How the body’s internal clock and aging affect each other

Time is a fundamental variable in life. Everything unfolds along a timeline, making biological processes either linear and irreversible, as in the case of aging, or repetitive and cyclical, as seen in virtually all biological functions regulated by the circadian system. Since the earliest stages of life on Earth, these two dimensions of time have coexisted in a finely tuned homeostasis, giving rise to what we now recognize as circadian aging.

Since the earliest prokaryotic life, the ability to sense external time has provided a biological advantage. Anticipating the day/night cycle by activating appropriate molecular pathways or behaviors improved adaptation and protection against the exposome, the full range of environmental factors that affect human health. As a result, an inner mechanism has appeared that regulates nearly all aspects of our biology, including behavior (sleepiness, hunger, and other physiological perceptions), hormone secretion, gene expression, molecular localization, metabolism, epigenetic marks, the immune system, cell proliferation, or, even more, the efficacy of therapy administration, according to time. This is the circadian system: a complex network that orchestrates that everything occurs cyclically, rhythmically, at the proper time to preserve our homeostasis.

At the molecular level, in mammals, circadian rhythms are regulated by transcriptional, post-translational and methylation feedback loops generated by a set of interplaying clock proteins (Orozco-Solis and Aguilar-Arnal, 2020). At the core of the mammalian molecular circadian clock, the transcription factors CLOCK and BMAL1/NPAS form a heterodimer that activates the expression of clock-controlled genes by binding to E-box elements, initiating the cycle. Among these target genes are Per and Cry families. Period proteins PER1–3 and Cryptochrome ones CRY1–2 form complexes, and translocate to the nucleus to inhibit CLOCK-BMAL1 activity, thus closing the negative feedback loop. To start a new cycle, PER and CRY proteins must be degraded via proteasomal degradation (through phosphorylation by CK1δ/ε, AMPK, and other kinases) relieves their inhibition of CLOCK-BMAL1 activity to re-start again the cycle (Eide et al., 2005; Lamia et al., 2009; Yoo et al., 2013; Masuda et al., 2020). Moreover, BMAL1–CLOCK heterodimer also drives the expression of NR1D1-2 genes, that encode REV-ERBα-β proteins respectively, and DBP. DBP binds D-box motifs to drive expression of genes encoding the transcriptional activators RORα and RORβ which compete with REV-ERBα and REV-ERBβ for binding to RORE elements as those located in Bmal1. These regulatory loops not only induce the expression of their core components but also regulate many other genes involved in key homeostatic processes, including metabolism or DNA replication (Cox and Takahashi, 2019; Mortimer et al., 2024). They also coordinate with epigenetic regulators and tissue-specific transcription factors to drive rhythmic gene expression (Mortimer et al., 2025) (Figure 1).

Beyond the molecular perspective, the circadian system encompasses additional layers of regulation (Figure 2). At the tissue level, paracrine signals are required to synchronize cell populations. In this regard, factors such as TGFβ, TNFα, and neurotransmitters including GABA, VIP, and AVP play crucial roles in coupling cell-autonomous circadian oscillators (Yoshida et al., 2018; Finger et al., 2021; Ono et al., 2021). At a higher level, organisms must also coordinate their rhythms to align physiology in a time-dependent manner. In this context, hormones such as melatonin and cortisol, as well as circulating elements in blood or lymphatic fluid, including immune cells, neuropeptides, and neurotransmitters like dopamine, noradrenaline, and serotonin, are key components of the circadian system (Linsell et al., 1985; Ciarleglio et al., 2011; Freyberg and McCarthy, 2017; Bonmati-Carrion and Tomas-Loba, 2021). Given the complexity of blood composition, the existence of yet undiscovered systemic circadian regulators cannot be ruled out. While both the organismal and tissue clocks act as endogenous entrainers, they operate at different scales and through distinct regulatory mechanisms: organismal clocks integrate and distribute systemic time cues, whereas tissue clocks require local synchronization, often via paracrine signaling, to ensure precise timing of specialized functions. Finally, ecosystem temporal cues, such as natural or artificial light and temperature, as well as behavioral inputs, including the social agenda and timing of nutrition, are also critical components of this complex system.

Time also occurs in a linear setting, very well represented by the irreversible process of aging. All living beings age, with the exception of a few organisms, including hydras (Hydra vulgaris) (Suknovic et al., 2021), jellyfishes (Turritopsis dohrnii) (Pascual-Torner et al., 2022) that escape this fate. Additionally, there are others in which aging progresses very slowly, like American lobsters (Homarus americanus) (Polinski et al., 2021), long-lived turtles (Testudines), cavefishes (including Phreatobius sanguijuela and Prietella phreatophila), and naked mole-rats (Heterocephalus glaber) (Montazid et al., 2023). Interestingly, species that exhibit delayed aging also tend to preserve solid circadian rhythms across their lifespan, suggesting that the maintenance of temporal homeostasis may be a hallmark of healthy aging (López-Otín and Kroemer, 2021). Notably, several aging-related signaling pathways are interconnected with the molecular clockwork. Among these, SIRT1, mTOR, AMPK, and insulin signaling present the strongest experimental support, with mechanistic studies across multiple species, including mammals. Others, such as FOXO and NRF2, are increasingly supported but still require deeper mechanistic resolution (Ramanathan et al., 2018; Acosta-Rodríguez et al., 2022; Das et al., 2023; Chhunchha et al., 2020).

