions, mitochondria undergo coordinated cycles of fusion and fission to maintain functional integrity and selectively eliminate damaged mitochondria via mitophagy or apoptosis. The PINK1/Parkin pathway, a well-characterized mitophagy mechanism, is impaired under chronic stress. Reduced PINK1 and Parkin expression has been observed in the hippocampus of a depressive mouse model, leading to diminished mitophagic activity (Yue et al., 2025). Activation of the PINK1/Parkin pathway in rats exposed to chronic restraint stress enhances mitophagy and restores mitochondrial quality control (Li et al., 2025). Impaired mitophagy can therefore promote the persistence of dysfunctional mitochondria and reinforce oxidative and cellular damage.

Importantly, the consequences of mitochondrial dysfunction directly intersect with multiple hallmarks of aging. Sustained mitochondrial ROS overproduction acts as a central mediator linking stress-induced mitochondrial damage to inflammation, genomic instability, telomere attrition, and cellular senescence. Excessive ROS not only damage mitochondrial components but also induce oxidative lesions in nuclear DNA (Mishra et al., 2009). Furthermore, mitochondrial dysfunction contributes to inflammation by facilitating the release of mtDNA and other danger-associated molecular patterns (DAMPs) into the cytosol and extracellular space, activating innate immune pathways such as cGAS-STING and the NLRP3 inflammasome (Kim J. et al., 2023). Elevated oxidative stress further accelerates telomere shortening by inducing oxidative base lesions and replication stress at chromosome ends, ultimately promoting cellular senescence (Metcalfe and Olsson, 2022).

Stress-induced impairment in mitochondrial function plays a critical role in the pathogenesis of age-related diseases. Psychological stress alters mitochondrial respiration and glycolysis, particularly in brain regions such as the prefrontal cortex (PFC) and substantia nigra (SN), which are implicated in the development of neurodegenerative diseases. In Parkinson’s disease (PD), oxidative stress can promote α-synuclein aggregation, which disrupts mitochondrial dynamics and contributes to neuronal degeneration (Banerjee et al., 2009). Genetic evidence further supports this link, as mutations in the mitophagy regulators PINK1 and Parkin are associated with familial early-onset PD (Lesage et al., 2020). Postmortem analyses further report mitochondrial bioenergetic defects in PD brain tissue, including impaired OXPHOS and increased mtDNA deletions. Notably, experimental delivery of damaged mtDNA into the brains of healthy mice induces PD-like neuropathology and functional deficits (Tresse et al., 2023). In Alzheimer’s disease, oxidative modifications to mitochondrial proteins impair ETC function, reducing ATP synthesis and increasing ROS production (Kriebel et al., 2020; Navarro and Boveris, 2004). Mitochondria-derived ROS increase amyloid-β levels, whereas lowering ROS levels decreases amyloid-β levels (Leuner et al., 2012). Beyond direct mitochondrial damage, stress-responsive nuclear receptors such as NR4A1 may further contribute to neurodegenerative vulnerability by reshaping mitochondrial function and neuronal energy homeostasis. NR4A1 regulates mitochondrial dynamics by modulating uncoupling proteins (Ucp2, Ucp4, and Ucp5). Sustained NR4A1 activation depletes ATP, activates AMP-activated protein kinase (AMPK), and promotes synaptic loss and neuronal atrophy (Jeanneteau et al., 2018; Sampath et al., 2017). The widespread impacts of stress-induced mitochondrial dysfunction are not limited to neurodegenerative diseases but also contribute to other age-related diseases (Somasundaram et al., 2024; Yang, 2025). In line with this central role, mitochondrial transplantation has shown therapeutic potential in preclinical models of PD, AD, and cardiovascular diseases by improving mitochondrial bioenergetics, reducing oxidative stress, and attenuating disease-related phenotypes (Eo et al., 2024; Gupta et al., 2025; Mokhtari et al., 2023).

