Observations of many species have revealed a variety of developmental changes in circadian rhythms of overt behaviors and physiology (see Figure 2 for an illustration of changes in human rhythms). In reviewing this literature, it is worthwhile to note some aspects of research design that may influence the conclusions that can be drawn. For example, the vast majority of research in this area is cross-sectional; as such, differences in dependent variables between older and younger individuals that are attributed to age could potentially reflect cohort effects or other confounders. This is a legitimate criticism; however, we believe it is mitigated by the number of studies that have identified similar patterns of results using different samples and age cohorts. We have included longitudinal studies here wherever possible, and suggest that further research in aging and circadian rhythms would benefit greatly from longitudinal designs.

Figure 2 Examples of circadian rhythms in older adults relative to rhythms in younger adults. In the 24-hour cycle, documented changes include rhythms of waking activity; core body temperature; SCN firing; release of hormones, such as melatonin and cortisol; and fasting plasma glucose levels. Relative to younger adults (blue lines), the amplitude of many rhythms dampens in older adults (red lines). In some cases, the peak of the rhythm also advances.

Other considerations pertain to the generalizability of findings made in nocturnal species, such as mice or rats, to diurnal species, such as humans. Although important differences exist in the organization of nocturnal and diurnal circadian systems (16), the high degree of conservation of circadian mechanisms across species supports judicious use of nocturnal animals as a translational model for the human circadian clock (13). Going forward, increased use of diurnal species like the grass rat (Arvicanthis ansorgei) in circadian research may enhance the generalizability of findings from animal models to human health.

Activity/rest rhythms. Shifts in preference for morningness versus eveningness, or chronotype, and in sleep cycles are among the most consistently observed age-associated circadian changes in many species. In humans, cross-sectional studies comparing older and younger adults’ responses to chronotype assessment tools (17) reliably show that adults in their 60s and above are significantly more likely to endorse a tendency for rising from and retiring to bed earlier than adults in their 20s and 30s (18–20). Although there are few longitudinal studies in humans to track individual changes in chronotype with age, those available support the results of cross-sectional designs. Broms and colleagues (21) tracked chronotype longitudinally in 567 adult men in Finland over 23 years (mean age of 56 years at study entry), and found a shift in the distribution toward a “mostly morning” type over years of study. Retrospective self-comparison studies in older adult participants (>60 years) also indicate a tendency to become a “morning person” with increasing age (19). Taken together, this shift in chronotype appears to be a reliable developmental pattern.

The preference for morningness in older adulthood is expressed in other aspects of behavior, such as cognitive skill performance. Performance on recognition memory and reaction time tasks exhibits clear time-of-day changes in accuracy and speed (22). Notably, the circadian profile of cognitive performance interacts with age, such that older adults who are tested on recognition memory tasks in the early morning perform as well as younger adults, but significantly worse when tested later in the afternoon (23, 24). This interaction has important implications for the assessment of cognitive functioning in older adults: apparent decrements in cognitive performance may be confounded by testing times in the late afternoon when alertness is decreasing (25).

Impaired phase shifting. The capacity of the circadian clock to accommodate a light/dark schedule change (e.g., rotating shift work or jet lag) varies with age. Studies using a jet lag–type design, in which the timing of light onset between one day and the next is advanced (e.g., a flight from New York to Paris) or delayed by a number of hours, have demonstrated a differential impact of the new schedule on older individuals compared with younger. Following a phase advance, older adults (mean age of 81 years) exhibited decreased sleep efficiency, self-reported alertness, and amplitude of the core body temperature rhythm that persisted for longer compared with younger adults (37–50 years) (26, 27). In contrast, a phase delay is better tolerated, with minimal differences observed between older and younger adults (27). Studies in rodents mirror these observations, whereby aged mice (about 2.5 years) subjected to repeated phase advances exhibit poorer glucose tolerance and increased mortality rates compared with younger rodents (1 year) or aged rodents subjected to phase delays (28). These age-associated differences may be attributable to the reduced responsiveness of the aged master circadian clock to light, as illustrated in smaller-magnitude light pulse–induced expression of Per1 mRNA in the SCN of aged hamsters and mice (29–32). Given the prevalence of rotating shift work schedules in industrialized societies, the implications of these findings for healthy aging are significant, and have served as impetus for recent position papers classifying exposure to “light at night” as hazardous to human health (33).