In aging mammals, these rhythms tend to adapt to the age stage by modifying its period, phase, and amplitude until later life, when these rhythms fragment or dampen, contributing to metabolic dysfunction, cognitive decline, immunosenescence, and sleep disruption (Liu et al., 2024). However, long-lived span organisms maintain stable internal rhythms over decades, highlighting the possibility that resilience of circadian oscillations, at molecular, cellular, and systemic levels, might underlie their sustained homeostasis. Indeed, recent studies show that age-related circadian decline may not be inevitable, but modifiable by enhancing circadian amplitude via light, feeding schedules, or genetic interventions. These interventions improve metabolic and cognitive function in aged mice, reinforcing the idea that the preservation of biological timing could be as critical to longevity and suggesting that negligible aging may, in part, reflect the capacity to maintain circadian synchrony in the face of time (Welz and Benitah, 2020; Belancio et al., 2015; Acosta-Rodríguez et al., 2022; Altamirano et al., 2024; Whittaker et al., 2023; Acosta-Rodríguez et al., 2021).

Circadian aging describes the convergence of linear time, associated with aging, and cyclical time, governed by circadian rhythms. At this intersection, circadian robustness declines, and aging phenotypes emerge in a mutually reinforcing process. Evidence indicates that restoring circadian function can improve health span, offering opportunities for chrono-geroprotective strategies. This review explores how circadian and aging processes interact in mice, humans and long-lived species, aiming to uncover mechanisms of chrono-aging and their implications for healthy longevity.

Most physiological and molecular processes in the organism are governed by the circadian system, which generates rhythmic oscillations throughout the lifespan. These rhythms adapt across different stages of life, fulfilling age-specific physiological requirements. At birth, neonates lack a fully matured central circadian clock, resulting in fragmented sleep-wake cycles. As the suprachiasmatic nuclei, in the brain, progressively synchronize with environmental cues, key circadian outputs, such as core body temperature, cortisol, and melatonin secretion, begin to exhibit defined periods, phases, and amplitudes. However, in advanced age, these rhythms often become dampened or desynchronized, leading to reduced circadian robustness and greater physiological variability (Figure 3).

Among the circadian changes across the lifespan described in Figure 3, there are several critical windows in which circadian control shifts and aging-associated phenotypes become more pronounced. Between the ages of 45–64, defined as middle age, disruptions in sleep architecture and circadian regulation begin to undergo significant transformations, with a remarkable change-point at the age of 60, that signals the early decline of the circadian system (Landolt et al., 1996; Carrier et al., 1997; Carrier et al., 2001; Carrier et al., 2005; Dijk and Duffy, 1999). Studies show that by their 40s and 50s, individuals already experience more fragmented sleep and reduced capacity to recover after extended wakefulness that drives a diminished ability to cope with stressors affecting sleep (Gaudreau et al., 2001). Comparative analyses reveal that middle-aged adults display a phase advance in both sleep timing and core body temperature rhythms, waking and sleeping earlier than younger adults, consistent with a reorientation of the circadian phase, even if the overall rhythmic amplitude remains stable (Carrier et al., 2002; Duffy et al., 2015). Moreover, melatonin rhythms also show early signs of decline. Starting around age 40, melatonin amplitude diminishes, down to about 60% of that seen in younger individuals, accompanied by lower daytime levels and prolonged nighttime peaks (Zhou et al., 2003). Notably, these changes occur independently of shifts in light exposure, indicating that the aging of the circadian system itself may drive this early erosion in temporal organization (Kawinska et al., 2005).

Studies in middle-aged female rats have shown that there are significant differences in the pattern of glucose utilization in the suprachiasmatic nucleus compared to young rats. The authors suggest that alterations in the synchronization and amplitude of luteinizing hormone peaks induced by estradiol during the transition to infertility in middle age could be triggering these changes (Wise et al., 1988). Menopause debut with a decline in estrogen levels, which has been linked to increased oxidative stress, an aging-driving agent (Rangel-Zuñiga et al., 2017). Moreover, postmenopausal women show reduced circadian robustness compared to premenopausal women, with lower amplitude in wrist temperature rhythms, lower average core body temperature during the sleep midopoint, earlier chronotype with a phase advance of approximately 1 hour, and blunted cortisol fluctuations (Gómez-Santos et al., 2016). In addition, they experienced greater sleep fragmentation and a higher frequency of sleep-related breathing abnormalities, such as apnea (Gómez-Santos et al., 2016). The loss of estrogen disrupts circadian rhythms, altering Per2 and Per3 gene expression in visceral and subcutaneous adipose tissue, respectively (Hernandez-Morante et al., 2012), which may contribute to fat redistribution and a higher risk of metabolic syndrome (Hernandez-Morante et al., 2012; Gómez-Santos et al., 2016; Verde et al., 2022), an aging-like phenotype. In fact, granulosa cells in women over 40 show a significant decrease in the expression of molecular clock genes, which negatively correlates with age (Jiang Z. et al., 2021). Additionally, apart from the Rev-erbα gene, all clock genes show also low expression levels in serum, which positively correlate with anti-Müllerian hormone levels (Jiang Z. et al., 2021). Overall, disrupted circadian rhythms in menopausal women are linked to increased multimorbidity and premature mortality (Ren et al., 2025) and coincide with other aging-like phenotypes that emerge profoundly, including bone demineralization, sarcopenia, skin and connective tissue decay or inflammaging.

At the peripheral level, in middle-aged individuals, and given the importance of circadian rhythms in lipid regulation and in their changing profile associated with metabolic problems (Dallmann et al., 2012; Gooley and Chua, 2014; Gooley, 2016; Rahman et al., 2023), it has been shown that the prevalence of endogenous circadian rhythms in the human plasma lipidome is maintained with healthy aging in middle age. Specifically, studies confirm that both young individuals and middle-aged individuals exhibit robust circadian regulation of the lipidome. However, in middle age, there is a reduction in the amplitude of lipid rhythmicity, a greater impact of factors such as sleep deprivation, a phase advance in the acrophase, and an alteration in the synchronization between central and lipid rhythms (Rahman et al., 2023).