Telomeres are repetitive short DNA sequences (TTAGGG), typically ranging from 5 to 15 kb, located at the ends of chromosomes where they function as protective caps essential for maintaining chromosomal integrity (Levstek et al., 2020). With each cell division, telomeres shorten due to the end-replication problem (Lulkiewicz et al., 2020). Before telomeres are entirely lost, they reach a critical length, known as the Hayflick limit, at which point cells can no longer divide. As a result, the cells either undergo apoptosis or exit the cell cycle and become senescent (Lyons et al., 2023). In certain cell types, such as stem cells and germ cells, telomere length is preserved by the enzyme telomerase, which adds repetitive DNA sequences to the ends of chromosomes. However, in most somatic cells, telomerase activity is insufficient to maintain telomere length, leading to gradual telomere erosion. As we age, telomeres progressively shorten, a phenomenon observed across multiple species (Whittemore et al., 2019). In humans, telomeres are estimated to shorten at a rate of approximately 20–40 base pairs per year (Brouilette et al., 2003; Daniali et al., 2013; Ye et al., 2023). The rate of telomere attrition is influenced by genetic, environmental, and lifestyle factors (Hecker et al., 2021).

Chronic psychological stress can exacerbate telomere shortening by increasing ROS production, primarily through mitochondrial dysfunction and inflammation. The overproduction of ROS leads to oxidative stress, which preferentially damages the guanine-rich telomeric regions, resulting in oxidative DNA lesions (Reichert and Stier, 2017). In addition, oxidative stress can cause single-strand breaks in telomeres (von Zglinicki et al., 2000) and halt the replication fork, leading to telomere erosion (Coluzzi et al., 2019; Jurk et al., 2014).

The connection between psychological stress and telomere length has attracted substantial attention following a study by Epel et al. (2004), which demonstrated that healthy women caring for chronically ill children had significantly shorter telomeres and lower telomerase activity than mothers of healthy children, independent of age. Moreover, the study showed that telomere length in caregiving mothers was negatively correlated with the perceived duration of stress; the longer the caregiving stress, the shorter the telomeres and the lower the telomerase activity. Subsequent research confirmed these findings. For example, individuals providing care for a spouse or parent with dementia had significantly shorter telomere length compared to those without caregiving responsibilities (Kiecolt-Glaser et al., 2010). Other studies have linked various life stressors and adversities, such as childhood physical neglect (Vincent et al., 2017), institutional discrimination (Thomas et al., 2021), and Socioeconomic deprivation (Powell-Wiley et al., 2020), with shortened telomere length. Chronic psychological stress can lead to dysregulation of the stress response and elevated cortisol levels (Karin et al., 2020). Elevated hair cortisol concentration in individuals with previous child welfare residential placements and a history of childhood maltreatment is associated with shorter leukocyte telomere length (Bürgin et al., 2022).

In vitro, studies have demonstrated that exposure of peripheral blood mononuclear cells (PBMCs) to cortisol significantly shortens telomere length (Vartak et al., 2014). Additionally, cortisol exposure decreases telomerase activity in PBMCs (Choi et al., 2008). Interestingly, prolonged exposure to cortisol does not affect telomere length in human fibroblasts (Zannas et al., 2020).

Genetics also plays a significant role in regulating telomere length. Several studies have confirmed that telomere length is a highly heritable trait (Andreu-Sánchez et al., 2022; Guo et al., 2022; Lee et al., 2014), and a strong association exists between parental and offspring telomere length (Broer et al., 2013; Chen et al., 2022; Njajou et al., 2007). Some studies have suggested a possible association between maternal psychological stress during pregnancy and shortened telomere length in newborns (Bosquet Enlow et al., 2021; Entringer et al., 2013; Khalil et al., 2023; Marchetto et al., 2016; Salihu et al., 2016). However, a major limitation of these studies is the relatively small sample sizes. Contrarily, larger studies have reported no significant association between maternal stress and newborn telomere length (Ämmälä et al., 2020; Izano et al., 2020; Naudé et al., 2023). The relationship between parental psychological stress and offspring telomere length remains inconclusive, with inconsistent findings across studies.

