Neuroendocrine-associated epigenetic factors in cellular senescence: mechanisms and therapeutic implications

Abstract

Ageing is a progressive biological process causing a reduction in tissue and cellular function due to accumulated molecular damage over time. Cellular senescence is a stable cellular state characterized by irreversible cell-cycle arrest accompanied by distinct molecular, epigenetic, and secretory alterations. Moreover, neuroendocrine signalling and epigenetic regulation have had a great impact on controlling ageing and senescence. As a part of the neuroendocrine system, the hypothalamic–pituitary–adrenal (HPA) axis and insulin-like growth factor-1 (IGF-1) mediate stress responses, circadian regulation, and homeostasis. Notably, fluctuations in the hormonal levels, including elevated glucocorticoid levels and reduced IGF-1 levels, result in chronic inflammation, tissue dysfunction, and compromised repair mechanisms as people age. As such, these hormonal changes affect the epigenome function and disrupt gene expression and hasten senescence through chromatin remodelling, histone modifications, and DNA methylation. Together, these effects worsen the condition by causing prolonged psychological stress, which activates the HPA axis over time, resulting in genomic instability, telomere shortening, and mitochondrial dysfunction. Thus, neuroendocrine imbalance and epigenetic drift act as major factors playing a regulatory role in ageing. Hence, hormonal regulation in conjunction with epigenetic treatments, such as DNA methyltransferase and histone deacetylase inhibitors, may provide effective ways to postpone senescence and prolong life. This review explores the regulation of cellular senescence by neuroendocrine-associated epigenetic mechanisms, highlighting their impact on age-related diseases and emerging therapeutic strategies. Gaining a deeper understanding of these interconnected pathways provides a foundation for developing precision medicine approaches targeting the molecular drivers of ageing and its associated disorders.

Graphical Abstract

Neuroendocrine Regulation of epigenetics and its role in ageing-associated disorders. Exogenous glucocorticoids and the HPA axis that regulate cortisol, which in turn affects epigenetic processes like chromatin remodelling, SASP, and redox balance. These alterations cause cellular senescence and are implicated in several age-related diseases that affect different organ systems

Introduction

Ageing is a dynamic, time-dependent process marked by the gradual loss of physical fitness and buildup of cellular damage (Tenchov et al. 2024). The progressive decrease in an organism's capability to maintain homeostasis increases its susceptibility and vulnerability to many ageing-related illnesses, such as immune system disorders, metabolic disorders, cardiovascular disorders, neurodegenerative diseases, and musculoskeletal disorders (Guo et al. 2022). Numerous studies have explored the processes of ageing and how it is governed by complex cellular and molecular mechanisms throughout different stages of life, which involve both cellular and systemic changes, shaped by molecular, physiological, and epigenetic factors. Recently, the interplay between neuroendocrine and epigenetic mechanisms has gained attention for its role in ageing and related diseases (Cai et al. 2022). Since ageing basically involves a process of damage over time, it gets reflected in key physiological hallmarks. The hallmarks include genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction and cellular senescence (Tenchov et al. 2024). Among these hallmarks, cellular senescence has been specifically identified as a significant source of ageing and the development of age-related diseases. Cellular senescence is a stable type of cell cycle arrest brought on by a variety of internal, external, or developmental cues. They occur in relation to variant stressors, including DNA damage, telomere attrition and chromatin remodelling. The development of metabolic alterations, altered gene expression, and persistent growth arrest are all characteristic features of this multi-step process (Kumari and Jat 2021). Cellular senescence was first identified as a crucial intrinsic mechanism for tumour suppression, which stops malignant or damaged cells from proliferating (Collado and Serrano 2006; Serrano and Blasco 2007). It is also known to play a role in important physiological processes, such as tissue remodelling, wound healing, and embryonic development (Domen et al. 2022). Senescent cells, however, contribute to tissue dysfunction and a pro-inflammatory environment as they build up over time, which accelerates the development of age-related diseases like osteoarthritis, atherosclerosis, and neurodegenerative disorders (Domen et al. 2022). Moreover, cellular senescence has both adverse and advantageous effects on organisms. It is frequently cited as a quintessential illustration of evolutionary antagonistic pleiotropy because of its dual nature (Kumari and Jat 2021). Notably, the tumour suppressor pathways, namely p53/p21/WAF1/CIP1 and p16INK4a/pRB (p53: Tumour suppressor protein 53, p21: Cyclin-Dependent Kinase Inhibitor 1 A, WAF1: Wild-type p53-Activated Fragment 1, C1P1: CDK-Interacting Protein 1, p16: Cyclin-Dependent Kinase Inhibitor 2 A, INK4A: Inhibitor of CDK4A, pRB: Retinoblastoma Protein) are responsible for the cell cycle arrest which occurs during ageing (Kobashigawa et al. 2019). These pathways control transcriptional programs that promote the senescent phenotype and orchestrate the cell cycle arrest. Epigenetic modifications like DNA methylation and chromatin remodelling, as well as mitochondrial ROS, reinforce senescence. Thus, developing interventions to reduce age-associated tissue decline and disease requires knowledge about the regulation and effects of senescence (Kobashigawa et al. 2019). In the context of the neuroendocrine system, which comprises the hypothalamic-pituitary axis (HPA), peripheral endocrine glands and the central nervous system (CNS), it is essential for preserving homeostasis because it controls immune function, stress reactions, metabolic activity, and circadian rhythms. It uses hormones to control stress and repair pathways, which impacts cellular senescence (Mulak et al. 2020). Specifically, two important hormone regulators in the ageing process are glucocorticoids and insulin-like growth factor 1 (IGF-1). A relatively decrease in IGF-1, which is mainly involved in growth and anabolic processes, leads to decreased tissue regeneration, muscle atrophy, and cognitive decline, leading to age-related disorders (Silverman and Sternberg 2012; Frater et al. 2018). On the other hand, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis causes glucocorticoids, such as cortisol, to rise with age, which results in increased inflammation, compromised immune responses, and neurodegeneration. Together, age-related disease progression, tissue dysfunction, and cellular senescence are all encouraged by the hormonal environment created by the imbalance between elevated glucocorticoids and reduced IGF-1 levels Furthermore, in the context of epigenetic modifications, its changes are well-known indicators of ageing and senescence (Lopez Otin et al. 2023) and they are important for maintaining cellular identity and regulating genes (Izadi et al. 2024). Epigenetics links genotype to phenotype through reversible modifications that control gene function without changing the DNA sequence. It has a significant impact on how the ageing process is shaped by environmental influences (Wang et al. 2022). Crucially, environmental factors that affect the course of ageing, such as diet, stress, and toxins, tend to have a significant impact on the epigenome. Evidentially, it was shown that senescent and aged cells displayed significant epigenetic alterations, such as promoter-specific hypermethylation of tumour suppressor genes and global DNA hypomethylation, that disrupt transcription and cause genomic instability (Pal and Tyler 2016). Additionally, epigenetic dysregulation is a major contributor to neuroendocrine ageing, as variations in the DNA methylation of genes linked to hormone receptors and neurotransmitters can interfere with neuroendocrine signalling (Wang et al. 2022). In particular, neuroendocrine-related hormones such as cortisol have the ability to alter the target tissues and epigenetic landscape, which hastens the ageing process (Hunter and McEwen 2013). Their reciprocal relationship emphasizes how interdependent they are. Furthermore, new epigenetic treatments that delay senescence and encourage tissue renewal, including DNA methyltransferase and histone deacetylase inhibitors, are currently in practice (Wang et al. 2022). Hence, together with reprogramming the epigenome, it may be possible to restore youthful gene expression profiles and enhance cellular resilience. Further, recent advances in research have highlighted that prolonged psychological stress can cause the HPA axis to become chronically activated, which can hasten the ageing process by encouraging oxidative stress, chronic inflammation, and telomere shortening, all of which are important indicators of biological ageing (Dirven et al. 2017; Hansen et al. 2025). Over time, elevated glucocorticoids contribute to tissue dysfunction and cellular senescence by impairing cellular repair mechanisms, interfering with mitochondrial function, and increasing DNA damage. Additionally, stress-induced epigenetic changes may affect how ageing-related genes are expressed, exacerbating immune dysregulation, age-related cognitive decline, and susceptibility to age-related illnesses. These results highlight how long-term psychological stress significantly alters the physiological and molecular processes that cause ageing (Dirven et al. 2017; Hansen et al. 2025). Thus, by connecting long-term changes in gene expression with systemic hormonal regulation, combining neuroendocrine and epigenetic viewpoints provides a comprehensive understanding of ageing. Epigenetic drift may upset hormone balance and lead to age-related dysfunctions, while neuroendocrine hormones can affect epigenetic marks. This interaction is essential to processes like inflammation and immunosenescence. Personalized anti-ageing treatments can be supported by biomarkers and targeted interventions from both systems (Franceschi et al. 2018). Deciphering the intricacies of how neuroendocrine-associated epigenetic factors influence ageing and age-related disorders requires an understanding of the dynamic interface between the cell's genomic architecture and environmental stimuli. It is crucial first to examine the basic elements of cellular senescence, such as its types, triggers, and distinguishing characteristics, in order to fully understand this interaction. This review addresses the implications of neuroendocrine-induced epigenetic alterations in cellular senescence and associated disorders for the diagnosis and treatment of age-related illnesses. Therefore, together we discuss the importance of these mechanisms, the difficulties in creating therapeutic approaches, and their consequences for the future diagnosis and management of cellular senescence (ageing)-related diseases.

Cellular senescence

Cellular senescence represents a stress-induced cellular program marked by irreversible cell-cycle arrest together with chromatin remodeling and acquisition of a senescence-associated secretory phenotype, thereby influencing tissue aging and dysfunction (Pizzul et al. 2023). Post activation of cellular senescence, senescent cells release a variety of cytokines, chemokines, and matrix metalloproteinases, which causes the emergence of senescence-associated secretory phenotype (SASP) (Beck et al. 2020). SASP factors influence nearby tissues by promoting inflammation and sustaining the senescent state. While regulated senescence supports tissue repair and remodelling, SASP-derived chemokines also recruit immune cells like macrophages for clearance. However, with ageing, immune dysfunction, or stressors like radiation, senescent cells may persist, leading to chronic SASP release, tissue damage, and organ dysfunction, contributing significantly to age-related degenerative diseases (Beck et al. 2020; Domen et al. 2022). The types of it were given in (Fig. 1).

Fig. 1.