Another step of time-fragility comes around age 70, when features such as sarcopenia rise steeply, causing accelerated loss of muscle mass and functionality, that are associated with an increased risk of falls, frailty, and mortality (Cruz-Jentoft and Sayer, 2019; Fernández-Martínez et al., 2023). Aging is one of the primary risk factors for the development of sarcopenia (López-Otín et al., 2023a), and age-related chronodisruption may initiate these pathways in skeletal muscle, preceding its onset (Fernández-Martínez et al., 2023). Notably, the core component of the circadian clock, Bmal1, regulates muscle homeostasis by controlling reactive oxygen species levels (ROS), so its decline with age promotes a pro-inflammatory environment (Kondratov et al., 2009). Over time, this situation leads to a chronic inflammatory state known as inflammaging (Franceschi and Campisi, 2014) characterized by the activation of the NF-κB pathway and an increase in the production of pro-inflammatory cytokines such as IL-6 and TNF-α (Fernández-Martínez et al., 2023). Sustained inflammation and the loss of circadian regulation interfere with muscle protein degradation and synthesis, also producing mitochondrial damage and thereby compromising energy production in muscle cells. These circadian metabolic changes contribute to the development and progression of sarcopenia. Indeed, Bmal1 deficiency in preclinical models impairs circadian behavior and accelerates aging, leading to muscle atrophy, reduced strength, disrupted sarcomere organization, and decreased mitochondrial content, all key features of sarcopenia (Kondratov et al., 2006; Christian and Benian, 2020; Gao et al., 2020). Consistent with these observations, Yang et al. (2016) reported that the absence of BMAL1 in mice not only disrupts circadian rhythms but also increases oxidative stress, impairs mitochondrial function, and perturbs metabolic pathways, pointing to a clock-independent role for BMAL1 in maintaining redox balance, proteostasis, and tissue integrity. Strikingly, brain-specific restoration of Bmal1 failed to rescue normal lifespan, underscoring the essential contribution of peripheral Bmal1 to longevity (Yang et al., 2016). While this finding was discussed in the context of peripheral clock function, we speculate that it may also suggest that the central pacemaker's role is less dominant than traditionally assumed, and that peripheral clocks can, under certain conditions, exert substantial autonomous control over specific physiological functions or even over organismal homeostasis.

This pronounced vulnerability around the seventh decade of life highlights the transition into a phase of systemic time-fragility, where the decline in circadian robustness intersects with the acceleration of aging phenotypes. As the circadian system becomes increasingly desynchronized, both centrally and peripherally, the organism's capacity to adapt to environmental and physiological stressors is diminished. This vulnerability is not merely the result of internal degeneration, but is also shaped by lifelong interactions with the external environment. Indeed, the aging circadian system becomes more susceptible to exogenous influences, suggesting that exposures accumulated across a lifetime may converge with intrinsic molecular changes to further destabilize temporal homeostasis. This interplay sets the stage for understanding aging not only as a biological process but also as an environmentally modulated trajectory, one that unfolds under the constant influence of time-bound cues and stressors. Within this framework, we propose a new concept called the chrono-exposome, in which external cues play a particularly relevant role in the biology of time.

The concept of the chrono-exposome encompasses the cumulative impact of environmental stressors on homeostatic processes throughout an individual's life, particularly through their effects on the circadian system and, consequently, on the physiological functions it regulates. Across the entire lifespan, global exposures such as seasonal photoperiod changes, urbanicity, noise, social jetlag, sedentary indoor lifestyles, erratic feeding schedules, poor sleep routines, artificial light, psychosocial stress, and endocrine-disrupting chemicals pose chronic threats to circadian stability, potentially accelerating aging and disease Nahmod et al., 2019; Huang et al., 2024) (Table 1). It has been observed that the exposure to circadian entrainers, such as light, food, stress and exercise at the inappropriate time, i.e., during the rest phase, can shape the circadian system at the molecular level (Wolff and Esser, 2012; Bolsius et al., 2021), altering molecular clock expression in the suprachiasmatic nucleus and peripheral organs, and affecting metabolic processes. Among the different effects, it can increase oxidative stress and contribute to tissue damage (Li et al., 2023; Makris et al., 2023; Ruan et al., 2021). Through this interaction, circadian entrainers, although essential for life, have the potential to shape different signatures of aging depending on their timing and the life stage.

In modern human societies, irregular exposure to circadian entrainers, as happens in shift work, is a common practice. This practice has been linked to the disruption of internal circadian clocks with external time cues, leading to a phenomenon known as chronic jetlag (Makris et al., 2023). This misalignment affects nearly half of the population and is associated with increased risks of cardiovascular disease, obesity, diabetes, and cancer; conditions commonly linked to aging (Covassin et al., 2016; Laermans and Depoortere, 2016; Albrecht, 2017). The disruption of circadian rhythms can induce oxidative stress in cells via Clock and Bmal1, important regulators of cellular senescence in vivo, a state in which the balance between ROS and antioxidants is disturbed (Yuan et al., 2017; Makris et al., 2023). At baseline levels, ROS support normal cellular functions, but when in excess, they can damage macromolecules such as lipids, DNA, and proteins (Sies, 2018), triggering cellular senescence. In this state, cells cease to proliferate and adopt a senescence-associated secretory phenotype, releasing inflammatory factors, including IL-6, TNF-α, CCL2, CXCL1, and matrix metalloproteinases (Ahmed et al., 2022; Zhang et al., 2022; Basisty et al., 2020). This phenomenon, alongside cellular senescence, contributes to inflammaging, a broader concept referring to the chronic, low-grade inflammation that arises with aging. Inflammaging plays a causal role in the aging process by promoting immunosenescence, mitochondrial dysfunction, and microbiome alterations (Liguori et al., 2018). However, other mechanisms, such as the dampening of the rhythmic expression of circadian genes in immune cells, may also contribute to the aging-associated inflammation (Blacher et al., 2022).