Cellular senescence is the irreversible arrest of cellular proliferation, typically triggered by various biomolecular changes, including DNA damage, metabolic stress, mitochondrial dysfunction, oxidative stress, and telomere shortening (Campisi and d’Adda di Fagagna, 2007; Frasca et al., 2021). Cellular senescence is considered a protective mechanism that halts the propagation of damaged cells that could otherwise develop into cancer (Mijit et al., 2020). Two tumor suppressor pathways mainly regulate this process: the p53/p21 pathway and the p16^INK4A/pRB pathway. Activation of one or both of these pathways results in cell cycle arrest (Roger et al., 2021).

Senescent cells are characterized by enlarged, flattened morphology, chromatin remodeling, metabolic alterations, resistance to apoptosis, and the secretion of a senescence-associated secretory phenotype (SASP) (Huang et al., 2022; Kumari and Jat, 2021). The load of senescent cells is higher in older individuals than in younger ones, although senescence rates vary across cell types (Tuttle et al., 2020). As senescent cells accumulate within tissues, they impair normal cellular function and contribute to the development of age-related diseases (Calcinotto et al., 2019).

Chronic psychological stress induces cellular senescence through several potential mechanisms, primarily by promoting oxidative stress and telomere shortening. These stress-induced cellular changes can activate the DNA damage response (DDR), a key pathway leading to cellular senescence (Feringa et al., 2018). DDR activates kinases such as ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related), which phosphorylate p53, stabilizing it and promoting its transcriptional activity. Activated p53 induces p21 expression, leading to cell cycle arrest. Another critical pathway involved in stress-induced senescence is the p16^INK4A/pRB pathway. p16^INK4A binds to CDK4/6, preventing the phosphorylation of the retinoblastoma protein (Rb), thereby suppressing E2F transcription factors and enforcing cell cycle arrest (Mansfield et al., 2024).

Several studies have linked psychological stress with the upregulation of key senescence markers. In an in vivo model, mice exposed to a chronic unpredictable stress paradigm for 2 months to induce depression-like symptoms exhibited increased protein expression of p16^INK4A and SA-β-gal in the hippocampus of stressed mice (Lin et al., 2021). Another study showed that mice subjected to chronic social stress exhibited elevated levels of p16^INK4A and p21 in various organs, as well as signs of DNA damage in hippocampal and cortical neurons (Lyons et al., 2025).

In humans, p16^INK4a expression is significantly upregulated in individuals with major depressive disorder (Teyssier et al., 2012). In stressful conditions such as sleep deprivation, p16^INK4a expression levels are elevated in individuals who experienced partial sleep deprivation (Carroll et al., 2016). Additionally, individuals with higher exposure to chronic stressors such as relationship conflicts, work-related stress, and financial strain showed increased expression levels of p16^INK4a (Rentscher et al., 2019). In a clinical study, tendon biopsies from patients treated with glucocorticoid injections for rotator cuff tendinopathy exhibited a significant increase in the percentage of p53 and p21 positive cells in biopsies obtain 7 weeks after treatment, compared to pre-injection samples from the same individuals, suggesting in vivo activation of the p53/p21 pathway (Poulsen et al., 2014).

Chronic Inflammation is another mechanism mediating psychological stress-induced senescence. The nuclear factor kappa B (NF-κB) is a central regulator of SASP and can be triggered by oxidative stress. The activation of the NF-κB pathway induces the production of pro-inflammatory SASP factors, which not only reinforce the senescent state but also promote paracrine senescence in neighboring healthy cells (Nelson et al., 2018).

