Circle(s) of Life: The Circadian Clock from Birth to Death

**Background:** Most lifeforms use endogenous circadian clocks to adapt to 24-hour environmental cycles. While most research has focused on adults (3–6 months in rodents, 20–40 years in humans), clock properties vary significantly with age. Circadian dysfunction is implicated in obesity, cancer, mood disorders, and neurodegeneration. This narrative review follows the circadian clock across the lifespan, from prenatal development through old age, with emphasis on reproductive systems and sex differences.

**Methods:** This is a narrative review synthesizing findings from human and rodent studies on circadian clock development and aging. The authors discuss evidence from molecular, physiological, and behavioral studies, including clock gene expression analyses, hormone measurements, sleep studies, and transplantation experiments.

**Key Results:** - *Prenatal period:* The fetal clock relies on the maternal circadian system. Melatonin and glucocorticoids (GCs) are key maternal-fetal synchronizers. Maternal melatonin crosses the placenta and binds to fetal melatonin receptors from embryonic day 18 (E18) in rats and week 19 of gestation in humans. GC levels gradually increase in pregnant females until the last day of gestation. The placenta protects the embryo from excessive GC exposure via 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Astiz et al. showed at E17 that hypothalamic diurnal expression rhythms of GR and REV-ERBα are anti-phasic in wild-type and absent in clock-deficient mice. Cecmanova et al. reported that GCs increase spontaneous rhythmicity in the fetal SCN. The fetal SCN is fully developed during early gestation, but clock gene expression in other tissues is low at E15. Tissue explants of PER2::LUC reporter mice at E15 show self-sustained circadian rhythms in vitro. - *Infancy:* At birth, the SCN contains 13% of adult AVP-expressing neurons and few VIP-positive cells. Clear oscillation of clock genes and proteins is observed by postnatal day 10. The retino-hypothalamic tract (RHT) innervates the SCN shortly after birth. ipRGCs are detectable from mid-gestation (E11) in mice. In humans, the RHT is detectable at week 36 of gestation. Breast milk contains high cortisol, tyrosine, and cytokines during the light phase, and high leptin, melatonin, and tryptophan during the night phase. Formula-fed children have lower urinary 6-sulfatoxymelatonin levels compared to breast-fed infants. - *Childhood and adolescence:* Young children are predominantly morning chronotypes with earlier DLMO. Preschool-attending children experience 26.3 vs. 17.6 minutes of social jetlag compared to home-staying peers. Up to 45% of US adolescents may not get adequate sleep, and up to 16% may suffer from delayed sleep phase disorder. Chronotype phase-delay peaks at around 20 years of age, with girls reaching latest chronotype approximately 1.5 years earlier than boys. A school start time shift from 8:50 AM to 10:00 AM showed a 12% improvement in academic progress and 50% drop in illness-related absences. - *Menopause:* Female mice with Bmal1 deficiency or double clock mutations in Per and Cry exhibit disrupted mating behavior and infertility. Single clock gene mutations in Per1 and Per2 lead to reduced ovarian function. In humans, high plasma estrogen concentrations are associated with HPG axis insensitivity to estrogen feedback. Aging acyclic rodents retain ovarian follicles but show reduced hypothalamic GnRH cell numbers. Aged ovaries transplanted into young ovariectomized rats restore ovulation. FSH concentration rise is a main feature of reproductive senescence in both humans and rodents. - *Old age:* Longevity is only ~15–30% explained by genetics. Across 26 mammalian species, genes negatively correlated with longevity are under tight circadian regulation. Aging reduces amplitude and phase-advances circadian rhythms of sleep, body temperature, cortisol, and melatonin. The eye loses 72% of transmissibility at 480 nm from age 10 to 80 years. AVP and VIP levels are reduced in aged humans and rodents. GABAergic synapses diminish in aged mice. Around 50% of elderly people suffer from poor sleep. Voluntary wheel running can restore activity rhythm dysfunctions in older mice, with females running significantly longer distances than males.

**Clinical Implications:** Understanding age-specific circadian changes can improve treatment timing and effectiveness. Chronotherapy approaches, including bright light exposure in nursing homes and delayed school start times for adolescents, show promise. Circadian phenotyping may improve interventions for reproductive success, especially with increasing age. The review highlights that considering patient age may critically affect the best time and choice of therapy, and that circadian rhythm disturbances could serve as early predictors of cognitive decline.