Artificial light at night (ALAN) has become pervasive in modern societies disrupting natural circadian rhythms. One well-known mechanism is its suppression of melatonin production (Lewy et al., 1980). Melatonin suppression leads to increased oxidative stress and DNA damage, mediated by pathways involving the p53 tumor suppressor and the NF-kB signaling cascade, which are implicated in cancer and metabolic disorders (Stevens and Zhu, 2015; Wang et al., 2015; Jiang et al., 2016; Stephenson et al., 2021). However, melatonin plays additional roles, acting as a scavenger of free radicals and as a chelating agent for heavy metals (Limson et al., 1998). For example, in human placental mitochondria, melatonin suppresses iron-dependent production of ROS (Milczarek et al., 2010). In addition, in a recent study, melatonin has been found to exert protective effects against hepatic fibrosis through melatonin receptor 2 activation, leading to the upregulation of Bmal1 and antioxidant enzyme pathways (Kim and Cheon, 2024). The repetitive suppression of melatonin cycles by ALAN thus has the potential to accelerate aging through DNA damage, while melatonin supplementation has repeatedly been found to attenuate oxidative stress damage in age-related diseases like diabetes (Mohammadpour Fard et al., 2024). Interestingly, new avenues are emerging in our understanding of how ALAN contributes to other pathophysiological scenarios, including obesity, type 2 diabetes, and broader metabolic disturbances. These effects are likely mediated through alterations in appetite-regulating hormones, leading to increased food intake, a preference for energy-dense foods, and even gut dysbiosis (Vujović et al., 2022; Thaiss et al., 2014). When it comes to food preferences, eating behavior is orchestrated by metabolic, hedonic, and circadian pathways, which together regulate not only how much and what we eat, but also when we eat. Alterations in the expression of clock genes within these brain regions result in heightened dopamine release in response to high-calorie foods, thereby enhancing their rewarding properties and driving a preference for energy-dense foods during periods of circadian disruption (Bainier et al., 2017).

On the other hand, the timing of food intake is a critical factor influencing circadian rhythms. Research on time-restricted feeding (TRF) indicates that aligning eating patterns with natural circadian cycles can improve metabolic health and potentially slow age-related decline (Longo and Panda, 2016; Ezpeleta et al., 2024). In older humans (Lages et al., 2024; Ezzati et al., 2025) and rodents (Milan et al., 2024), restricting food intake to the active phase of the photoperiod improved markers of oxidative stress, suggesting that eating during the rest phase can result in increased oxidative stress damage compared to eating during the active phase. In a rodent model of liver ischemia-reperfusion, TRF for 8–10 h during the active phase, compared to 24 h food access, improved tissue regeneration, reduced pro-inflammatory (like IL-6) and augmented anti-inflammatory (like IL-10) markers, prevented ROS production and increased systemic β-hydroxybutyrate (BHB) (Ren et al., 2019). Fasting decreases glycogen stores in the liver, and cells shift from carbohydrate to lipid and ketone metabolism, increasing BHB levels and blocking the NLRP3 inflammasome (Youm et al., 2015), which is implicated in age-related functional decline (Youm et al., 2013). Conversely, TRF during the rest phase in rodents (Ye et al., 2024), and eating during the late active phase in humans (Allison et al., 2021) exacerbated systemic insulin resistance, a common feature in aged populations. Regarding the long-term effects, a study in a rodent model found that restricting feeding to the rest phase promoted hepatic lipid accumulation by suppressing hepatic miR-27b-3p, thereby enhancing PPARγ activity and upregulating CD36-mediated lipid transport into the liver (Tsurudome et al., 2022). These results suggest that lifelong exposure to misaligned eating patterns might potentially accelerate aging, but long-term experimental approaches are required to assess these changes.

Finally, the benefits of physical exercise in slowing the aging process have been extensively studied (Garatachea et al., 2015). However, exercise also elicits distinct effects depending on the time of the day, with morning exercise benefiting lipolysis, and evening exercise muscle mass (Gabriel and Zierath, 2019; Kim et al., 2023). At the molecular level in rodent models, exercise entrains the core clock by shifting expression patterns of Per2 (Kemler et al., 2020), and can prevent oxidative damage derived from melatonin deficit or circadian disruption (Jana et al., 2020; Gu et al., 2024). In humans, it is challenging to determine the effects of exercise during normal sleep time. Rodent models of exercise during the rest phase are also limited. It has been reported that exercise during the rest phase, compared to the active phase, increases systemic energy expenditure without enhancing lipid oxidation according to the muscle transcriptome, an effect mediated by the fed status (Sato et al., 2019; Sato et al., 2022; Pendergrast et al., 2024). However, the effects of exercise during the rest phase on oxidative stress and tissue damage require further exploration.

Lifelong environmental exposures, such as light pollution, nutrition timing, and shift work, play crucial roles in shaping circadian health. Understanding the circadian molecular and physiological impacts of these factors can offer valuable insights into the mechanisms of aging. While targeting lifestyle and chrono-exposome factors holds promise for promoting healthy aging, the bidirectional relationship between circadian disruption and aging remains incompletely understood. To bridge this gap, there is an urgent need for both preclinical and clinical studies that clarify how environmental timing influences age-related decline. Complementing this environmental perspective, insights from biological extremes, such as premature aging syndromes and exceptionally long-lived species, offer powerful models to dissect the resilience or vulnerability of the circadian system in aging.