A study showed that dexamethasone (a synthetic glucocorticoid) treatment induces cellular senescence in bone marrow adipocyte (BMAd) lineage cells isolated from adult mice. Glucocorticoid-induced senescence spread to neighboring bone and bone marrow cells via SASP factors. Furthermore, the treatment increases the synthesis of SASP factors, including oxylipins, particularly prostaglandin D2 (PGD2), which activates peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ, in turn, upregulates the expression of key senescence genes, including p16^INK4a and p27^KIP1 (Liu et al., 2023). A similar PPARγ-driven induction of senescence has been reported in human cells (Gan et al., 2008).

Epigenetics refers to chemical modifications to DNA or histones that influence gene expression without altering the underlying DNA sequence, including DNA methylation and histone modifications. These alterations can be influenced by environmental and lifestyle factors, such as stress, physical activity (Fiorito et al., 2021), diet (Kim et al., 2022), smoking (Klopack et al., 2022a), and alcohol consumption (Nannini et al., 2023). The current understanding of the interplay between chronic psychological stress, epigenetic regulation, and aging suggests that chronic psychological stress induces epigenetic alterations, which, in turn, dysregulate gene expression profiles crucial for maintaining cellular and systemic homeostasis.

Aging is associated with distinct alterations in epigenetic signatures, particularly changes in DNA methylation. As a result, age-related DNA methylation patterns have been proposed as biomarkers of biological aging. In 2013, Steve Horvath developed the first “epigenetic clock” by identifying a set of CpG sites whose methylation levels strongly correlate with chronological age (Horvath, 2013). Since then, multiple epigenetic clocks have been developed to predict biological age and health outcomes, providing an opportunity to evaluate the impact of psychological stress on epigenetic aging.

Several studies have investigated the association between psychological stress and epigenetic age acceleration. Fiorito et al. (2017) demonstrated that low socioeconomic status (SES) is associated with accelerated epigenetic aging across three cohort studies involving over 5,000 individuals. Participants with low SES showed an estimated 1-year acceleration in biological age compared to those with high SES. A recent cohort study of 3,963 participants from the National Longitudinal Study of Adolescent to Adult Health, a U.S.-based longitudinal population study, found an association between familial loss (loss of a parent, sibling, child, or partner/spouse) and epigenetic alterations associated with aging Moreover, individuals who experienced two or more familial losses showed greater biological age acceleration than those with one or no losses. The study found that familial losses occurring during adulthood were associated with accelerated biological aging, whereas losses during childhood or adolescence did not appear to influence biological age in adulthood. These findings suggest that the impact of familial loss on epigenetic aging may be reversible or age-dependent (Aiello et al., 2024).

Other types of psychological stressors, including violence exposure (Jovanovic et al., 2017), racial discrimination (Cuevas et al., 2024; Ruiz-Narváez et al., 2024), and traumatic experience (Boks et al., 2015), have also been linked to accelerated biological aging. However, some studies have reported no association between psychological stress and accelerated biological aging. For example, Vetter et al. found no significant association between perceived psychological stress and epigenetic age acceleration in older individuals (mean age, 75.6 years) across five epigenetic clocks (Vetter et al., 2022). Similarly, a study involving 1,762 women from the ALSPAC and NSHD cohorts found no association between childhood adversities, including socioeconomic status, and various types of cumulative psychosocial adversity, with epigenetic age acceleration in adulthood, except in cases involving sexual abuse (Lawn et al., 2018).

Although growing evidence supports a link between psychological stress and epigenetic age acceleration, findings across studies remain inconsistent. Several factors may explain these discrepancies. First, epigenetic clocks are based on different sets of CpG sites, and while some clocks may capture stress-related epigenetic changes, others may not. This variability has been observed across multiple studies in which associations were identified with certain clocks but not others (Hamlat et al., 2021; Joshi et al., 2023; Klopack et al., 2022b; Marini et al., 2020; Rampersaud et al., 2022). Second, individual differences such as psychological resilience and self-control may mediate the effects of psychological stress on epigenetic aging. It has been shown that individuals with higher levels of self-control and resilience exhibit slower stress-induced epigenetic aging compared to those with lower levels (Fogelman et al., 2021; Zhang et al., 2023). Third, the timing of stress exposure appears to influence its impact on epigenetic aging. Recent studies suggest the existence of sensitive periods during which psychological stress may have a more pronounced effect on epigenetic aging (Chang et al., 2024; Lussier et al., 2023).