Cellular senescence types and inducing factors. This figure illustrates the three principal types of cellular senescence—replicative, oncogene-induced, and stress-induced and their associated inducers, including telomere attrition, oncogenic signaling, and external or internal stressors. Stress-induced senescence encompasses diverse intrinsic and extrinsic stimuli, including oxidative stress, DNA damage, developmental cues, irradiation, and chemotherapeutic agents

Types of cellular senescence

Replicative senescence (RS)

Replicative senescence is brought on by progressive telomere shortening during cell division, which stops the cell cycle and sets off a DNA damage response. Current research emphasizes how telomeric R-loops and DNA repair function in this process. Notably, the replicative senescence plays a significant role in ageing and age-related illness (Kumari and Jat 2021; Herr et al. 2024). It interferes with proper DNA synthesis and adds to genome instability, which is typified by slowed or stopped replication fork progression. Despite being frequently associated with DNA damage, its role in ageing is becoming more widely studied. Moreover, defects in proteins that regulate replication stress are implicated in a number of premature ageing disorders, underscoring the role that these proteins play in age-related decline. Recent studies have also highlighted that replicative stress also activates cellular pathways and phenotypes that are consistent with important ageing hallmarks (Herr et al. 2024). Moreover, the primary cause of genomic imbalance, which leads to ageing-related DNA double-strand breaks (DSBs), is replication stress. Prolonged DSBs induce senescence in aged cells and cause aneuploidies in human embryos, while targeted DSBs can cause premature ageing traits in mice. Replication stress has also been linked to ageing-related cellular alterations, as nuclear deformation has been demonstrated to stall replication forks, further increasing DSBs under mechanical stress (Burhans and Weinberger 2007; Yousefzadeh et al. 2021). Further, evidentially in a study it was highlighted that replication stress plays a universal role in aging whereas with relevance to premature aging phenotypes in a variety of eukaryotes has mutations in conserved RecQ helicases, such as yeast's Sgs1, which suggest that RecQ helicases, while not necessary for survival, aid in the stability of the genome during replication by resolving aberrant recombination intermediates, stabilizing stalled forks, and activating checkpoints (Burhans and Weinberger 2007; Yousefzadeh et al. 2021). Furthermore, Werner syndrome, a rare autosomal disorder characterized by early-onset ageing characteristics, shortened lifespan, and genome instability, which shows an elevated risk of cancer, is caused by mutations in RecQ helicases such as WRN in humans. Similar flaws in RECQL4 (RECQ-like Helicase 4) and BLM (Bloom Syndrome Protein) cause Rothmund–Thomson and Bloom syndromes, respectively, which are both connected to cancer and early ageing (Burhans and Weinberger 2007; Yousefzadeh et al. 2021).

Stress-induced premature senescence (SIPS)

Stress-induced premature senescence (SIPS) describes the early onset of senescence in proliferative cells that mimics the characteristics of replicative senescence, which is caused by prolonged exposure to sub-cytotoxic stress. It can be induced in both primary and immortalized cells by repeated, nonlethal doses of different stressors, and it usually happens at lower population doublings than normal senescence. This early ageing process is largely caused by chronic oxidative stress (Ott et al. 2018). Additionally, some of the stressors that cause SIPS include oxidative stress, DNA damage, mitochondrial dysfunction, epigenetic stress, and Senescence-associated secretory phenotype (SASP), which is produced by primary senescent cells (Polsky et al. 2022). It is distinctive from RS, where this is a telomere-independent process causing several age-related disorders which occur randomly all over the genome and after subsequent activation of a DDR (DNA damage Response) (Hewitt et al. 2012). More recent studies have clarified that SIPS plays an important role in ageing and age-related illnesses. According to a study by Takenaka et al. when mitochondrial complex III was transiently inhibited, SIPS, which was brought on by disturbances in proteostasis, was progressively reduced in human fibroblasts.

Hence, the crucial role of mitochondrial respiration in the development of SIPS was highlighted by this intervention, which also decreased intracellular reactive oxygen species (ROS) levels and protein aggregates, and these findings suggested possible therapeutic approaches to slow down premature cellular ageing (Takenaka et al. 2023). In another study, the effect of SIPS on vascular health was determined, where the findings highlighted that stress-induced senescent vascular smooth muscle cells (VSMCs) accumulated and contributed to the cause of abdominal aortic aneurysms (AAA). The study discovered that fibroblast growth factor 9 (FGF9), which is secreted by senescent VSMCs, encourages phenotypic switching of nearby VSMCs and speeds up the progression of AAA. Targeting SIPS in vascular ageing has therapeutic potential, as the study showed that removing these senescent cells with senolytic agents like ABT263 successfully stopped AAA formation (Xie et al. 2023).

Oncogene-induced senescence (OIS)

Oncogene-induced senescence (OIS) is a powerful tumour-suppressive mechanism that responds to oncogenic activation by stopping cell cycle growth. The discovery of the senescence-associated secretome has demonstrated its wider function, which includes triggering immune responses and affecting the surrounding microenvironment. According to recent research, the specific oncogenic trigger can affect the senescence characteristics (Zhu et al. 2020). Similar to replicative and stress-induced senescence, OIS is characterised by irreversible growth arrest, DNA damage, enlarged cells, elevated reactive oxygen species, SA-β -gal activity, and upregulation of p21/WAF1/CIP1 and p16INK4a (cyclin-dependent kinase inhibitors). The observation of senescent cells in premalignant and early neoplastic lesions in both human and mouse models provides compelling evidence for OIS as an early defense mechanism against cancer. Interestingly, the loss of these senescence markers frequently corresponds with the development of advanced cancers (Toropov et al. 2023). In order to regulate cell division, proliferation, and apoptosis, the tumour suppressors p53 and p16INK4a are essential. These pathways are the primary mechanisms through which OIS occurs in normal rodent cells (Bianchi-Smiraglia and Nikiforov 2012). Moreover, OIS and replicative senescence (RS) have been shown to express different gene expression profiles even though they both have traits in common, such as stable proliferation arrest and SASP. These variations might affect how each of them contributes to ageing and tumour suppression. According to the findings by Nelson et al. OIS's distinct features may be a factor in age-related tissue dysfunction, underscoring the intricate relationship between ageing, cancer prevention, and senescence (Nelson et al. 2014).

Senescence marker

p16INK4a

p16INK4a is a well-known indicator of cellular senescence. Telomere shortening, oxidative stress, oncogene activation, and DNA damage are some of the stressors that cause senescence, an essential tumour-suppressive mechanism. Senescence induction causes a marked upregulation of p16INK4a expression, leading to cell cycle arrest in the G1 phase and thereby preserving the senescent phenotype by blocking the cyclin-dependent kinases CDK4 and CDK6, which stops the retinoblastoma protein (pRb) from being phosphorylated (Sharpless and Sherr 2015). Further, it has been reported that p16INK4a expression rises with organismal ageing and accumulates in a variety of tissues, including the skin, liver, pancreas, and hematopoietic cells, which leads to increased levels that have been linked to age-related conditions such as neurodegeneration, atherosclerosis, and osteoarthritis (Sharpless et al. 2004; Janzen et al. 2006; Ressler et al. 2006; Wagner and Wagner 2022). It has been demonstrated that p16INK4a-positive senescent cell clearance in mouse models improves health span and delays ageing-related diseases, highlighting its functional significance (Sharpless and Sherr 2015). However, p16INK4a should be combined with additional markers, such as SA-β-gal (senescence-associated β-galactosidase), phosphorylated histone variant H2AX (γ-H2AX), and SASP factors for accurate identification, as some senescent cells rely on p53/p21/CIP1 pathways instead. In senescence research and treatment approaches, p16INK4a is a crucial target due to its specificity and strong association with ageing (Beck et al. 2020).

p21

The cyclin-dependent kinase inhibitor p21/CIP1/WAF1 (CDKN1A) is mainly controlled by the tumour suppressor p53. It plays a critical role in the initiation of cellular senescence by causing cell cycle arrest in response to a variety of stressors, such as oxidative stress, DNA damage, and telomere attrition (Beck et al. 2020). Moreover, recent studies have highlighted its importance in age-related tissue dysfunction. For instance, Sarcopenia, a disorder marked by a loss of muscle mass and function, has been linked to increased p21 expression in aged skeletal muscle (Beck et al. 2020; Goyal et al. 2024; Kim et al. 2025). In senescent myoblasts, inhibition of p21 has been demonstrated to decrease senescence-associated characteristics and restore differentiation capacity. Furthermore, the development of chronic kidney disease (CKD) has been linked to p21-mediated senescence, whose upregulation causes the kidneys to age more fibrosically and have a reduced capacity for regeneration. Additionally, the SASP is influenced by p21, which increases the expression of extracellular matrix elements that support tissue fibrosis. Thus, as a possible therapeutic target for interventions p21 meant to mitigate senescence-associated pathologies, these findings highlight the complex role of p21 in ageing and age-related diseases (Beck et al. 2020; Goyal et al. 2024; Kim et al. 2025).

SA-β-gal

Senescence-associated β-galactosidase (SA-β-gal) is a widely used biomarker of cellular senescence, particularly in the context of ageing. It was first described by Dimri et al (1995) and is characterized by β-galactosidase activity detectable at pH 6.0, resulting from increased lysosomal β-galactosidase content in senescent cells. Elevated SA-β-gal activity represents a hallmark feature of senescent cells and has been shown to accumulate in multiple tissues with advancing age, contributing to age-related functional decline. Increased SA-β-gal activity is associated with telomere dysfunction and reduced proliferative capacity and has been reported in peripheral blood mononuclear cells, including CD8⁺ T lymphocytes (Lee et al. 2006; Martinez et al. 2021). However, SA-β-gal activity is not entirely specific to senescence, as increased activity can also be observed in confluent cell cultures and during embryonic development. Therefore, although SA-β-gal remains a valuable tool for identifying senescent cells, it is commonly used in combination with additional senescence markers such as p16INK4a, p21/CIP1/WAF1, and DNA damage indicators including γ-H2AX to enhance specificity and accuracy (Lee et al. 2006; Martinez et al. 2021).

SASP

Senescent cells are defined by the senescence-associated secretory phenotype (SASP), which significantly influences the ageing process. Although these cells no longer divide, they remain metabolically active and secrete a wide range of inflammatory cytokines, chemokines, proteases, and growth factors. This secretome contributes to tissue dysfunction, chronic systemic inflammation, and the onset or progression of age-related diseases, including osteoarthritis, cardiovascular disorders, and neurodegeneration. SASP factors can propagate senescence to neighboring healthy cells through paracrine signaling, thereby amplifying tissue damage (Guo et al. 2022). Evidence suggests that SASP plays a role in chronic inflammation associated with ageing. Strategies such as senolytic agents, which eliminate senescent cells, or senomorphic interventions, which suppress SASP components, have been shown to reduce pro-inflammatory cytokine expression. Moreover, SASP factors are estimated to account for roughly 40% of the age-related increase in plasma proteins (Banerjee et al. 2021). SASP also recruits immune cells to clear senescent cells, but this immune-mediated clearance declines with age, leading to increased inflammation and chronic inflammatory conditions (Yamauchi and Takahashi 2025). In addition, SASP can promote a pro-tumorigenic microenvironment, inducing malignant characteristics in neighboring cells and supporting tumor growth. While direct causal links between SASP and ageing remain limited, studies have shown that inhibiting its main regulator, NF-κB, can suppress SASP and enhance both lifespan and healthspan (Yamauchi and Takahashi 2025).