The molecular architecture of the circadian clock is a deep-rooted legacy of life's earliest adaptation to Earth's rotation. Organisms began developing intrinsic timekeeping mechanisms over 2.5 billion years ago, with cyanobacteria evolving the KaiABC protein clock system, that regulated global gene expression in alignment with day/night cycles (Swan et al., 2018; Jabbur and Johnson, 2022). In animals, this ancestral timekeeping framework evolved into transcription–translation feedback loops involving core genes like Clock, Bmal1, Per, and Cry, which share homology with ancient microbial photoreceptors and transcription factors (Stanton et al., 2022). This remarkable evolutionary continuity underscores the fundamental role of circadian timing in coordinating whole body physiology including metabolic homeostasis, DNA repair, and protein quality control, key processes implicated in aging (López-Otín et al., 2023a). By situating premature aging syndromes and long-lived species within this evolutionary framework, we highlight how these extreme models can reveal whether circadian resilience or vulnerability meaningfully influences longevity. However, it is remarkable how little primary evidence exists regarding circadian system regulation in these species and, consequently, about its potential relationship with their long or short lifespan. In the following sections, we summarize the limited literature available on their circadian systems and propose possible correlations between circadian regulatory pathways and aging, with the aim of opening new avenues for future research.

Aging studies have explored the major regulatory pathways involved in this complex process. The Hallmarks of Aging, published in 2013 by López-Otín and colleagues, and subsequently updated into their "expanding universe" a decade later, has ended on 14 hallmarks of aging providing an overview of the key biological features that influence aging (López-Otín et al., 2013; López-Otín et al., 2023b; Kroemer et al., 2025). Further attempts to understand the intricate connections between aging and the circadian system were reviewed in Impact of the Circadian Clock on the Aging Process by Fonseca Costa and Ripperger in 2015 and later by Welz and Aznar-Benitah (Fonseca Costa and Ripperger, 2015; Welz and Benitah, 2020). Premature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), or other progeroid syndromes including Werner syndrome or Néstor-Guillermo progeria syndrome, offer unique windows into the mechanisms of accelerated aging. They serve as valuable models for exploring the interplay between aging and circadian regulation, precisely at the moment when both times meets, out of time.

Hutchinson-Gilford progeria syndrome is a premature aging disorder caused by mutations in the LMNA gene, that produce a defective protein called progerin leading to a disorganized nuclear architecture (Eriksson et al., 2003). This syndrome is characterized by accelerated aging, with affected individuals displaying features such as hair loss, joint abnormalities and cardiovascular disease, with a reduced lifespan. Research into HGPS hallmarks could help explore the potential role of circadian dysfunction in its pathology and identify crosstalk between both biological time systems. Genomic instability, a hallmark of HGPS, may be worsened by circadian disruption of DNA repair pathways involving Sirt6 and Bmal1 through nicotinamide adenine dinucleotide (NAD⁺), a seminal metabolite in aging and circadian system regulation (Kolinjivadi et al., 2021; Toiber et al., 2013; Nakahata et al., 2009). Similarly, the epigenetic alterations observed in HGPS, including loss of heterochromatin and aberrant histone modifications, likely impair the circadian regulation of chromatin accessibility and gene expression (Oh et al., 2019). The disorganized nuclear architecture in HGPS, driven by progerin, may interfere with the spatial organization of circadian gene loci, compromising rhythmic transcription. Studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences (Liang et al., 2021). Mitochondrial dysfunction and oxidative stress, common in HGPS cells, could be exacerbated by disruption of circadian control over mitochondrial dynamics and metabolism via NAD + -dependent pathways. Loss of proteostasis, due to impaired autophagy and accumulation of misfolded proteins, may also reflect a breakdown in circadian regulation of cellular quality control systems. Proteostasis, under the regulation of the circadian system (via mTOR, and proteasome activity) (Juste et al., 2021) reciprocally induces the degradation of core circadian proteins like BMAL1, contributing to age-associated circadian disruptions and accelerated aging phenotypes (Lipton et al., 2017; Khapre et al., 2014a). Additionally, stem cell exhaustion and premature cellular senescence in HGPS resemble age-associated decline in circadian coordination of stem cell renewal and senescence-associated gene expression. Vascular dysfunction, a critical cause of morbidity in HGPS, is linked to circadian regulation of endothelial tone and inflammation (Kunieda et al., 2008). Together, these features underscore a possible bidirectional relationship between nuclear envelope defects and circadian misalignment in the pathogenesis of HGPS.

Other progeroid syndromes, while mechanistically distinct from HGPS, may also involve circadian alterations. In Néstor–Guillermo Progeria Syndrome (NGPS), caused by mutations in BANF1 (encoding BAF1), loss of BAF disrupts nuclear architecture and chromatin organization without progerin accumulation (Cabanillas et al., 2011). Although circadian rhythms have not been directly studied in NGPS, BAF's interaction with MAN1, a nuclear envelope protein that binds the BMAL1 promoter, and its role in chromatin tethering suggest potential circadian disruption (Zhang et al., 2015; Brunet et al., 2019). Similar gaps exist in Werner syndrome, a segmental progeria caused by mutations in WRN, a gene involved in DNA repair, telomere maintenance, and epigenetic stability (Milosic et al., 2024). While direct links between WRN and core circadian genes remain elusive, overlapping pathways such as chromatin remodeling, metabolic regulation, and epigenetic modifications, all influenced by circadian clocks, indicate possible crosstalk (Bellet and Sassone-Corsi, 2010; Koike et al., 2012; Chang and Guarente, 2013; Pacheco-Bernal et al., 2019; Acosta-Rodríguez et al., 2022).

Collectively, these observations point to a potential bidirectional relationship among nuclear envelope defects, circadian misalignment, and the accelerated aging phenotypes observed in progeroid syndromes, highlighting the need for direct studies on circadian system integrity in these conditions.