Beyond DNA methylation changes captured by epigenetic clocks, stress exposure induces methylation changes in genes that regulate the stress response, including NR3C1, which encodes the glucocorticoid receptor (GR), and FK506 binding protein 51 (FKBP5), a co-chaperone of GR that influences receptor sensitivity. Hypermethylation of NR3C1 reduces GR expression and decreases cortisol sensitivity (Kolb et al., 2023). Several studies have demonstrated that exposure to chronic psychological stress is associated with increased methylation on NR3C1. For example, children with a history of maltreatment have been found to exhibit increased methylation of the NR3C1 promoter region compared to non-maltreated children (Cicchetti and Handley, 2017). Similarly, in a postmortem study, hippocampal tissue from suicide victims with a history of childhood abuse showed increased methylation at the NR3C1 promoter, along with decreased expression of GR mRNA (McGowan et al., 2009).

Elevated FKBP5 levels reduce GR sensitivity to cortisol, disrupting negative feedback mechanisms and leading to sustained activation of the HPA axis and elevated circulating cortisol levels (Häusl et al., 2021; Zannas et al., 2016). FKBP5 expression increases with age in both mice (Sabbagh et al., 2014) and humans (Matosin et al., 2023) and has been linked to psychiatric disorders (Binder et al., 2008; Matosin et al., 2023). Early life stress and childhood trauma have been found to accelerate the age-associated decrease in FKBP5 methylation in peripheral blood (Zannas et al., 2019). Decreased methylation at two CpG sites in intron 7 of FKBP5 has also been reported in maltreated children (Tyrka et al., 2015). A postmortem study found increased FKBP5 mRNA and protein expression and lower methylation at the FKBP5 promoter in the prefrontal cortex and hippocampus of suicide victims, most of whom had psychiatric disorders (Rizavi et al., 2023). Additionally, Everson et al. (2023) reported decreased FKBP5 promoter methylation in buccal and blood cells of children with abusive injuries compared to children with accidental injuries. These epigenetic dysregulations of NR3C1 and FKBP5 lead to the dysregulation of the HPA axis (Sharan and Vellapandian, 2024).

One biological mechanism linking chronic psychological stress to accelerated aging is the inflammatory pathway (Franceschi and Campisi, 2014; Liu et al., 2017). Accumulating evidence indicates that psychological stress can activate inflammatory responses in the brain and peripherally through interactions between the neuroendocrine and immune systems (Calcia et al., 2016; Rohleder, 2014). Physiologically, our body responds to stress stimuli in a state called “allostasis,” in which stress response pathways are activated, leading to the release of chemical mediators such as glucocorticoids (GCs), adrenaline, and noradrenaline, which evoke a defensive response. In addition, GCs are known to suppress immune cell activity, reduce the production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and promote anti-inflammatory cytokines, such as interleukin-10 (IL-10) and Transforming Growth Factor beta (TGF-β) (Maydych, 2019; Miller et al., 2002). This is a protective mechanism that prevents an overactive immune response during a stressful event, allowing the body to focus its resources on immediate survival.