Neuroendocrine regulation of senescence

The neuroendocrine-immune (NEI) axis is an essential integrative system that coordinates communication between the immune, endocrine, and neurological systems to preserve physiological homeostasis. This triad helps the body to regulate metabolism, inflammation, and tissue repair while also allowing it to respond to external and internal stressors like infection, trauma, and psychosocial stress (Ring and Kern 2024). There is growing evidence that the dysregulation of the NEI axis contributes to chronic inflammation, which is a factor in age-related diseases such as cancer, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. The NEI axis is also a key player in ageing and cellular senescence (Franceschi and Campisi 2014). Ageing is linked to changes in signalling throughout the NEI axis, such as decreased neuroimmune communication, endocrine imbalances that impair immune regulation, and impaired hypothalamic–pituitary–adrenal (HPA) axis function. Important signalling molecules, including hormones (e.g., cortisol, DHEA), neurotransmitters (e.g., norepinephrine, serotonin), and cytokines (e.g., IL-6, TNF-α), affect pathways essential to cellular senescence, particularly NF-κB and mTOR signalling, and modulate immune cell activity (Acosta et al. 2008; Zhou et al. 2019). In addition to mediating stress and inflammatory reactions, these pathways also control the expression of the senescence-associated secretory phenotype (SASP), which is a group of pro-inflammatory cytokines, chemokines, proteases, and growth factors released by senescent cells that worsen tissue damage and encourage additional immune dysregulation (Acosta et al. 2008; Zhou et al. 2019). Furthermore, new research shows that as people age, their ability to communicate with the brain and the peripheral immune system is weakened. Chronic neuroinflammation brought on by microglial senescence, for instance, can disrupt neuroendocrine feedback loops, reducing immunological surveillance and accelerating cognitive deterioration (Guo et al. 2022). Similarly, women who experience hormonal imbalances, such as low melatonin or sex steroid levels, may become less resilient to infections and autoimmune diseases. Therefore, it is essential to preserve the integrity of the NEI axis and encourage healthy ageing by preventing age-related diseases (Liang et al. 2022).

HPA axis and hormonal regulators' involvement in senescence regulation

The hypothalamic–pituitary–adrenal (HPA) axis, which is present at the centre, plays a role in neuroendocrine control of ageing and cellular senescence. The HPA axis becomes dysregulated as people age, which is manifested by increased cortisol secretion and decreased glucocorticoid receptor (GR) feedback sensitivity (Silverman and Sternberg 2012). Hormones perform an important role in controlling cell death and ageing by coordinating intricate physiological reactions that affect tissue homeostasis and longevity. Upon blocking DNA signalling pathways via enhancing stress, the glucocorticoid cortisol, which is released in response to stress, encourages cellular senescence (Sapolsky et al. 2000). Moreover, elevated levels of cortisol are linked to Hippocampal atrophy, cognitive decline, and compromised immune function, which are frequently seen in older adults (Lupien et al. 2009). Further, recent research work highlighted that cortisol promotes senescence by activating the SASP in human fibroblasts through the glucocorticoid receptor (Zannas et al. 2019; Zou et al. 2019). Estrogen, on the other hand, has anti-ageing and protective properties, especially in bones, neurons, and the heart. Its ability to increase telomerase activity and modulate mitochondrial function mainly depends on its high antioxidant properties (Marais et al. 2018). Further, inflammatory signalling is also modulated by estrogen, which delays the onset of age-related illnesses. Moreover, according to a recent study, it was highlighted that estrogen signalling via ERβ reduces inflammation and endothelial senescence, thereby preventing vascular ageing (Mendelsohn and Karas 2005). Another hormone is melatonin, which is the primary source of the pineal gland that is closely linked to the regulation of ageing. Melatonin functions as a strong scavenger of free radicals, promoting DNA repair, increasing mitochondrial efficiency, and preventing the activation of senescence-related pathways like p53 and NF-κB. In a study, it was highlighted that melatonin supplementation can prolong life and improve health span in rodents by lowering age-related oxidative and inflammatory markers (Reiter et al. 2020). Further, growth hormone (GH) and insulin-like growth factor-1 (IGF-1), its downstream effector, play a complex and situation-specific role in ageing and senescence. In general cases, GH and IGF-1 induce promotion of tissue growth, wound healing, and cellular proliferation in young adults. However, hyperactivation of GH/IGF-1 signalling is linked to a lower lifespan and a higher risk of cancer, most likely as a result of decreased autophagy and increased metabolic activity. Conversely, GH-deficient animal models, like Ames and Snell dwarf mice, exhibit longer lifespans and delayed ageing, underscoring the benefits of decreased GH/IGF-1 signalling for pro-longevity (Sun et al. 2017).

A hormonal chain reaction triggered by stress causes the hypothalamic–pituitary–adrenal (HPA) axis to release glucocorticoids (GCs), primarily cortisol. The sleep–wake cycle, light exposure, and circadian signals all affect the diurnal rhythm of cortisol secretion when there is no stress (Gaffey et al. 2016). A negative feedback loop governs baseline cortisol levels, which reflect the function of the HPA axis. High cortisol inhibits the release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), restoring equilibrium to the system. However, feedback efficiency varies from person to person and is determined by the brain's sensitivity and availability of glucocorticoid receptors (GR) (Gaffey et al. 2016). Prolonged cortisol elevation can result from chronic stress's disruption of this system, which weakens negative feedback and lowers GR sensitivity. Additionally, genetic factors, early life trauma, or ongoing stress can cause GR dysfunction. The immune, neurological, and endocrine systems are all impacted by chronic stress, which is linked to both hyper-and hypocortisolism (Guo et al. 2022; Tenchov et al. 2024). Further, a study has also highlighted that prolonged cortisol elevation accelerates tissue ageing and inflammation by causing mitochondrial dysfunction, oxidative stress, telomere shortening, and the senescence-associated secretory phenotype (SASP). Therefore, Hormonal balance is further upset by ageing-related disorders of the hypothalamus, including decreased gonadotropin-releasing hormone (GnRH) and changed neuropeptides. Over-activation of HPA has been associated with immunosenescence, cognitive decline, and heightened vulnerability to age-related diseases (Padro and Sanders 2014; Yiallouris et al. 2019).

Circadian rhythm and ageing

Circadian rhythms give living organisms an adaptive way to synchronise physiological functions, cellular activities and behavioural patterns with the regular 24-h light–dark cycle. Cellularly, the circadian clock is made up of a core set of genes that use a network of interconnected negative-feedback loops to control their own transcription and translation throughout the course of a day (Arendt et al. 2012).“Clock” genes not only control their own expression levels within a 24-h cycle, but they also act as transcription factors for numerous other genes involved in a multitude of processes (Hood and Amir 2017). Through neural and hormonal signals, the hypothalamic suprachiasmatic nucleus (SCN) central clock synchronizes peripheral clocks in different tissues. Peripheral clocks depend on transcriptional/translational feedback loops with activators (CLOCK/BMAL1) and repressors (PER/CRY), despite being impacted by the SCN. Gene oscillations necessary for cellular processes are triggered by these loops. Circadian rhythms regulate metabolic processes like the metabolism of glucose, lipids, and cholesterol, and health is adversely affected when clock genes are disrupted. Additionally, by directly interacting with core clock genes, nutrient-sensing pathways associated with ageing exhibit tissue-specific rhythms (Acousta et al. 2021). There is a clear connection between longevity and circadian regulation. A study demonstrated that calorie restriction restored circadian rhythms in aged mice, reprogramming liver metabolism, improving mitochondrial function, and lowering senescence markers (Sato et al. 2017; Xu and Li 2023; Jain et al 2024). Additionally, without changing the core clock, ageing has been demonstrated to impair mitochondrial rhythmicity and raise oxidative stress, suggesting downstream effects on metabolic gene expression (Sato et al. 2017; Xu and Li 2023; Jain et al 2024). Additionally, circadian misalignment modifies DNA methylation and histone marks, which are the two crucial mechanisms necessary for controlling gene expression and preserving genomic stability by changing the epigenetic landscape of ageing cells (Pal and Tyler 2016; Wang et al. 2022). These results bolster the idea that circadian-targeted therapies, like chronotherapy and lifestyle modifications, can delay ageing and encourage long, healthy lives.

Epigenetic mechanisms in senescence

Senescence is largely regulated by epigenetic modifications, which are heritable shifts in gene expression that do not involve changes in the DNA sequence. These alterations include chromatin remodelling, histone modifications, DNA methylation, and non-coding RNA activity. When senescence begins and continues, these processes work together to coordinate the genome's dynamic reprogramming (Crouch et al. 2022).

DNA methylation and epigenetic clocks

DNA methylation is one of the main epigenetic modifications that contribute to the different mechanisms that control senescence. The process of DNA methylation usually results in transcriptional repression. Site-specific hypermethylation at the promoters of genes involved in cell cycle regulation, like CDKN2A (p16INK4a), is often observed alongside global DNA hypomethylation during ageing and senescence. These alterations impact the release of pro-inflammatory factors that make up the SASP and contribute to the permanent cell cycle arrest that defines senescence (Lopez et al. 2023). Furthermore, chromatin accessibility and structure are the two actions which are impacted by alterations in DNA methylation that occur during senescence, which further affects gene expression and cellular function. The scientific understanding of biological ageing has greatly improved with the advent of epigenetic clocks (Horvath et al. 2013). Methylation levels at 353 CpG sites throughout the genome are used by the Horvath clock, one of the most popular models, to calculate biological age variations in this clock, known as epigenetic age acceleration, can be attributed to environmental exposures or disease risk, but it has been confirmed in several tissues and has a strong correlation with chronological age (Horvath et al. 2013). In order to improve predictive power, recent developments have improved epigenetic clocks for particular uses. For instance, GrimAge and PhenoAge integrate mortality data and age-related biomarkers (Lu et al. 2019). These tools are being used more and more to determine the risk for age-related diseases and to evaluate the efficacy of anti-ageing interventions. Crucially, pharmacological or lifestyle interventions that target epigenetic changes may provide new ways to prevent senescence and encourage healthy ageing.

Histone modifications

Histone modifications, which are controlled by chromatin-modifying enzymes that add or remove particular residues, are covalent post-translational changes to histone proteins. By changing how DNA and histones interact or how histones interact with one another, these changes affect chromatin structure. Further, this found to be a noteworthy association between ageing of the brain, histone acetylation and methylation (Ding et al. 2023). It involves the Histone acetylation and methylation process.

Histone acetylation

HDAC4 (Histone deacetylase-4) a protein with a variety of cellular functions, is downregulated in senescence brought on by oncogenes as well as replication The knockout of this HDAC4 caused senescence in BJ/hTERT/Ras/E1A (BJ-TERT) cells, which are designed to avoid ageing, by upregulating genes linked to senescence and raising SA-β-galactosidase activity (Wang et al. 2022). Similarly, in leiomyosarcoma cells, where HDAC4 is normally overexpressed, its deletion led to senescence and increased the expression of SASP. Subsequent ChIP-seq data demonstrated HDAC4's function in suppressing the senescence program by confirming its interaction with H3K27ac at senescence-related super-enhancers (Di Gorgio et al. 2020, 2021). Conversely, in another study, fibroblasts' replicative senescence was postponed, and DNA damage indicators were decreased when the histone acetyltransferase (HAT) p300 was disrupted. While p300 depletion markedly decreased the expression of super-enhancer target genes, p300 overexpression did not cause premature senescence. ChIP-seq also demonstrated that p300 binds to super-enhancers linked to senescence, proving that it is a crucial mediator of acetylation linked to senescence (Sen et al. 2019).