The evolutionary strategies that long-lived species have developed to couple aging with circadian clock homeostasis could shed light on the interaction between biological processes. Although this remains a complex and somewhat controversial area of study, many aged animal tissues exhibit dampened rhythms characterized by reduced amplitude, increased fragmentation, and impaired stability. Consequently, the expression of genes under circadian control, including those involved in metabolism, is also affected (Nakamura et al., 2016; Wallace et al., 2020; Cai et al., 2023; Masuda et al., 2023; Wolff et al., 2023; Buijink et al., 2024). Understanding whether rhythms in long-lived animals maintain their amplitude and acrophase, and how they achieve this, could help unravel the relationship between aging and the temporal dynamics of various biological pathways. Also, species adapted to extreme photoperiods demonstrate a high degree of behavioral plasticity and not only reveal how circadian rhythms adjust to challenging environments but also provide insights into the resilience of the biological clock under environmental stress, identifying mechanisms that promote greater circadian stability and, consequently, help delay aging. Since the circadian system can be entrained and stabilized by external cues, this field offers a valuable opportunity to explore new avenues for understanding the aging process. In this section, we will explore the strategies and evolutionary insights of long-lived animals such as the naked mole-rat, cavefish, and whales, to open new perspectives in the chrono-aging process.

Insights from long-lived species offer a valuable evolutionary perspective on how the circadian system may be optimized to promote resilience against aging and disease. A recurrent feature in these organisms is the enhanced coupling between the molecular clock and key metabolic pathways, including insulin/IGF-1 signaling, glucose metabolism, and mTOR regulation, which are centrally involved in human aging and its associated pathologies, as well as in maintaining DNA integrity. In contrast, humans exhibit a progressive erosion of circadian robustness with age, a decline that exacerbates the risk and severity of chronic diseases by disrupting metabolic, neuronal, and cardiovascular homeostasis. This reciprocal reinforcement between aging and chronodisruption establishes a maladaptive cycle. While circadian rhythms are not defined as a standalone hallmark of aging, their disruption intersects with multiple established hallmarks, such as chronic inflammation, mitochondrial dysfunction, epigenetic alterations, cellular senescence, and particularly psychosocial isolation, a newly proposed hallmark (Kroemer et al., 2025).

In this section, we analyze four major aging-related diseases—neurodegenerative, cardiovascular, metabolic disorders, and cancer—and explore how the interplay between linear time, represented by the aging process, and cyclical time, embodied by the circadian system, shapes their pathophysiology. Our main goal is to identify the common pathways shared by these two processes, which could then be studied in depth and targeted in future circadian aging therapies (Table 2).

Pharmacotherapy, traditionally based on standardized dosing protocols, presents considerable challenges when applied to the geriatric population. Older adults exhibit specific physiological changes that increase their vulnerability to adverse drug reactions and toxicity, forming the foundation of geriatric pharmacology for decades. However, emerging evidence highlights that circadian dysregulation with age adds a crucial, often overlooked dimension to this vulnerability. The progressive deterioration of the suprachiasmatic nucleus impairs responsiveness to environmental cues, contributing to internal desynchrony and promoting a breakdown in physiological homeostasis. This circadian misalignment impacts key processes, including sleep-wake cycles, metabolic regulation, immune responses, and cognitive resilience.

Notably, psychosocial isolation, which increases with age (Dahlberg et al., 2024), compounds circadian disruption by weakening social and environmental zeitgebers, activating neuroendocrine stress responses and sleep disturbances (Stafford et al., 2013; Meyer et al., 2024; Yeom et al., 2024; Liu and Jiang, 2025). This establishes a vicious cycle in which aging and chronodisruption reinforce each other, accelerating biological decline and disease susceptibility (Kroemer et al., 2025). Given that circadian rhythms modulate both pharmacokinetics and pharmacodynamics, governing drug absorption, distribution, metabolism, and elimination, understanding the chronobiological underpinnings of organ function becomes essential to optimize pharmacological interventions in aging individuals.

Integrating circadian biology into clinical practice thus adds a multidirectional perspective: the circadian system influences aging, is influenced by it, and critically modulates therapeutic efficacy and safety. As such, preserving circadian integrity emerges as a strategic target in precision geromedicine, not only to mitigate systemic aging but also to tailor pharmacological treatments.

On one hand, it is important to know the circadian physiological detoxification ratio to understand pharmacokinetics. In this regard, precision geromedicine should take into account that the expression of metabolizing enzymes (such as cytochrome P450 isoforms) and hepatic membrane transporters are regulated, like many other genes, by clock-dependent mechanisms, and influence intestinal absorption, hepatic uptake, and biliary and renal excretion of various drugs (Zhang et al., 2009; Ohdo, 2010; Dallmann et al., 2016; Kobuchi et al., 2018; Mukherji et al., 2019; Ayyar and Sukumaran, 2021; Geng et al., 2021; Ma et al., 2023). The alteration of these mechanisms generates distinct temporal windows of bioactivation, efficacy, and toxicity, even under physiological conditions. In addition to this molecular regulation, pharmacokinetics is also influenced by circadian variation in physiological processes such as hepatic blood flow, gastrointestinal motility, gastric pH, renal perfusion, and plasma concentration of binding proteins, which vary rhythmically and interfere with the absorption, availability, metabolism, and excretion of drugs.

However, during aging, a number of molecular, structural, especially in the suprachiasmatic nucleus, and physiological alterations occur (Hood and Amir, 2017; Buijink and Michel, 2021), leading to reduced clock gene expression, particularly in hepatic, intestinal, and renal tissues (Nakamura et al., 2011; Kobuchi et al., 2018; Xu et al., 2023). As a result, the circadian expression of metabolizing enzymes becomes erratic, such as carboxylesterase-1, essential for prodrug bioactivation and hepatic detoxification, affecting drug clearance (Dallmann et al., 2016; Ballesta et al., 2017; Ma et al., 2023). NAD⁺ metabolism is another molecular axis disrupted during aging, impairing hepatic circadian rhythms through three pathways: by reducing sirtuin activity, the function of the CLOCK:BMAL1 complex, and the acetylation of protein targets, not only in the liver, but also in the intestine and the central nervous system. In this way, changes in NAD⁺ metabolism also promote generalized peripheral desynchronization (Massudi et al., 2012; Gomes et al., 2013; Imai and Guarente, 2014).