However, when stress stimuli are prolonged, it can lead to chronic “allostasis,” which contributes to pathophysiology and stress-related diseases. Chronic elevation of cortisol and related hormones leads immune cells to become less sensitive to the anti-inflammatory effects of glucocorticoids, thereby impairing their ability to suppress inflammation (Pariante, 2017). This state, known as glucocorticoid resistance, enables the continued production of pro-inflammatory cytokines, such as IL-6, TNF-α, and interleukin-1 beta (IL-1β), despite high cortisol levels (Miller et al., 2002). Pérez-Nievas et al. (2007) found that, after acute immobilisation stress, rats with higher baseline plasma corticosterone levels accumulated more prostaglandin E2 (PGE2) and showed a weaker anti-inflammatory response. Further study revealed that parents of children with cancer, experiencing chronic stress, showed decreased immune cell sensitivity to dexamethasone in inhibiting IL-6 production (Miller et al., 2002). Furthermore, Pace et al. (2006) found that male patients with major depression and increased early life adversity (ELA) exhibited significantly increased activation of IL-6/NF-κB pathway in response to the Trier Social Stress Test compared to those who were not, with these inflammatory markers correlating with depression severity. These results were in line with several studies that have associated exposure to ELA with increased inflammation in later life (Coelho et al., 2014; Danese et al., 2008; Kiecolt-Glaser et al., 2010; Maydych, 2019).

Within the brain, psychological stress triggers a cascade of neuroimmune interactions, especially involving microglia, the brain’s resident immune cells. Chronic stress can also dysregulate the sympathetic nervous system activity, with norepinephrine acting via adrenergic receptors on microglia to stimulate the production and release of inflammatory mediators, such as IL-6 and TNF-α, through MAPK pathway activation and enhancement of inflammasome components (Carrier et al., 2021; Huang et al., 2012; Liu et al., 2017). Simultaneously, elevated norepinephrine mobilizes monocytes from the bone marrow into the bloodstream. Sustained microglial activation recruits peripheral monocytes. Increased brain macrophages and circulating monocytes contribute to further elevated levels of pro-inflammatory cytokine production in the brain (Wohleb and Delpech, 2017). This further amplifies neuroinflammatory signaling, disrupts microglia–neuron communication, impairs microglial phagocytosis, and contributes to oxidative stress and synaptic dysfunction (Şahin and Aslan, 2024). Collectively, these findings suggest that prolonged stress impairs the body’s natural anti-inflammatory processes, potentially increasing vulnerability to inflammation-related diseases.

Importantly, while psychological stress can trigger inflammation, elevated inflammatory activity can, in turn, promote stress-related symptoms and psychological disorders. Several studies have been positively associated with proinflammatory cytokine levels and stress-related symptoms such as depression, anxiety, and cognitive impairment (Liu et al., 2017; Maydych, 2019). This bidirectional relationship reflects the complex communication between the immune system and the central nervous system. Proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, can signal to the brain through humoral, neural, and cellular pathways, ultimately affecting neurotransmission, neuroendocrine activity, and neural circuits implicated in mood and cognition (Yang et al., 2022). Neuroimaging studies have shown that elevated levels of these cytokines are associated with increased activation of the amygdala and prefrontal cortex, brain regions involved in threat processing, emotional regulation, and executive function (Inagaki et al., 2012; Muscatell et al., 2015). As a result, individuals exposed to chronic inflammation are more sensitive to negative emotional stimuli and have an increased risk for symptoms such as persistent anxiety, anhedonia, and cognitive slowing (Rhie et al., 2020).

The clinical phenomenon of “sickness behavior” is a striking example: acute or chronic inflammation from infection, autoimmune disease, or experimental immune activation can induce fatigue, social withdrawal, reduced motivation, and low mood symptoms closely resembling those in depressive and anxiety disorders (Henry et al., 2008; Liu et al., 2017). Experimental studies have shown that administering proinflammatory cytokines, vaccines, or bacterial endotoxin to healthy participants rapidly induces a negative mood, heightens attentional bias toward threatening or negative stimuli, and impairs cognitive performance (Benson et al., 2017). Importantly, individuals with existing mood disorders often display exaggerated inflammatory responses to psychological stress, suggesting a vulnerability to both heightened inflammation and psychological distress (Mucci et al., 2020).