Histone methylation

The process of adding methyl groups (-CH₃) to histone lysine or arginine residues affects gene expression and is known as histone methylation. Mono-, di-, or tri-methylation of lysine residues is catalysed by histone–lysine N-methyltransferases, whereas arginine N-methyltransferases catalyse symmetric or asymmetric forms of mono- or di-methylation (Ding et al. 2023). These different methylation states make the regulation of genes more complicated. Protein arginine methyltransferases (PRMTs) or lysine methyltransferases (KMTs) are two types of histone methyltransferases (HMTs) that mediate this process. On the other hand, JmjC domain-containing demethylases (JMJCs) and lysine-specific demethylases (LSDs) remove methyl groups from histones using different methods (Ding et al. 2023). Histone methylation is essential for controlling gene expression and chromatin structure as people age. Transcriptional activation and repression are linked to particular methylation marks, such as trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3). Genes involved in stress response, DNA repair, and inflammatory pathways have been shown to express differently as a result of global changes in these histone marks that occur with age. Further, Higher expression of SASP-related factors has been linked to decreased levels of the repressive mark H3K27me3, which is catalysed by the polycomb repressive complex 2 (PRC2) and causes tissue malfunction and chronic inflammation in aged cells (Dozmorrow et al. 2015; Wang et al. 2022). According to Hsu et al., transcriptional noise and epigenetic drift have also been linked to the abnormal accumulation of activating marks such as H3K4me3 during cellular ageing (Hsu et al. 2021). Additionally, the epigenetic landscape is remodelled as a result of the altered expression or activity of histone methyltransferases (HMTs) and demethylases (KDMs), two enzymes that control histone methylation. As an example, loss of genomic stability and increased cellular senescence have been linked to dysregulation of the H3K9me3 mark, which is involved in heterochromatin maintenance (Wood et al. 2010). Genes needed for regeneration and repair are permanently suppressed when KDM6B, a demethylase for H3K27me3, is reduced with age. Using small molecules to target these enzymes has demonstrated promise in modifying pathways linked to ageing and prolonging healthspan in model organisms. Thus, histone methylation offers potential for therapeutic intervention as it is both a marker and a modifiable factor in the ageing process (Pereira et al. 2024).

Senescence-related chromatin alterations and histone-modifying enzymes

There are two types of eukaryotic chromatin available, namely euchromatin, which is relaxed and transcriptionally active, and heterochromatin, which is compact and transcriptionally silent (Grewal et al. 2023).In organisms such as humans, C. elegans, and S. cerevisiae, ageing is linked to heterochromatin loss, which results in inappropriate gene activation (Smeal et al. 1996; Larson et al. 2012; Perez-Jimenez et al. 2014). Heterochromatin architecture disruption is also seen in early ageing conditions like Werner's syndrome and Hutchinson-Gilford progeria (Goldman et al. 2004; Zhang et al. 2015). Moreover, prolonged DNA damage causes senescent cells to produce fewer histones and have lower levels of chaperones, which leads to chromatin disarray (O’Sullivan et al. 2010). Heterochromatin loss is further exacerbated by the expulsion and degradation of chromatin fragments into the cytoplasm (Ivanov et al. 2013). By changing the chromatin structure, histone modifications control the expression of genes. By adding acetyl groups to histones, histone acetyltransferases (HATs) loosen chromatin and increase transcription; histone deacetylases (HDACs) have the opposite effect. Depending on the location and degree of methylation, lysine or arginine residue methylation can either increase or decrease gene expression. For example, transcription is repressed by H3K9 and H3K27 methylation, whereas it is activated by H3K4, H3K36, and H3K79 methylation. Chromatin regulation also involves other modifications such as phosphorylation, ubiquitylation, and ADP-ribosylation (Wang et al. 2019).

Senescence-associated heterochromatin foci (SAHF)

Senescence-associated heterochromatic foci (SAHFs) are dense chromatin structures that are characteristic of senescent human diploid fibroblasts (HDFs) and are enriched with heterochromatin markers. The senescence trigger and cell type have an impact on how they form. SAHF formation is frequently prominent in oncogene-induced senescence (OIS), while SAHF presence is reduced in replicative senescence (RS) brought on by telomere shortening or DNA damage-induced senescence (Narita et al. 2003; Olan et al. 2023). Conversely, chromatin structure is smoothed out and SAHF formation is reduced in NOTCH-induced senescence (NIS). Additionally, SAHF formation differs depending on the type of cell. For example, mouse embryonic fibroblasts (MEFs) and BJ fibroblasts exhibit limited SAHF formation, despite MEFs exhibiting higher levels of SAHF-associated components. The p16-RB pathway is a key regulator of SAHF that facilitates the formation of SAHF. Proteins like the histone demethylase JMJD3 and the SWI/SNF complex component BRG1 interact with RB to alter SAHF dynamics. Reduced SAHF formation results from the structural component HMGA1's repression by NOTCH signalling in NIS, which is necessary for SAHF integrity. In OIS, on the other hand, blocking NOTCH signalling promotes the formation of SAHF. Additionally, NOTCH can contribute to the heterogeneity of SAHF formation by influencing nearby cells through lateral induction (Narita et al. 2003; Olan et al. 2023). Studies have shown that heterochromatin levels both rise and fall during senescence, indicating the complex role of heterochromatin in ageing. Replicative senescence and oncogene-induced senescence (OIS) are two examples of senescence types that involve different physiological contexts and molecular mechanisms, which may be the cause of this variability. Additionally, senescence suppresses tumorigenesis while also promoting ageing (Di Micco et al. 2011; Graziano and Gonzalo 2017). Particularly during OIS, senescent cells develop large SAHFs H3K9me3, HP1γ, macroH2A, and HMGA proteins, which are examples of heterochromatic features found in these structures, which are formed by histone chaperones like ASF1a and HIRA. At first, SAHFs were believed to repress genes linked to proliferation, which in turn contributed to the tumour-suppressive effects of senescence. They are absent in some progeroid syndromes and less common in replicative senescence, indicating that the underlying stressor and the specific senescence type affect the production of SAHF (Di Micco et al. 2011; O’Sullivan and Karlseder 2012; Graziano and Gonzalo 2017). Nevertheless, their formation is not consistent across all senescent cells (Because of this, SAHFs may reinforce cell cycle arrest, but they are not necessary for all types of senescence, and their role in tumour suppression and ageing may differ based on the cellular surroundings.

Role of non-coding RNAs (ncRNA) in senescence regulation

Recent research has demonstrated the important roles that different classes of non-coding RNAs (ncRNAs) play in controlling cellular senescence. Among these, the most research has been done on circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). These ncRNAs use a variety of methods to alter the expression of genes. By attaching themselves to messenger RNAs (mRNAs) and causing mRNA degradation or translation inhibition, miRNAs mainly work at the post-transcriptional level (Dianatpour and Ghafouri-Fard 2017). LncRNAs, on the other hand, have the ability to affect gene expression at the transcriptional, post-transcriptional, and epigenetic levels. As molecular sponges or "decoys," lncRNAs and circRNAs can both sequester miRNAs and decrease their availability to suppress target mRNAs. In addition to their decoy role, lncRNAs impact the transcription or translation of tumour suppressor genes, control the levels of nuclear hormone receptors, and alter telomere length (Dianatpour and Ghafouri-Fard 2017). DNA methylation is one epigenetic mechanism that can affect the expression of these non-coding transcripts (Ji et al. 2020). Crucially, a promising approach to treating a number of illnesses is the therapeutic targeting of miRNAs and lncRNAs. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are two of the most promising approaches being investigated for this purpose (Ji et al. 2020; Winkle et al 2021). Significantly, therapeutic targeting of lncRNAs and miRNAs has recently surfaced as a viable approach to treating a number of diseases.

Long non-coding RNA (lncRNA)

LncRNAs have become important regulators of ageing and age-related diseases (Statello et al. 2021) (Table 1). Chromatin remodeling, transcription, post-transcriptional processing, and signal transduction are some of the ways they alter gene expression (Tavares et al. 2024). Numerous lncRNAs exhibit dynamic changes in expression as people age, and these changes impact important ageing characteristics like cellular senescence, telomere attrition, genomic instability, and epigenetic modifications (Oliva-Rico and Herrera 2017). For instance, it has been demonstrated that the lncRNA TERRA (Telomeric Repeat-containing RNA) delays replicative senescence by preventing telomere shortening, which is crucial for telomere maintenance (Oliva-Rico and Herrera 2017). In the same way, MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) controls cellular senescence pathways and oxidative stress responses in ageing tissues (Ni et al. 2022). LncRNA dysregulation has also been connected to age-related illnesses. Using lncRNA profiling in conjunction with multi-omics techniques is revealing new information to support healthy ageing (Wu et al. 2021). Recent evidence has highlighted long non-coding RNAs as key integrators of neuroendocrine signaling and epigenetic regulation during senescence (Grossi et al. 2025).

Table 1.

Key mechanisms and effects of non-coding RNAs in cellular senescence and aging

ncRNA class	Representative ncRNAs	Key mechanisms	Senescence/aging effects	References
lncRNAs	TERRA, MALAT1	Chromatin remodeling; transcriptional control; post-transcriptional regulation; telomere maintenance; epigenetic modulation; hormone receptor interaction	Delayed replicative senescence; oxidative stress regulation; telomere stability; genomic integrity; epigenetic alterations	Oliva-Rico and Herrera (2017), Statello et al. (2021), Ni et al. (2022), Grossi et al. (2025)
miRNAs	miR-34a, miR-29, miR-146ª	mRNA degradation; translational repression; inflammatory signaling control; mitochondrial regulation	Cellular senescence induction; SASP activation; chronic inflammation; metabolic dysregulation; aging biomarkers	Dimmeler and Nicotera (2013), Olivieri et al. (2021), Turko et al. (2025)
circRNAs	circPVT1, circFOXO3, circCCNB1	miRNA sponging; protein binding; p53/p21 signaling; p16INK4a/Rb regulation; inflammatory modulation	Context-dependent senescence; SASP regulation; vascular aging; age-related inflammation	Du et al. (2017), Kotla et al. (2019), Qiu et al. (2024), Kim et al. (2025)

miRNA

MicroRNA (miRNAs), which are small non-coding RNAs that control gene expression, are important factors in ageing because they alter oxidative stress, inflammation, stem cell function, and cellular senescence (Dimmeler and Nicotera 2013). SASP and chronic inflammation are caused by dysregulation of miRNAs such as miR-34a, miR-29, and miR-146a. Age-related decline can also be attributed to changes in miRNA expression, which impact metabolism and mitochondrial function (Olivieri et al. 2021). Moreover, circulating miRNAs are promising biomarkers of biological age and age-related disease risk. Thus, miRNAs are being therapeutically modulated to prevent functional decline and encourage healthy ageing (Turko et al. 2025) (Table 1).

circRNA

The process of cellular senescence, which is connected to ageing and age-related disorders, is largely regulated by circular RNAs (circRNAs). Through mechanisms like protein interactions and miRNA sponging, their covalently closed structure enables them to be stable modulators of gene expression (Greene et al. 2017). Remarkably, circPVT1 (circular RNA derived from the plasmacytoma variant translocation 1) gene delays senescence in mesenchymal stem cells via the miR-199a-5p/SIRT1 axis, whereas circFOXO3 promotes senescence by binding to anti-senescent proteins like ID1 (Inhibitor of DNA binding-1) and E2F1 (E2 Transcription Factor1) (Du et al. 2017). The wide-ranging effects of circRNAs on senescence are further highlighted by their influence on important pathways like p53/p21 and p16INK4a/Rb (Kim et al. 2025). According to recent research, SASP, which causes chronic inflammation in ageing tissues, may be influenced by circRNAs (Qiu et al. 2024). CircRNAs are implicated in vascular ageing because, for instance, circCCNB1 (circular RNA from cyclin B1 gene) controls the expression of pro-inflammatory cytokines in senescent endothelial cells (Kotla et al. 2019). Furthermore, circRNA expression changes dynamically as people age and in age-related conditions like cancer and neurodegeneration. CircRNAs' cell-type-specific roles in ageing are being further clarified by developments in single-cell and spatial transcriptomics, which position them as promising biomarkers and therapeutic targets (Salzman et al. 2013; Yang et al. 2018a, b) (Table 1).