In addition to these molecular and epigenetic changes, anatomical and functional alterations characteristic of older adults negatively influence pharmacokinetics in this population. A reduction in hepatic blood flow, renal function, and gastric pH, as previously mentioned, compromises drug excretion, while the loss of lean mass and increased body fat alter drug distribution, aggravating the effects of chronodisruption (Hämmerlein et al., 1998; Baraldo and Furlanut, 2006; ELDesoky, 2007).

All these alterations contribute not only to the weakening of the response to conventional therapy in this population, but also to chronotherapy, which presupposes a physiological rhythmicity that is not observed in these patients, particularly in the presence of comorbidities, polypharmacy, or sleep disorders (Lévi et al., 2010; Ohdo, 2010; Dallmann et al., 2016). A paradigmatic example is the nighttime administration of antihypertensives aimed at attenuating the morning blood pressure surge. In the elderly, this response may be paradoxical or even absent, due to the deterioration of blood pressure rhythms and age-related autonomic dysfunction (Albuquerque et al., 2021; Akyel et al., 2023). Oncology protocols based on chronotolerance and chronoefficacy often result in poorer outcomes in older adults, with high interindividual variability and an increased risk of hematologic, neurologic, and gastrointestinal toxicity (Ballesta et al., 2017; Puppala et al., 2021; Amiama-Roig et al., 2022).

This loss of chronobiological responsiveness stems both from the desynchronization between central and peripheral clocks, and from the chronotype heterogeneity observed with aging, as the geriatric tendency toward morning chronotypes may not align with dosing regimens designed for younger adults with evening chronotypes (Dallmann et al., 2014; Kara et al., 2023). Added to this is the pharmacodynamic remodeling associated with aging, with changes in receptors, ion channels, and signaling pathways linked to the circadian system (Ozturk et al., 2017; Zhao et al., 2020).

In light of this scenario, personalized medicine emerges as a promising strategy to counteract the deleterious effects of aging on biological rhythmicity and to enhance therapeutic responses in elderly patients. Devices capable of accurately estimating an individual's circadian phase have become increasingly valuable tools for aligning interventions not only with the disease but also with the residual rhythmicity of older individuals (Dose et al., 2023). Among these technologies, TimeTeller utilizes transcriptomic data from a single biological sample to analyze the coordinated expression of a multigenic panel composed of core elements of the molecular clock, enabling the inference of internal biological time with high precision. This approach is highly innovative and overcomes the limitations of traditional methods, which rely on indirect markers or behavioral measurements (Dose et al., 2023; Vlachou et al., 2024).

In this regard, as the circadian system is plastic and modifiable, chronomodulation, the strategic alignment of behaviors, treatments, and molecular interventions with the body's internal clock, offers a compelling and multifaceted strategy to counteract the circadian system decay. Beyond lifestyle-based approaches such as timed light exposure, structured sleep, and feeding-fasting cycles that enhance circadian amplitude and metabolic resilience, molecular chronotherapeutics are gaining traction. Central to this molecular axis are chrono-metabolites, endogenous compounds like NAD⁺, polyamines, and urolithins, whose rhythmic oscillations bridge circadian regulation with metabolic integrity. With aging, the decline in these oscillations compromises core clock function, disrupts mitochondrial homeostasis, and weakens stress responses. Targeted restoration of their rhythmicity, via supplements such as nicotinamide riboside, dietary polyamines, or urolithin A, has been shown to rejuvenate circadian gene expression, synchronize metabolic rhythms, and improve physical performance in aging models. Together, these interventions illustrate how chronomodulation, from behavior to metabolite, stands not only as a preventive strategy but as a foundational pillar of precision geroscience, where aging is rhythmically recalibrated to preserve physiological harmony (Sato et al., 2017; Mukherji et al., 2019; Dong et al., 2020; Verma et al., 2023; Xu et al., 2023). Moreover, circadian-aligned interventions, such as timed light exposure, structured physical activity, meal scheduling, and sleep optimization, hold promise for enhancing drug tolerability, improving therapeutic outcomes, and promoting healthspan in the elderly.

Moreover, understanding whether the target molecule for treating a specific disease is subject to circadian regulation could aid in optimizing the timing of drug administration. In this context, ALZ-801, which targets APOEε4 in Alzheimer's disease, is currently being evaluated in two clinical trials (NCT04693520, NCT06304883) (Kroemer et al., 2025). Notably, APOE^−/− mice exhibit altered rhythms of peripheral and central clock genes in heart and liver tissues, characterized by increased amplitudes and phase shifts, effects that are further exacerbated by a high-fat diet (Xu et al., 2009). Additionally, disruption of the core clock gene Bmal1 in the brain leads to elevated Apoe expression and accelerated amyloid plaque accumulation (Hussain et al., 2024). Another example is Resmetirom, a thyroid hormone receptor-β agonist used to treat non-alcoholic fatty liver disease, a condition highly prevalent in aging, which reduces the expression of DBI, a gene classified as a gero-gene (Kroemer et al., 2025). DBI exhibits circadian oscillation in both the suprachiasmatic nucleus and the liver (Montégut et al., 2023). Thus, it would be of particular interest to further investigate the chronotherapeutic potential of ALZ-801 or Resmetirom to determine whether its efficacy or tolerability is influenced by the timing of administration, in alignment with the circadian nature of their targets.