Inflammation can also potentiate stress sensitivity by altering the regulation of the HPA and SAM axes, which are core mediators of the body’s response to psychological challenges (Liu et al., 2017). Chronic inflammatory signaling disrupts feedback mechanisms within these systems, leading to heightened baseline anxiety, increased perceived stress, and exaggerated stress responses to even minor environmental challenges (Dooley et al., 2018). This creates a self-perpetuating loop in which inflammation and psychological stress continually reinforce each other, increasing vulnerability to mood and anxiety disorders and compounding the risk of chronic disease (Nelles et al., 2025).

Cognitive functions are directly involved in this process. Inflammatory activity is associated with negative attentional bias, greater focus on and difficulty disengaging from negative or threatening information, which is a hallmark of depression and anxiety. Such biases reinforce negative mood, promote rumination, and reduce the capacity to recover from stress (Benson et al., 2017; Boyle et al., 2017).

Societal and environmental factors can further amplify these interactions. Chronic discrimination, socioeconomic hardship, and poor social support are each associated with elevated proinflammatory markers and greater risk of psychological stress and mood disorders. When systemic inflammation is heightened by social adversity, the psychological toll of stress is magnified, illustrating how biological and psychosocial pathways converge to influence mental health outcomes (Androulakis, 2024).

Chronic psychological stress accelerates biological aging by inducing DNA damage. This process is mediated by multiple interconnected mechanisms, including oxidative stress, inflammation, dysregulation of the HPA axis, epigenetic alterations, and impaired DNA repair systems (Gaffey et al., 2016). These mechanisms collectively disrupt cellular homeostasis, compromise genomic stability, and increase susceptibility to age-related diseases (Jurk et al., 2014).

One of the principal mechanisms through which chronic psychological stress induces DNA damage is oxidative stress. Under persistent stress conditions, there is an overproduction of ROS, which are chemically reactive molecules capable of damaging cellular structures, including nucleic acids. The interaction between ROS and DNA results in base modifications, single- and double-strand breaks, and the formation of oxidized nucleosides such as 8-oxo-dG (Goh et al., 2021). This oxidative stress is further intensified by the upregulation of ROS-producing enzymes, such as NADPH oxidase 4 (NOX4), and the downregulation of antioxidant defense mechanisms involving SOD1 and SOD2, thereby reducing the cell’s capacity to neutralize ROS (Boonpraman and Yi, 2023; Dokic et al., 2012).

In addition to oxidative stress, chronic psychological stress activates inflammatory pathways that further contribute to DNA damage. The NF-κB signaling pathway is commonly activated by stress and plays a crucial role in regulating the expression of pro-inflammatory genes. Activation of this pathway leads to the release of cytokines such as IL-6 and TNF-α, both of which promote oxidative stress and interfere with DNA repair mechanisms (Lam et al., 2022; Picard et al., 2015). TNF-α, for instance, has been shown to suppress the function of 8-oxoguanine DNA glycosylase (OGG1), an essential enzyme in the base excision repair (BER) pathway that repairs oxidative DNA lesions (Hassa and Hottiger, 2008). Furthermore, inducible nitric oxide synthase (NOS2) can produce reactive nitrogen species (RNS), which exacerbate DNA damage through nitration and deamination reactions, leading to mutagenic lesions (Flaherty et al., 2017).

Another critical pathway affected by chronic psychological stress is the HPA axis. Prolonged activation of this axis results in sustained cortisol secretion. Cortisol modulates the expression of several DNA repair genes and has been implicated in the suppression of genes such as BRCA1 and RAD51, which are vital for homologous recombination (HR) repair of double-strand breaks (Werner, 2022). Cortisol also modulates FKBP5 expression, further influencing the genomic stress response (Fries et al., 2017). In addition, cortisol reduces the expression of XRCC1 and APE1, genes critical for the base excision repair and DNA damage response pathways, thereby diminishing cellular ability to address DNA insults) Clementi et al., 2020).