Neuroendocrine-associated epigenetic factors

The body's epigenetic landscape is significantly impacted by neuroendocrine factors, especially stress hormones, with DNA methylation being one of the most impacted mechanisms (Hunter et al. 2015). Notably, chronic stress results in consistently high levels of glucocorticoids, including cortisol, which cause widespread and frequently permanent changes in DNA methylation patterns. These epigenetic modifications are particularly noticeable in the hippocampus and prefrontal cortex, the two important brain areas that are involved in memory, emotion, and cognition (Hunter et al. 2015). Crucially, these changes can persist long after the resolution of the initial stressor, suggesting that stress leaves an epigenetic "memory" that may make people more susceptible to a range of mental illnesses, including anxiety disorders, depression, and post-traumatic stress disorder (PTSD). It may also hasten biological ageing processes by disrupting cellular pathways (Polsky et al. 2022). Furthermore, the central nervous system is not the only organ affected by stress-induced epigenetic changes. Additionally, DNA methylation alterations in peripheral organs impact the expression of genes linked to immunological control, inflammatory pathways, and metabolic processes (Moosavi and Motevalizadeh Ardekani 2016). The complex interaction between the neuroendocrine system and epigenetic regulation is highlighted by this systemic influence, which also emphasises how long-term stress can cause maladaptive physiological changes throughout the body (Moosavi and Motevalizadeh Ardekani 2016). Moreover, melatonin, which plays a crucial function in controlling circadian rhythms, has recently come to light as a powerful epigenetic modulator with wide-ranging effects on both health and illness. Beyond keeping the biological clock in sync, melatonin regulates gene expression by influencing important epigenetic processes. According to recent research, it can alter the expression and function of sirtuins, a highly conserved family of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases that are essential for metabolic regulation, stress tolerance, and ageing (Duan et al. 2013; Jenwitheesuk et al. 2014). Melatonin affects transcriptional outcomes and chromatin architecture by promoting histone deacetylation through the upregulation of sirtuin activity, specifically SIRT1 and SIRT3 (Duan et al. 2013; Jenwitheesuk et al. 2014). Further, histone acetylation markers, which are important factors influencing chromatin accessibility and gene transcription, are especially affected by this melatonin-induced epigenetic modification, which specifically helps deacetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac) to transcriptionally activate chromatin (Sharma et al. 2008). leading to chromatin condensation, which suppresses the expression of pro-inflammatory genes, helping to create a cellular environment which is less inflammatory. Moreover, melatonin's neuroprotective, anti-inflammatory, and anti-senescent effects have been shown in preclinical and clinical research, which paves the way for a molecular basis to this mechanism. Significantly, this epigenetic action makes melatonin a potentially effective adjuvant in the treatment of age-related illnesses, such as metabolic syndromes, chronic inflammatory diseases, and neurodegenerative disorders (Alamdari et al. 2021). Through its capacity to alter the epigenome through the sirtuin-histone axis, melatonin presents promising therapeutic opportunities for preventing chronic inflammation, preserving neuronal integrity, and postponing the onset of cellular ageing.

Similarly, steroid hormones such as estrogen and androgens play pivotal roles in regulating diverse physiological processes, including development, metabolism, and reproduction. Traditionally, their effects were attributed to ligand-dependent activation of nuclear receptors, namely, estrogen receptor (ER) and androgen receptor (AR), which function as transcription factors upon hormone binding. However, emerging evidence highlights that these receptors also modulate chromatin architecture, adding a complex epigenetic dimension to their mode of action (Nair and Kumar 2012; Severson et al. 2018). Basically, when hormones bind to DNA, ER and AR move into the nucleus and attach to hormone response elements (HREs). This binding recruits chromatin remodeling complexes such as the SWI/SNF (SWItch/sucrose non-fermentable) family, which use ATP hydrolysis to reposition or evict nucleosomes By facilitating or impeding the binding of transcriptional machinery, these locus-specific changes in chromatin accessibility can modify the expression of genes involved in vital cellular functions like survival, apoptosis, differentiation, and proliferation (Nair and Kumar 2012; Severson et al. 2018).

Androgens and estrogen are steroid hormones that are essential for controlling a variety of physiological functions, such as metabolism, reproduction, and development. It has long been noted that their effects are due to the ligand-dependent activation of nuclear receptors, specifically the estrogen receptor (ER) and the androgen receptor (AR), which act as transcription factors when hormones bind to them (Nair and Kumar 2012; Severson et al. 2018). However, research indicates that these receptors also modify the structure of chromatin, which gives their mode of action a complex epigenetic component. Thus, upon binding of estrogen receptors (ER) and androgen receptors (AR) to hormone response elements (HREs) they engage SWI/SNF (SWItch/sucrose non-fermentable) family of chromatin remodeling complexes, which use ATP hydrolysis to reposition or eliminate nucleosomes As a result, locus-specific variations in chromatin accessibility can either promote or inhibit transcriptional machinery binding, which in turn can alter the expression of genes involved in vital cellular functions like survival, apoptosis, differentiation, and proliferation functions that are intimately related to the development of cancer (Nair and Kumar 2012; Severson et al. 2018). Moreover, certain unsuitable gene activation or silencing resulting from the aberrant recruitment of chromatin remodelers by overexpressed or mutated ER/AR can cause oncogenesis, metastasis, and resistance to endocrine therapies. For instance, even in the absence of estrogen, mutations in the ligand-binding domain of the ER can cause constitutive receptor activation in breast cancer, promoting transcriptional programs linked to tumour progression. Similar to this, AR splice variants lacking the ligand-binding domain cause therapy resistance in prostate cancer. Clinical research is being conducted to determine whether epigenetic drugs, such as histone deacetylase (HDAC) inhibitors and bromodomain and extra-terminal motif (BET) inhibitors, might rectify aberrant transcriptional states and enhance hormone sensitivity (Garcia et al. 2012; Jeselsohn et al. 2015; Watson et al. 2015; Jeppsson et al. 2017; Mohammad et al. 2019; Shorstova et al. 2021).

Moreover, ageing is also regulated by the complex interactions between neuropeptides and non-coding RNAs (ncRNAs). In addition to being neurotransmitters, neuropeptides like substance P and neuropeptide Y (NPY) also modify gene expression via post-transcriptional and epigenetic mechanisms. According to recent research, NPY can increase the expression of senescence-associated microRNAs (miRNAs), including miR-34a, a p53 signalling direct downstream effector. Therefore, by targeting cyclin-dependent kinases, miR-34a causes cell cycle arrest and promotes the senescence-associated secretory phenotype (SASP), which includes the release of growth factors, chemokines, and pro-inflammatory cytokines (Okada et al. 2014; Jeppsson et al. 2017). The long non-coding RNAs (lncRNAs) that interact with miRNAs through chromatin state modulation or sponging mechanisms are also influenced by neuropeptides. For instance, in a context-dependent manner, some lncRNAs triggered by substance P can sequester miRNAs that typically prevent senescence, thus promoting a senescent phenotype. The intricate biology of cellular ageing is highlighted by this multilayered regulatory network, which highlights the function of neuropeptides as both upstream modulators and downstream effectors (Dianatpour and Ghafouri-Fard 2017; Winkle et al. 2021).

Neuroinflammation is the central nervous system’s chronic low-grade inflammatory state, which is a major cause of age-related cognitive decline and neurodegenerative illnesses like Parkinson’s and Alzheimer’s. The relation and connectivity between neuroinflammation and epigenetic drift have recently been elevating the accumulation of stochastic epigenetic changes over time. Notably, an ongoing cycle of inflammation and epigenetic disruption is produced by the activation of inflammatory cytokines like interleukin-1β (IL-1β) and tumour necrosis factor-alpha (TNF-α), which can cause histone post-translational modifications (like H3K27 acetylation) and changes in DNA methylation, which can reinforce the transcriptional activation of inflammatory genes. Additionally, oxidative stress brought on by inflammation speeds up epigenetic drift by damaging DNA and compromising the integrity of histone-modifying enzymes and DNA methyltransferases (Franceschi et al. 2018). The accumulation of this epigenetic drift compromises gene regulatory networks and genomic integrity by increasing the variability in DNA methylation patterns between cells (Horvath et al. 2013; Zhang et al. 2015). Moreover, epigenetic instability in neurons leads to decreased neurogenesis, impaired synaptic plasticity, and decreased stress-resilience, all of which eventually contribute to neurodegenerative pathology (Culig et al. 2022) (Table 2).

Table 2.

Molecular mechanism of ageing

Diseases	Key pathological mechanisms	References
Heart failure (HF)	Senescent cardiomyocytes contribute to fibrosis, mitochondrial dysfunction, and inflammatory signalling via SASP; oxidative stress and telomere shortening further impair cardiac function; epigenetic and metabolic reprogramming (e.g., p53/GLUT1-4, miR-195, KDM4D, m6A RNA methylation) accelerate heart failure	Dai et al. (2012), Shimizu et al. (2012), Zhu et al. (2015), Dong et al. (2019)
Alzheimer’s disease (AD)	The main marker of AD is the progressive loss of neurons in the cortex and hippocampus as a result of hyperphosphorylated tau tangles and aberrant amyloid-β (Aβ) plaque accumulation. DNA damage and impaired repair brought on by ageing result in inflammation and oxidative stress. Histone modification and DNA methylation are examples of epigenetic modifications that affect gene expression. While impaired mitophagy exacerbates Aβ/tau buildup, Aβ disrupts mitochondrial function and encourages the production of ROS.ASP factors, which are released by senescent astrocytes, exacerbate neurodegeneration	Jeppesen et al. (2011), Nisbet and Götz (2018), Han et al. (2020), Knopman et al. (2021), Ashrafian et al. (2021), Gaikwad et al. (2021)
Parkinson’s disease (PD)	PD is characterised by the degeneration of dopaminergic neurons and the cytoplasmic buildup of α-synuclein (α-syn) in Lewy bodies. By spreading through LAG3-mediated endocytosis, misfolded α-syn aids in the advancement of the disease. There are two main causes: neuroinflammation caused by NLRP3 inflammasome activation, IL-1β, and IL-6, and genetic mutations (e.g., SNCA, PARK7, LRRK2, PINK1). Additionally, neuronal dysfunction is promoted by cytokine secretion and markers linked to senescence	Rocha et al. (2018), Guo et al. (2019), Polymeropolous (2019), Shahanawaz et al. (2020), Blauwendraat et al. (2020), Zhong et al. (2022) and Sengupta and Kayed (2022)
Osteoarthritis (OA)	Chondrocyte senescence leads to increased secretion of MMP-13 and ADAMTS-5, resulting in ECM degradation; telomere shortening and oxidative stress contribute to OA; ageing increases senescent chondrocytes and upregulates p16 and SA-β-Gal	Price et al. (2002), Loeser (2009), Jeon et al. (2017)
Type 2 diabetes mellitus (T2DM)	Senescent β-cells impair insulin secretion via p16/p21 activation and mitochondrial damage; increased ROS, ER stress, SASP (IL-6, CCL4) promote inflammation; senescent adipocytes contribute to systemic insulin resistance; gut microbiota dysbiosis exacerbates metabolic dysfunction	Rera et al. (2012), Aguayo et al. (2019) and Thompson et al. (2019)
Nonalcoholic fatty liver disease (NAFLD)	Hepatic fat accumulation triggers oxidative stress, mitochondrial dysfunction, and ER stress; senescent hepatocytes show increased p16/p21 and telomere loss; SASP and impaired autophagy promote inflammation and fibrosis; gut dysbiosis and insulin resistance aggravate NAFLD progression	Younossi et al. (2016), Loomba et al. (2017), Chen et al. (2020), Tilg et al. (2021)
Cancer	Ageing based on genomic instability, including telomere attrition and chronic inflammation, contributes to tumorigenesis. Cellular senescence, while initially tumour-suppressive, may promote malignancy via the senescence-associated secretory phenotype (SASP). Age-related decline in immune surveillance, increased somatic mutations, and stem cell dysfunction also foster cancer development	Campisi (2013), Domen et al. (2022), Lopez et al. (2023)