In parallel, chronotimed drug delivery technologies and stimulus-responsive nanoparticles (e.g., to pH and temperature) represent other technological advances that have also shown the capacity to align drug administration with the patient's biological phase. These tools contrast with strategies that aim to reprogram hepatic rhythmicity, such as compounds that act on the molecular clock (e.g., RORα agonists and REV-ERB inhibitors).

Currently, several chronomodulated therapies have proven their efficacy. In this regard, in cardiovascular diseases, it has been evaluated that taking a low dose of acetylsalicylic acid (ASA) in the evening, rather than the morning, is more effective since it aligns better with the body's circadian rhythm, potentially reducing the risk of cardiovascular events. The limited 24-h efficacy of once-daily ASA is partly explained by its pharmacokinetics and the circadian physiology of platelets. ASA is rapidly absorbed and eliminated, so newly produced platelets, released at a rate of 10%–15% per day, escape COX-1 inhibition and can form clots. Effective platelet inhibition requires ∼95% COX-1 blockade, yet studies show that 24 h after morning intake, a quarter of cardiovascular patients have insufficient inhibition. Notably, platelet production follows a circadian rhythm, peaking in the late night and early morning, coinciding with the timing of adverse cardiovascular events (Buurma et al., 2019).

In epilepsy, administering a higher evening dose of clobazam has been shown to improve seizure control in patients whose seizures occur predominantly at night or in the early morning. Tailoring drug administration to individual seizure susceptibility patterns exemplifies how chronotherapy can optimize epilepsy management: differential dosing allows for delivering higher treatment levels at the times of greatest vulnerability, while minimizing side effects during periods of lower risk (Thome-Souza et al., 2016).

Chronomodulated treatment also shows promise in metabolic diseases, particularly via time-restricted eating and timed administration of antihypertensives or metformin (Hermida et al., 2011; Türk et al., 2023). Several clinical trials and modeling studies support the concept that aligning treatment with circadian rhythms can enhance efficacy and reduce risks.

The convergence of circadian biology and aging research reveals time not merely as a backdrop but as a dynamic biological force, where Kronos, that represents the linear progression of age, and Kairos, the opportune moment dictated by biological rhythms, co-determine the trajectory of health and disease.

The circadian system emerges as a central integrator of internal physiology and external temporal cues, shaping molecular pathways implicated in longevity, age-related diseases, and the systemic resilience observed in long-lived species. Disruptions to this temporal architecture, whether through genetic mutations, lifestyle factors, or social disconnection, can accelerate the hallmarks of aging and compromise physiological homeostasis, as seen in natural aging. It would be worthwhile to understand how the circadian system operates in contexts of accelerated aging, such as in progeroid syndromes, both in preclinical models and in humans, to uncover potential shared mechanisms.

This lesson is being learned from long-lived species such as the naked mole-rat, cavefish, and certain whales, which appear to age at a slower pace than other animals. The studies suggest that genome stability, modulation of the mTOR pathway, glucose metabolism, and circadian plasticity act in concert in these species to delay aging and extend lifespan. A key factor underlying this phenomenon is the stable environment in which these species live, coupled with their remarkable ability to adapt swiftly and with high plasticity to external changes when necessary. Conceptually, as with the stem cell pool, the less you exhaust it, the more reserve you retain later in life. In this light, living in a stable environment may reduce the need for constant circadian adjustments, thereby preserving the integrity of the circadian system over time.

The concept of the chrono-exposome, introduced in this review, broadens this perspective by situating circadian rhythms within the wider context of temporal environmental and behavioral exposures throughout life. From this viewpoint, lifelong exposure to various stressors can disrupt circadian homeostasis and accelerate aging. Such disruptions can begin early, for example, when neonates in intensive care units are exposed to inappropriate light cycles, continue through infancy and adolescence with irregular exposure to screens and erratic eating patterns, persist into adulthood where jetlag and shift work are common, and extend into older age with increased sedentarism and psychosocial isolation.

In this context, the interplay between circadian rhythms and pharmacological responses gains critical relevance in the aging population. As aging weakens both the amplitude and synchronization of circadian oscillations, the efficacy and safety of pharmacological interventions are increasingly compromised. This decline in circadian robustness affects drug metabolism, detoxification, and target engagement, while also contributing to the heterogeneity in therapeutic outcomes among older adults. Chronotherapeutic approaches, though promising, must account for the altered rhythmic landscape of the elderly, whose chronotypes, molecular clocks, and peripheral rhythms are no longer aligned with standard dosing paradigms. Innovations such as transcriptome-based circadian phase estimators, rhythmic biomarker profiling, and chrono-active compounds open new avenues for aligning treatments with residual circadian function. As such, circadian-informed precision geromedicine, where both the timing and the nature of interventions are tailored to the aging clock, emerges as a foundational strategy not only to enhance therapeutic efficacy and reduce toxicity, but also to recalibrate biological time itself, preserving physiological harmony across the aging trajectory.

As we advance toward precision geromedicine, recognizing the plasticity of the circadian system to recalibrate homeostasis, restoring circadian integrity through personalized, time-aligned interventions emerges as a promising strategy to mitigate age-related decline and improve therapeutic outcomes. Embracing time not merely as a measurable factor but as a modifiable variable may ultimately enable us to harmonize human aging with biological opportunity.

Future circadian aging research should integrate molecular, environmental, and therapeutic approaches, deciphering shared longevity pathways with those that keep a healthy circadian system, mitigating chrono-exposome insults, and tailoring chronotherapy to the changing clock across life. Protecting genome stability, metabolic balance, and circadian plasticity emerges as essential for the health of both the organism and its circadian system. Ultimately, preserving temporal harmony may prove as vital as preserving life itself.