Empirical evidence from both animal and human studies supports these molecular findings. In an in vivo study in mice, Jurk et al. (2014) observed that chronic inflammation associated with psychological stress led to marked telomere dysfunction, accumulation of DNA damage, and downregulation of key DNA repair genes. These changes were related to features of accelerated aging. Human studies have provided comparable results. A longitudinal study involving caregivers of chronically ill patients found elevated levels of IL-6 and markers of oxidative DNA damage, coupled with reduced DNA repair capacity, in caregivers compared with non-caregiver controls (Kiecolt-Glaser et al., 2003).

Moreover, chronic psychological stress induces epigenetic alterations that further compromise DNA integrity. Epigenetic modifications, particularly changes in histone acetylation and methylation, affect chromatin structure and gene expression. These changes can limit the accessibility of DNA repair enzymes to damaged sites and enhance the vulnerability of genomic regions to damage (Zannas et al., 2015). For example, stress-related epigenetic repression of p53, a gene central to cell cycle regulation and DNA repair, may impair the cellular capacity to respond to genotoxic stress, increasing the risk of mutagenesis and disease progression (Busbee et al., 2022).

Altogether, these are the current evidence of the relationship between chronic psychological stress and aging. Chronic stress utilizes mitochondrial dysfunction, oxidative stress, telomere attrition, cellular senescence, epigenetic alterations, inflammation, and genomic instability to accelerate aging and increase vulnerabilities to age-related diseases (Figure 3).

Multi-component and community-based approaches are increasingly recognized as effective strategies for reducing chronic psychological stress and promoting healthy aging, with the literature supporting their potential to address both physiological and psychosocial dimensions of stress while fostering broader wellbeing. Meta-analytic evidence demonstrates that psychological interventions, such as mindfulness-based stress reduction (MBSR), CBT, progressive relaxation, and cognitive restructuring, consistently reduce both subjective and biological markers of stress, including improved immune function and altered cortisol levels in healthy adults (Rogerson et al., 2024; Schakel et al., 2019). However, heterogeneity in intervention components, delivery formats, and engagement levels across studies complicates direct comparisons. It underscores the need for tailored, multimodal programs that integrate cognitive, behavioral, physical, and social elements (Schakel et al., 2019). Randomized controlled trials illustrate the added value of multi-component interventions. For example, a multidisciplinary program integrating workplace-focused psychotherapy and MBSR not only reduced stress symptom levels but also significantly increased return-to-work rates among employees on sick leave due to work-related stress, compared to usual care (Netterstrøm et al., 2013). Similarly, even brief multimodal prevention programs, incorporating health coaching, relaxation, physical activity, and psychoeducation, yielded meaningful reductions in perceived and chronic stress, with sustained improvements in wellbeing and quality of life at follow-up, particularly when refresher or booster sessions were included (Kus et al., 2021; Throner et al., 2023). The success of these programs appears to depend on regular practice and participant engagement, with a positive dose–response relationship between self-practice frequency and intervention outcomes (Schakel et al., 2019). Community-based interventions further extend these benefits by leveraging peer support, social networks, and accessible settings to reinforce sustained behavior change, especially relevant in older populations where social isolation can exacerbate stress and limit access to formal services.

In clinical populations, targeted stress management has improved weight management and mental health in children, suggesting that these approaches may interrupt stress-related metabolic dysregulation and unhealthy behaviors that contribute to accelerated aging and chronic disease (Stavrou et al., 2016). For healthcare workers and other high-stress groups, complex interactive programs that include physical activity, mindfulness, and deep breathing have demonstrated feasibility and preliminary effectiveness in increasing the use of stress management strategies (Wang et al., 2023). While the optimal combination of components remains an active area of research, the current evidence base robustly supports multi-component and community-based interventions as a promising, adaptable framework for both mitigating chronic psychological stress and enhancing the prospects of healthy aging across diverse populations.