Relation between neuroendocrine signals and epigenetic regulators

Neuroendocrine signaling and epigenetic regulation are tightly interconnected systems that maintain physiological homeostasis and coordinate adaptive responses to internal and external stressors. Hormones such as melatonin, glucocorticoids, estrogens, thyroid hormones, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) influence gene expression not only through classical receptor-mediated pathways but also by reshaping epigenetic landscapes, leading to long-lasting transcriptional effects (Xiao et al. 2020). Conversely, chromatin state and epigenetic modifications regulate hormone receptor sensitivity and availability, creating bidirectional feedback loops that govern ageing, metabolism, stress adaptation, and developmental timing (Hunter and McEwen 2013). Age-related dysregulation of these neuroendocrine–epigenetic interactions contribute to systemic decline and increased susceptibility to age-associated diseases (Goncharova et al. 2023). Among neuroendocrine axes, the hypothalamic–pituitary–adrenal (HPA) axis undergoes pronounced age-related alterations that profoundly influence ageing trajectories. With advancing age, cortisol secretion increases, circadian rhythmicity flattens, and glucocorticoid receptor–mediated negative feedback becomes impaired due to hypothalamic and pituitary dysfunction (Ferrari et al. 2008; Jones and Boelaert 2015; Van der et al. 2023). Chronic HPA axis activation induces persistent epigenetic modifications in stress-responsive genes such as NR3C1 and FKBP5, enhancing inflammatory sensitivity and promoting stress-induced cellular senescence (Zannas et al. 2019). Epidemiological studies, including the MIDUS cohort, demonstrate that lifelong stress exposure correlates with elevated cortisol, increased inflammatory markers, and ageing-associated transcriptional changes, linking HPA dysregulation to cognitive, metabolic, and immune decline (Hansen et al. 2025; Vander et al. 2023).

Ageing also alters adrenal and anabolic hormone balance, shifting physiological dominance from anabolic to catabolic signaling. Dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) decline markedly with age (adrenopause), resulting in an increased cortisol/DHEA ratio that predicts frailty, immune dysfunction, cardiovascular risk, and neurodegeneration (Allard and Duan 2011; Yiallouris et al. 2019; Apsley et al. 2024). Similarly, age-related reductions in GH and IGF-1 signaling (somatopause) impair tissue repair, metabolic homeostasis, and autophagy through dysregulation of the PI3K–Akt–mTOR pathway, leading to senescent cell accumulation and mitochondrial dysfunction (Junnila et al. 2013; Hara et al. 2019). Experimental models and clinical evidence indicate that reduced GH/IGF-1/mTOR signaling and pharmacological mTOR inhibition extend lifespan and delay age-associated diseases (Johnson et al. 2013). Additional neuroendocrine factors further shape ageing through oxidative, inflammatory, and epigenetic mechanisms. Melatonin levels decline with age, contributing to increased oxidative stress, circadian disruption, and immune dysregulation, while melatonin signaling via SIRT1-centered pathways protects against premature senescence by suppressing ROS, NF-κB activation, and p53/p21-mediated cell cycle arrest (Shah et al. 2017; Huang et al. 2018). Gonadal hormone decline, particularly estrogen and testosterone, disrupts hypothalamic–pituitary–gonadal axis homeostasis, accelerating immunosenescence, neurodegeneration, and metabolic dysfunction through loss of ER-mediated anti-inflammatory and epigenetic regulation (Villa et al. 2016; Tramunt et al. 2020). Collectively, age-associated hormonal imbalance is reflected in epigenetic biomarkers such as DNA methylation changes, histone modifications, and non-coding RNAs, including methylation of NR3C1 and miRNAs like miR-34a and miR-29, which serve as indicators of neuroendocrine ageing and senescence (Horvath et al. 2013; Dionisio et al. 2023; Dimmeler and Nicotera 2013).

Ageing is associated with early microstructural deterioration of the hypothalamus, reflecting neuroendocrine disruption that correlates with increased waist circumference and elevated hair cortisol levels in older adults (Spindler et al. 2023). This dysregulation contributes to frailty, mood disturbances, and cognitive decline. Although the cortisol awakening response diminishes with age, overall cortisol secretion particularly during the evening tends to increase, in contrast to the general decline observed in most other hormones. Elevated cortisol levels are strongly associated with frailty, weight loss, anorexia, and muscle atrophy. Moreover, increased activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in ageing tissues further elevates local cortisol concentrations, thereby exacerbating osteoporosis, sarcopenia, and neurodegenerative processes (Gardner et al. 2013). In parallel, reduced levels of dehydroepiandrosterone sulfate (DHEAS) have been linked to increased frailty, type 2 diabetes, and depression, whereas higher DHEAS concentrations are associated with improved physical and psychological outcomes (Jones and Boelaert 2015; Rotter et al. 2015; Kalyani et al. 2023). Ageing is also accompanied by declines in renin activity and aldosterone secretion, impairing blood pressure regulation. Additionally, reduced catecholamine synthesis or impaired sympathetic signaling leads to diminished epinephrine and norepinephrine responses during stress (Musso and Jauregui 2014). Melatonin levels similarly decline with age, contributing to increased oxidative stress, impaired immune regulation, and sleep disturbances. Emerging evidence suggests that melatonin supplementation may improve sleep quality and reduce cardiovascular risk. Collectively, these hormonal alterations reflect a systemic shift from anabolic to catabolic dominance, driving cognitive decline, metabolic dysfunction, and frailty during ageing (Bueno et al. 2023). Neuroendocrine ageing is governed by complex interactions among hormonal feedback loops, intracellular signaling pathways, and epigenetic mechanisms that together maintain cellular integrity and systemic homeostasis. Key neuroendocrine hormones including cortisol, melatonin, dehydroepiandrosterone (DHEA), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) coordinate immune function, metabolism, circadian rhythm, and stress responses. Dysregulation of these hormonal axes with advancing age initiates a cascade of physiological impairments that contribute to organismal decline (Tsigos et al. 2000).

A central feature of neuroendocrine ageing is dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, commonly assessed using the cortisol-to-DHEA ratio (CDR). DHEA and its sulfated form, DHEAS, counterbalance cortisol by supporting estrogen and androgen synthesis and exerting metabolic, immunomodulatory, and neuroprotective effects (Kamin and Kertes 2017). Elevated CDR is associated with increased neurotoxicity, chronic stress, immune suppression, and heightened susceptibility to age-related diseases. While glucocorticoids suppress natural killer cell activity, DHEAS enhances immune responsiveness, particularly in premenopausal women (Ahmed et al. 2023; Suh et al. 2023). Consequently, a higher CDR reflects an imbalance favoring catabolic processes and reduced immunological resilience, increasing vulnerability to chronic pain, stress-related disorders, and ageing-associated conditions (Bauer et al. 2005) (Fig. 2).

Fig. 2.

HPA axis and DHEA balance under stress. The HPA axis is shown to be activated by stress, starting with hypothalamic stimulation, which connects the pituitary gland to act on the adrenal cortex. Along with other adrenal steroids like DHEA/DHEA-S, the adrenal cortex releases cortisol, which has a negative feedback loop on the pituitary and hypothalamus. Although it keeps hormones in balance, this regulatory loop can become dysregulated under long-term stress, which can affect ageing and general health

Melatonin (MT) is essential for halting early cellular senescence because it alters important signalling pathways, mainly by activating sirtuin 1 (SIRT1). Antioxidant enzyme activity, including glutathione peroxidase, catalase, and superoxide dismutase, decreases with age, which causes an excessive build-up of ROS stress, leading to mitochondrial dysfunction and cellular senescence. To combat this, MT scavenges ROS, enhances mitochondrial health, and activates SIRT1, which deacetylates and activates Forkhead box O1 (FoxO1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), lowering ROS production and boosting antioxidant defenses (Kulbacka et al. 2009; Edwards and Hori et al. 2013). In order to boost catalase activity and stop mesenchymal stem cell senescence, MT also triggers the Akt signalling pathway. MT reduces oxidative damage by upregulating nuclear factor erythroid 2 2-related factor 2 (Nrf2) through the SIRT1/Nrf2 axis, which promotes the transcription of antioxidant enzymes through antioxidant response elements (AREs) (Yang et al. 2018a, b). In addition to its antioxidant function, MT controls senescence and cell cycle arrest via the SIRT1/p53/p21 pathway. SIRT1 deacetylates p53, which lowers p21 expression and prevents senescence in normal and stem cells, while promoting p53/p21 expression causes senescence in cancer cells mostly carried out through SIRT1 signalling pathways (Mediavilla et al. 1999; Kim et al. 2007; Chen et al. 2014). Additionally, also MT inhibits inflammation-induced senescence through the SIRT1/NF-κB pathway, in which SIRT1 deacetylates NF-κB's RelA/p65 subunit, lowering its transcriptional activity and related pro-senescent signalling. In stress-induced models like H2O₂-treated neuroblastoma cells, notably MT restores autophagy and inhibits NF-κB activation, as shown in (Fig. 3). Together, these processes demonstrate how melatonin's various range of anti-inflammatory, antioxidant, and cell cycle-regulatory properties, which are primarily mediated through SIRT1 signalling pathways leading to the prevention of premature ageing (Hwang et al. 2013).

Fig. 3.