Sleep. Sleep timing and architecture undergo a number of changes in late adulthood. Consistent with the transition to a morning chronotype in older adult humans, the circadian phase of sleep onset and wakening advances with age, whereby older adults (mean age of 68 years) report preferred bedtimes 1 to 2 hours earlier, on average, compared with younger adults (mean age of 23 years) (34, 35). Older adults experience significantly more wakenings, have longer latencies to fall asleep, and spend less time in stage 3, stage 4, and rapid eye movement (REM) sleep compared with younger adults (18, 36–38). Similar observations of sleep fragmentation have been made in aged rhesus monkeys (38), hamsters (39), and Drosophila (40). Van Cauter and colleagues (41) estimate that these age-associated disruptions in human sleep consolidation lead to a loss of approximately 30 minutes of sleep every 10 years, beginning in the fourth decade of life. These changes in amount and quality of sleep likely contribute to an increase in daytime sleepiness experienced by many older adults, which may negatively affect quality of life (42, 43) and exacerbate risks of cognitive decline and falls (44, 45).

It is important to note that timing of sleep is driven not only by a circadian clock, but also by a homeostatic system that interacts with the circadian rhythm to produce a consolidated period of nightly sleep in humans (46, 47). This interaction appears to be highly sensitive to misalignments; as such, age-related changes in this homeostatic mechanism may affect sleep timing, quantity, and quality (48).

Temperature rhythms. In young adult humans (mid-20s), core body temperature rhythm normally peaks in the early evening and reaches its nadir in the early morning (49). In older adults (late 60s), the period of this rhythm remains stable (50); however, the amplitude of the rhythm decreases in older adult men by 20% to 40%, such that the nadir of core body temperature does not fall as low as in younger adults (36, 51, 52) (note that this change has not been observed consistently in older women; ref. 53). In addition to a smaller amplitude, a 1- to 2-hour phase advance in this rhythm has been observed in adults in their 60s to 80s, compared with younger adults in their 20s and 30s (34, 51).

Melatonin and cortisol. The circadian profiles of the release of several hormones undergo a number of age-related changes, although supporting evidence is not entirely consistent (54). Of the wide variety of hormones that are under circadian control, melatonin and cortisol are of particular interest, as they have a direct influence in regulating rhythms downstream of the master circadian clock. For example, melatonin release regulates core body temperature, promotes sleep onset, and modulates the activity of intrinsically photosensitive retinal ganglion cells that provide time-keeping signals to the SCN (55, 56). Total melatonin secretion declines with age, beginning perhaps as early as the third decade of life (57, 58). Evidence in humans, rhesus monkeys, and hamsters suggests that the normal nighttime peak in older adults is reduced and shifts to earlier in the evening compared with that in younger adults (35, 38, 59, 60).

However, other evidence suggests that a “young” melatonin rhythm is in fact preserved in very healthy older adults, and a reduction in peak melatonin may occur only in older individuals whose total melatonin levels are at the lower end of the population distribution (61, 62). For example, a 6-year longitudinal study found no evidence of a decrease in total melatonin secretion in healthy older adults (ages ranging from 55 to 74 years) (62). This discrepancy in findings may suggest that a reduction in the melatonin rhythm is not a feature of a healthy aging process, and in fact may signal underlying pathology. To this end, Waller and colleagues (63) reported a lower nightly melatonin peak in middle-aged men (mean age of 57 years) with cognitive impairment compared with age-matched healthy controls. Furthermore, significant reductions in melatonin synthesis and expression of melatonin receptors in the SCN have been documented in individuals with neurodegenerative diseases such as Alzheimer’s or Parkinson’s, or those with prodromal symptoms (64–66). The relation between melatonin and age-associated neuropathologies has been explored in recent reviews (67, 68).