SIRT-1 mediated Melatonin signalling pathways in cellular senescence. Illustrates the role of melatonin, which suppresses reactive oxygen species (ROS) and preserves redox homeostasis by activating SIRT-1 and its downstream signalling pathways, reducing oxidative damage. This regulation postpones the onset of cellular senescence. -Activation; - Inhibition

In addition to hypothalamic–pituitary–adrenal (HPA) axis dysregulation, age-related declines in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) signaling during somatopause impair skeletal integrity, glucose metabolism, and tissue repair. The GH/IGF-1 axis regulates cellular growth and longevity primarily through the PI3K–Akt–mTOR pathway, a nutrient-sensing cascade controlling protein synthesis, autophagy, and cell survival. Persistent activation of mTOR complex 1 (mTORC1) with ageing promotes senescent cell accumulation, mitochondrial dysfunction, and reduced autophagic capacity, thereby accelerating ageing and age-related disease progression (Kim et al. 2007). Concurrently, dysregulated cortisol secretion resulting from chronic HPA axis activation contributes to catabolic dominance, immunosuppression, and neurodegeneration in older adults. In contrast, melatonin levels decline with age, leading to impaired circadian regulation, increased oxidative stress, and reduced antioxidant defense, further exacerbating cellular senescence and neuroendocrine dysfunction. Gonadal hormones, particularly estrogen and testosterone, are critical regulators of immune–endocrine homeostasis and neurophysiological health. Age-related declines in these hormones, especially during menopause and andropause, disrupt hypothalamic–pituitary–gonadal (HPG) axis feedback, contributing to immunosenescence, neurodegeneration, and cognitive decline (Giefing et al. 2015; Taneja et al. 2018). Estrogens exert potent anti-inflammatory and neuroprotective effects by suppressing NF-κB–mediated cytokine production via estrogen receptor signaling pathways (Martínez-Magaña and Murbartián 2024). Deficiencies in both estrogens and androgens impair neurogenesis and synaptic plasticity, highlighting the importance of gonadal hormone regulation in healthy ageing (Rettberg et al. 2014). Finally, ageing-associated neuroendocrine dysfunction is reinforced by epigenetic alterations, including changes in DNA methylation, histone modifications, and non-coding RNA expression. Reduced histone H3K9 acetylation has been linked to decreased gonadotropin-releasing hormone (GnRH) expression and reproductive senescence (Liang et al. 2022). These epigenetic modifications influence hormone synthesis, circadian regulation, and metabolic control, positioning them as emerging biomarkers and therapeutic targets for mitigating neuroendocrine ageing.

Glucocorticoid signalling in ageing

The adrenal cortex produces steroid hormones called glucocorticoids (GCs), which are mainly cortisol in humans, in response to stress through the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis becomes more dysregulated as people age, and this is frequently indicated by flattened diurnal rhythms and persistently high cortisol levels (McManus et al. 2022). Age-related pathologies such as immunosenescence, sarcopenia, impaired cognitive function, and metabolic disorders are all influenced by these changes. Glucocorticoids work at the molecular level by controlling the expression of genes related to inflammation, glucose metabolism, and apoptosis through the glucocorticoid receptor (GR), a ligand-activated transcription factor. Prolonged exposure to glucocorticoids can be caused by altered GR sensitivity and expression in ageing tissues, which can hinder feedback inhibition of the HPA axis. Upon chronic GC elevation, memory loss and an increased risk of neurodegenerative diseases like Alzheimer’s disease are caused, especially in the hippocampus (Sapolsky et al. 2021). Furthermore, tissue atrophy and frailty are promoted by excessive glucocorticoid signalling, which enhances catabolic pathways while suppressing anabolic ones (like IGF-1 and mTOR). In older adults, glucocorticoids also inhibit immune responses, making them more susceptible to infections and decreasing the effectiveness of vaccinations. Further, Dysregulated GC signalling is therefore a key mediator of physiological ageing and a possible target for treatment to slow down age-related decline (Xiao et al. 2020; Lin et al. 2022).

Potential therapeutic targets of ageing

Epigenetic changes are becoming more widely acknowledged and present promising targets for treatment. DNA methylation drift, histone modification imbalances, and chromatin remodelling are examples of global epigenome changes associated with ageing that collectively impair transcriptional homeostasis and cellular identity (Bettio et al. 2017). Epigenetic medications that reverse age-related transcriptional silencing and encourage cellular renewal, such as DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), have become promising anti-ageing treatments. By reactivating dormant neuroprotective genes, DNMTi guadecitabine has been shown in recent studies to reverse neuroinflammation and synaptic degradation in the aged mouse hippocampus, indicating a neurorestorative effect in the context of cognitive ageing (Bettio et al. 2017). Likewise, it has been demonstrated that HDAC inhibitors like panobinostat enhance chromatin accessibility and lessen heterochromatin foci linked to senescence, allowing older cells to be reprogrammed to a more youthful state. According to these findings, epigenetic medications may be used to delay age-related deterioration in a variety of tissues in addition to treating cancer (Moshref et al. 2021).

Similarly, DNA methylation and acetylation, histone methylation dynamics are also important in cellular ageing and can be pharmacologically targeted to reduce tissue degeneration and senescence. Essential transcriptional programs involved in inflammation, DNA repair, and metabolism are regulated by enzymes such as histone methyltransferases (HMTs) and demethylases (KDMs). The methyltransferase enhancer of zeste homolog 2 (EZH2), which catalyses the trimethylation of H3K27 and results in transcriptional repression, is one intriguing target. According to recent research, EZH2 inhibition in aged fibroblasts improves cellular bioenergetics and viability by lowering senescence markers and restoring mitochondrial respiration (Guo et al. 2024). Similarly, chronic inflammation and inflammaging have been linked to KDM6B (JMJD3), a demethylase involved in immune activation. JMJD3 inhibition decreased systemic inflammation, suppressed inflammatory gene expression, and increased lifespan in a progeroid mouse model, offering compelling evidence that addressing histone methylation may be a useful tactic in the fight against age-related inflammatory diseases. Results emphasise how crucial it is to precisely alter the epigenetic landscape in order to reverse ageing-related dysfunction and restore aged cellular phenotypes (Zhang et al. 2019).

In addition to epigenetic strategies, Hormone modulators are becoming more popular as focused treatments to address endocrine imbalances and age-related functional decline. Elevations of sex hormones like testosterone and estrogen decrease with age, which has a major impact on immune regulation, bone density, and cognitive function (Chen et al. 2017). Bastedoxifene and lasofoxifene are examples of selective estrogen receptor modulators (SERMs) that have been demonstrated to have neuroprotective effects by reducing inflammation and altering estrogen receptor signalling in the ageing brain. A recent study found that bazedoxifene improved cognitive function in aged female mice by lowering pro-inflammatory cytokine release and microglial activation (Chen et al. 2017). Men are developing selective androgen receptor modulators (SARMs), like enobosarm, to fight sarcopenia and frailty. In older adults, Enobosarm showed promise in boosting lean muscle mass and enhancing physical performance without the negative side effects typically associated with testosterone therapy. These hormone modulators raise older adults' quality of life while lowering their risk of age-related comorbidities like osteoporosis and neurological disorders (Dubois et al. 2015).

An additional crucial axis being studied is the growth hormone/insulin-like growth factor-1 (GH/IGF-1) signalling pathway, which is closely related to tissue repair, metabolic homeostasis, and longevity. The sustained activation of the GH/IGF-1 axis in later life has been linked to elevated oxidative stress, insulin resistance, and cancer risk, even though it stimulates anabolic processes in youth. Instead of total inhibition, targeted modulation seems to be the key to a positive result. The GH receptor antagonist pegvisomant, for example, has been demonstrated to improve insulin sensitivity, lessen the generation of reactive oxygen species (ROS), and alleviate metabolic dysfunction in aged mouse models (Fukushima et al. 2014). However, in older people with metabolic syndrome, growth hormone-releasing hormone (GHRH) agonists, like tesamorelin, have shown promise in improving lipid profiles, decreasing visceral adiposity, and restoring mitochondrial function. The importance of hormonal balance in promoting healthy ageing is highlighted by these dual strategies, which, depending on the situation, either dampen or stimulate the pathway (Lake et al. 2021; Amorim et al. 2022). Hormone modulators are part of an integrative toolkit that targets the complex and multifactorial biology of ageing in conjunction with epigenetic interventions.

Therapeutic and clinical interventions

A progressive deterioration in the human body's capacity to handle stress is a primary marker of ageing, a complicated biological process that can result in a number of diseases. While achieving a healthy lifespan has always been a goal, the various mechanisms involved make managing and preventing these conditions both promising and difficult. Currently available interventions include both drug-based therapies that target particular ageing pathways and disease symptoms, as well as non-pharmacological strategies like dietary restriction, nutrition, exercise, and gut microbiota transplantation. Recent clinical and laboratory developments in these therapeutic approaches for various ageing-related illnesses are highlighted in this review.

Alzheimer’s disease

Alzheimer's disease (AD) treatment approaches emphasize both pharmacological and lifestyle changes. Certain lifestyle choices, such as regular exercise, omega-3 fatty acids, and Mediterranean and ketogenic diets, have been shown to have the ability to slow cognitive decline (Kivipelto et al. 2013; Lehtisalo et al. 2019). By lowering inflammation and oxidative stress, natural substances and antioxidants such as curcumin, Ginkgo biloba, and traditional Chinese herbs may have neuroprotective benefits (Howes et al. 2017; Korabecny et al. 2019; Remya et al. 2021; Uddin et al. 2021; Li et al.2022). NMDA(N-methyl-D-aspartate) receptor antagonists (like memantine) and cholinesterase inhibitors (like donepezil) are pharmacological treatments for symptom relief; aducanumab, a more recent drug, targets amyloid-β but has conflicting clinical outcomes (Howes et al. 2017; Korabecny et al. 2019; Remya et al. 2021; Uddin et al. 2021; Li et al. 2022). New approaches focus on impaired mitophagy and mitochondrial dysfunction; substances like kaempferol show promise in these areas (Sun et al. 2016; Kerr et al. 2017). Although there is still a lack of clinical evidence, altering the gut microbiota is also being investigated.

Parkinson’s disease

According to research, the Mediterranean diet, which emphasises unsaturated fats, whole grains, fruits, and seafood, may help lower the risk of Parkinson's disease (PD). Moreover, antioxidants with neuroprotective properties include resveratrol, flavonoids, carotenoids, quercetin, and curcumin, which also do the same (Ciulla et al. 2019; de Carvalho et al. 2022). Certain traditional Chinese herbs, including ginseng, dogwood, skullcap, and pueraria, may have anti-PD properties, and including NAD⁺ supplements may postpone age-related neurodegeneration (Lautrup et al. 2019; Abdul et al. 2021). Notably, Microglial activation is a major contributor to PD-related neuroinflammation, which can be brought on by ageing, infections, oxidative stress, or genetics, and can act as a promising target for treatment. Furthermore, Gene therapy and cell transplantation are promising treatments for the future, but they are still in the experimental stage (Baker et al. 2011; Hou et al 2019). Moreover, research on Human-induced pluripotent stem cell transplantation into primates has encouraged the development of dense neurites in the striatum. Furthermore, deep-brain stimulation and physical therapy are examples of nonpharmacological methods that aid in symptom management. Dopamine-targeting medications and anticholinergics are the mainstays of contemporary pharmacological treatment (Hvingelby et al. 2022). Relatively, there is an ongoing investigation into methods to decrease the expression of α-synuclein or its altered forms, such as phosphorylated or nitrated. Masitinib, a tyrosine kinase inhibitor, may be helpful by preventing the activation of mast cells and microglia. Also, anti-inflammatory medications such as ibuprofen and aspirin have been associated with a lower risk of Parkinson's disease. Studies on the relationship between exposure to specific oral antibiotic classes and a higher risk of Parkinson's disease, however, have produced conflicting and contentious findings. Additionally, there are variations between the outcomes of current human and animal studies concerning the therapeutic effectiveness of FMT (Sampson et al. 2016; Vermersch et al. 2022).

Heart failure (HF)

Heart failure (HF) is a risk factor for ageing because it affects cardiac function (Palmer et al. 2018). Despite poor adherence, anti-ageing strategies like weight control, dietary changes, regular exercise, and medications that target cellular senescence may help slow the progression of heart failure (Cassetta and Pollard 2018; Nassif et al. 2021). Though its effects on ageing-related diseases are complicated, calorie restriction also shows promise. Patients with HF who have preserved ejection fraction have demonstrated improved cardiac function when dapagliflozin is administered pharmacologically (Nassif et al. 2021). Animal models of myocardial fibrosis are lessened by the Bcl-2 inhibitor like Navitoclax, which preys on senescent cells. Cycloastragenol is one of the natural substances that can improve heart health and postpone telomere shortening. Treatments based on plants, such as Eriobotrya japonica and Aconitum carmichaelii, have cardioprotective and anti-inflammatory qualities. Also, Sca1⁺ cell-based stem cell treatments present a viable method for heart regeneration in ageing hearts (Zhou et al. 2015; Chang et al. 2016a, b).

Type II diabetes mellitus (DM)

Type 2 diabetes mellitus (T2DM) is a lifestyle disease which can be prevented and maintained by implementing lifestyle changes, especially weight loss through diet and exercise (Weber et al. 2021). Usually, senescent adipocytes and β-cells are linked to insulin resistance and compromised metabolic balance, which leads to T2DM (Ho et al. 2020). Because of the differences in their senescence mechanisms, specific senotherapeutic approaches are required (Aguayo et al. 2019; Murakami et al. 2022). Notably, transgenic models have demonstrated the potential for senolytics such as ABT263 and B/B homodimerizer to selectively eradicate senescent cells while enhancing β-cell function and glucose metabolism. Nevertheless, ABT263 may result in side effects such as thrombocytopenia. Although they also eliminate senescent cells, other senolytics such as ABT-199, ABT737, dasatinib, and quercetin may have context-specific side effects, such as exacerbating liver disease in certain models (Aguayo et al. 2019; Thompson et al. 2019). Additionally, human β-cells react to senolysis as well. Supporting its translational potential. In addition to senolytics, senomorphics such as metformin and resveratrol have been demonstrated to enhance metabolic function by lowering β-cell senescence (Smith et al. 2010). Although metformin improves glucose tolerance, it may cause older adults to become deficient in B vitamins. Furthermore, insulin secretion can be restored by using modulators such as 4-PBA, TUDCA, and PERK inhibitors to target ER stress. It is also encouraging to alter the gut microbiota by faecal transplantation, probiotics, and synbiotics. Notably, by changing the composition of the gut microbiota in Chinese populations, berberine (BBR), a naturally occurring alkaloid derived from Berberis aristata and Coptis chinensis, has shown hypoglycemic effects (Tang et al. 2012; Kim et al. 2019; Zhang et al. 2020).

Osteoarthritis

Osteoarthritis (OA) can be reduced by a number of therapeutic agents that target inflammation and senescent cells (Tang et al. 2012; Farr et al. 2017). In a recent research, it has been highlighted that drugs. For instance, it has been demonstrated that dasatinib and quercetin combined create a senolytic mixture that efficiently eliminates senescent cells from joints and reduces the symptoms of OA in old animals (Hickson et al. 2019). Moreover, in a similar way in a mouse model, the UBX0101, an E3 ubiquitin-protein ligase, specifically reduces cartilage degradation and pain by eliminating senescent cells through the disruption of p53–MDM2 binding (Jeon et al. 2017). Fenofibrate, fisetin, and navitoclax are examples of other senolytics that promote senescent chondrocytes to undergo apoptosis in order to lower inflammation and preserve joint health (Chang et al. 2016a, b; Yousefzadeh et al. 2018; Nogueira et al. 2019). Clinical trials have shown promising results for senomorphics like canakinumab, etanercept, and lutikizumab, which target SASP components like TNF and IL-1(Ridker et al. 2017; Fleischmann et al. 2019). Senomorphics that target SASP components have demonstrated promising results in clinical trials. Therefore, by maintaining collagen and halting chondrocyte death, MMP13 inhibition achieved by gene knockout or CL821989 treatment protects cartilage Metformin, quercetin, A-769662, and Protectin DX are AMPK pathway activators that also slow the progression of OA (Wang et al. 2013) Whereas Rapamycin slows down cartilage degradation by triggering autophagy but it found to have some reversible side effects (Carames et al. 2012). Some of the additional anti-inflammatory substances, including Wogonin, genistein, Sargassum serratifolium, apremilast and sinomenine, have also been found to act as therapeutic drugs for osteoarthritis treatment (Wu et al. 2023).

Nonalcoholic fatty liver disease (NAFLD)

The key to managing nonalcoholic fatty liver disease (NAFLD) is changing one's lifestyle, particularly losing weight through diet and exercise. A 5% reduction in weight can reduce liver fat by approximately 30%, and a 7–10% reduction may reduce inflammation (Chalasani et al. 2012). Moreover, antioxidants such as polyphenols and vitamin C (800 mg/day) are showing beneficial effects in non-diabetic NASH (While FMT enhances gut integrity with minimal impact on the liver, probiotics reduce inflammation in the liver (Lavekar et al. 2017; Allegretti et al. 2019). Drugs for obesity and type 2 diabetes have not yet received approval, but agents like metformin, PPAR agonists (saroglitazar, elafibranor), and GLP-1 agonists (liraglutide, semaglutide) have demonstrated efficacy as promising targets (Ratziu et al. 2016; Gawrieah et al. 2021; Newsome et al. 2021; Sharma et al. 2021). Similarly, for traditional Chinese medications like berberine, cordycepin and more, research studies are needed to target lipid metabolism and fibrotic pathways, such as berberine, cordycepin, and breviscapine, but they need more research studies (Zhang et al. 2008; Chang et al. 2016a, b; Lan et al. 2021, 2022).

Cancer

A new antitumor tactic is to induce senescence in cancer cells, which stops cell division and promotes the senescence-associated secretory phenotype (SASP), which attracts immune cells and inhibits the growth of neighbouring tumours (Coppe et al. 2008).On the contrary, extended exposure to SASP may paradoxically encourage tumour growth and metastasis (Faget et al. 2019).To successfully control tumour growth, a two-step strategy has been proposed: senescence-inducing therapy followed by senolytic therapy (Childs et al. 2015). Activation of oncogenes, telomere attrition, CDK inhibition, chemotherapy, and epigenetic modification can all cause senescence. Senescence in a variety of cancer types is known to be induced by chemotherapeutic agents, including microtubule inhibitors (paclitaxel, vincristine), platinum-based substances (oxaliplatin, cisplatin), alkylating drugs (busulfan, temozolomide), and topoisomerase inhibitors (doxorubicin, camptothecin) (Ferguson et al. 2015). Moreover, the cell cycle can be stopped and senescence triggered by CDK inhibitors such as Palbociclib (CDK4/6), PF-06873600 (CDK2/4/6), and CDK7/12 inhibitors (e.g., SY-5609, CDK12-IN-3) (Asghar et al. 2015; Kwiatkowski et al. 2014). Similarly, the induction of senescence is also facilitated by telomerase inhibitors such as BIBR1532 and GRN163L (Shay and Wright 2011), epigenetic modulators like Decitabine (a DNA methyltransferase inhibitor), and HDAC inhibitors (e.g., Tip60, p300/CBP) (Domen et al. 2022). Even though SASP components can help the immune system get rid of tumour cells, their long-term buildup could encourage the growth of new tumours. In order to combat this, natural substances like dasatinib, quercetin, and fisetin that inhibit the PI3K–AKT pathway and senolytic agents like Navitoclax (ABT-263), which targets BCL-2 family proteins, are being investigated to reduce therapy-related side effects and specifically eradicate senescent tumour cells (Zhu et al. 2015; Yosef et al. 2016).

Future directions

Although the understanding of the impact of neuroendocrine signals on epigenetic regulation during cellular senescence is expanding, there are still important unresolved questions that need to be explored. The way in which the epigenomic landscape of senescing cells is shaped by dynamic neuroendocrine fluctuations across circadian and life stages is still unknown. Furthermore, systematic research is needed to understand how neuroendocrine-driven epigenetic modifications interact with other ageing characteristics like mitochondrial dysfunction, compromised proteostasis, and genomic instability. Novel technologies such as spatial transcriptomics and single-cell multi-omics provide effective means of elucidating the temporal and tissue-specific functions of neuroendocrine epigenetic factors during the progression of senescence. Further, translational studies on epigenetic medications that alter neuroendocrine pathways, such as methylation modulators, sirtuin activators, and HDAC inhibitors, may also lead to novel anti-senescence treatments. Thus, certain therapeutic designs must be taken into consideration, which show variability in hormone-epigenome interactions across sexes, tissues, and disease contexts. Notably, more studies on in vivo and human models are highly needed to demonstrate the categories in which lifestyle factors, stress exposure, and metabolic status interact with neuroendocrine-epigenetic circuits throughout the ageing process. Therefore, the development of precision medicine strategies to postpone senescence and enhance healthspan will ultimately be guided by a deeper mechanistic understanding of these interrelations.

Conclusion

Recent developments in neuroendocrine research have revealed the crucial influence of epigenetic mechanisms on cellular senescence. Gene expression is influenced by neuroendocrine factors such as glucocorticoids, insulin-like growth factor-1 (IGF-1), and melatonin through mechanisms like DNA methylation, histone modifications, and non-coding RNAs. It establishes a molecular connection between systemic hormonal cues and cellular ageing. Research using animal models and human tissues has shown that when neuroendocrine signalling is dysregulated, it results in abnormal epigenetic reprogramming that fosters the development of senescence phenotypes, chronic inflammation, and functional decline associated with ageing. In this review, it is worth mentioning that the hypothalamic–pituitary–adrenal (HPA) axis and its downstream hormonal mediators can influence chromatin accessibility and heterochromatin stability, thus affecting gene networks associated with senescence. These insights underscore the significance of combining neuroendocrine signalling with epigenetic profiling to enhance our understanding of senescence at both cellular and systemic levels. In summary, neuroendocrine-associated epigenetic changes show considerable potential as biomarkers and therapeutic targets in the context of ageing and age-related diseases.

Author contributions

S.J. and S.R.S. conceived and supervised the study. A.E. collected literature and drafted the manuscript. P.R., S.J. and S.R.S. contributed to framework and critical revision. C.P.P. assisted in review and figure preparation. V.P.V. managed data, references, and editing. V.P.V.K. contributed to concept synthesis and proofreading. All authors reviewed and approved the final manuscript.

Funding

Open access funding provided by Sultan Qaboos University. This study has no funding.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.