Like melatonin, rhythmic cortisol release is under control of the SCN (69) and regulates downstream rhythmic expression of clock genes in peripheral tissues in humans, rodents, and dogs (70–74). Cortisol rhythms exhibit age-related changes including a reduction in amplitude (due to higher cortisol secretion at night; refs. 75, 76), and a phase advance in the peak of cortisol to earlier in the morning (77). Like disruption of the melatonin rhythm, disruption of the cortisol rhythm in aged humans may indicate progressive neurodegeneration (78–80), although not all evidence supports this idea (63).

Metabolism and inflammation. In mammals, circadian clocks within tissues like the liver and pancreas regulate rhythms of metabolism such as glucose homeostasis, lipid metabolism, and xenobiotic detoxification (reviewed in refs. 12, 14). Many metabolic rhythms exhibit progressive dampening with age (76, 81, 82). These changes are underscored by evidence of age-related decreases in the amplitude of clock gene expression rhythms in clocks outside of the master pacemaker (83, 84). Dampening of these rhythms is suspected to contribute to the increased risk in older adults of metabolic diseases such as diabetes, dyslipidemia, and hypertension (12, 85).

Inflammatory processes, heavily implicated in cellular aging, are also rhythmic. Plasma levels of hematopoietic cells and proinflammatory cytokines are among the components of the immune system that fluctuate in accordance with an animal’s rest/activity cycle (reviewed in ref. 86). Recent evidence indicates a direct role for clock genes in regulating inflammation: for example, bone marrow–specific knockout of Bmal1 in mice leads to exaggerated inflammation responses to infection or high-fat diet (87). In response to progressive immunosenescence, chronic, low-grade activation of proinflammatory processes develops within aging organisms, the development of which may increase risk of chronic disease states, such as metabolic syndrome and neurodegenerative diseases (88). Taken together, these findings suggest that age-related changes in circadian clockwork throughout the body may promote chronic inflammation and pathologies including metabolic disorders.

Circadian clock gene expression. In humans and rodents, the expression patterns of clock genes in a variety of tissues exhibit change with age. For example, Chen and colleagues (89) recently reported that in adults over 60 years of age the rhythms of expression of the PERIOD genes PER1 and PER2 in human orbitofrontal cortex are flattened and phase-advanced by approximately 4 to 6 hours, and the expression of CRY1 became arrhythmic, in comparison with adults under 40 years of age. In peripheral blood cells, level of BMAL1 expression was found to correlate negatively with age in women (range 20–79 years) (90).

Findings of age-associated changes in the master clock have been inconsistent in nonhuman species. In Per2-luciferase reporter mice (PER2::LUC mice) housed in constant dark, older (13–15 months) mice demonstrated a rhythm of PER2 protein in the SCN that was of smaller amplitude and shorter period relative to younger mice (3–5 months) (91). These PER2 data conflict with other reports of no differences in SCN rhythms of expression of Period genes Per1 and Per2 between young and old animals (29, 84, 92). However, age-associated reductions were found in the overall expression of Clock and Bmal1 transcripts in the hamster (17–20 months) and mouse (22 months) SCN (30, 93).

In contrast, a dampening of rhythmic clock gene activity has been observed in peripheral oscillators in rodents and Drosophila. In tissues such as the lungs, the rhythm of Per1 expression seen in young rats (2 months) was absent in old animals (24–26 months) (84). In Drosophila, the amplitude of clock gene expression and protein rhythms in head and body tissues decreased in aged flies (58 days old), despite the persistence of a robust PER2 rhythm in brain clock neurons (83). These declines in peripheral clocks may have important implications for the susceptibility of aged animals to various disease states, given evidence demonstrating links between loss of rhythmic clock gene expression and the development of metabolic disease states and cancers (94, 95).

The interaction of circadian clock genes with the aging process is complex, in that evidence supports a bidirectional relation between them. Not only do clock gene expression patterns appear to change as a function of age, but also these changes may drive the rate of aging. For example, mutations of the clock gene Bmal1 and the Period genes yield an accelerated aging phenotype in Drosophila and mice, with faster rates of tissue decline, impairments in cognitive function, and shorter lifespan relative to age-matched wild-type controls (96–98). The causal role that altered clock gene expression may play in the circadian changes typically observed in aging will be explored further in the next section.