Circadian Rhythms in Aging and Age-Related Neurogenerative Disease

Abstract

Purpose of Review:

Age-related changes in the circadian timing system may play a role in the development of disorders in older age. We review key aspects of the human circadian system that change with aging, discuss recent evidence of how changes in sleep and circadian rhythms manifest in neurodegenerative diseases, and summarize research on new therapies.

Recent Findings:

Several mechanisms have been proposed to underlie age-related changes in sleep and circadian rhythmicity. These mechanisms include changes in the suprachiasmatic nucleus, melatonin production, and light sensitivity as well as impaired glymphatic drainage, buildup of amyloid-beta, hypoxia from sleep-disordered breathing, and increased levels of orexin. While light-based therapies and lifestyle interventions have been under investigation for years, newer interventions include treatment with orexin antagonists and gamma stimulation to improve sleep and circadian rhythmicity.

Summary:

Despite growing interest, our understanding of how sleep and circadian rhythms contribute to the development of age-related neurodegenerative diseases is still limited. More research is needed to understand the bidirectional relationship between circadian rhythms, sleep, and neurodegenerative diseases to develop targeted interventions.

INTRODUCTION

By 2050, the number of Americans over age 65 is projected to increase from 56 to 82 million people (a 47% increase from 2022 [1]). Fifty-two percent of older adults are estimated to experience chronic sleep problems [2], and these sleep difficulties are exacerbated by normal age-related changes in the circadian timing system. Moreover, pathological changes in circadian rhythms are frequently reported in age-related conditions such as Alzheimer’s Disease and other dementias which impact roughly 1 in 9 older adults [3]. In this article, we will briefly summarize what is known about normal age-related changes in sleep and circadian rhythms. Next, we will focus our discussion on recent findings about the complex relationship between circadian rhythm disruptions and age-related neurodegenerative diseases.

THE CIRCADIAN SYSTEM IN HUMANS

In humans and other mammals, the primary brain structure regulating circadian rhythms is the suprachiasmatic nucleus (SCN), located in the anterior hypothalamus. The function of the SCN has already been comprehensively reviewed elsewhere [4]; briefly, SCN neurons are intrinsically rhythmic and generate the approximately 24-hour cycles governing sleep-wake timing, body temperature, hormone production, and other physiological functions. However, because the intrinsic cycles are not precisely 24-hours, the circadian system relies on external cues to synchronize these biological rhythms to the external light-dark cycle.

The main external cue for the mammalian circadian timing system is light. The SCN receives light information from intrinsically photosensitive retinal ganglion cells (ipRGCs), a third class of photoreceptors in the eye that respond primarily to blue light with the photopigment melanopsin [5]. It projects to the pineal gland to mediate secretion of the hormone melatonin in a circadian manner. This secretion is acutely suppressed by light exposure, but under normal circumstances begins to rise in the evening before habitual bedtime to promote sleep, and then peaks during the night. Through a combination of neuroendocrine and autonomic signals, the SCN serves as the central pacemaker by coordinating local circadian rhythms throughout the body, thus maintaining internal synchrony among different organs.

Circadian rhythms are approximately 24-hour cycles that are described by three parameters: amplitude, phase, and period. Amplitude is typically measured by the difference between the peak and trough values and reflects the robustness of the rhythm; larger amplitudes generally signify stronger rhythms, while lower amplitudes indicate weaker rhythmicity. Phase is defined as the timing of a reference point in the cycle and can be shifted earlier (advanced) or later (delayed) by signals known as zeitgebers (German for “time giver”) including light, meals, or physical activity. Period is the length of time required for the cycle to repeat; by definition, circadian rhythms have a period of approximately 24-hours.

In humans, the circadian timing system interacts with the sleep homeostat to regulate sleep and wakefulness [6]. The sleep homeostat is a mechanism that regulates the need for sleep such that sleep pressure increases with increasing time awake and decreases during sleep. The relative timing between circadian rhythmicity and the sleep homeostat is critical to allow for consolidated sleep (and wake). When behavioral rhythms are misaligned with internal circadian rhythms (for example, when trying to sleep during the day), sleep and other physiological functions can be impaired due to occurring at an adverse biological time (i.e., phase). The two most commonly used methods to modify human circadian rhythm timing (phase) are timed light exposure and exogenous melatonin. Both light and melatonin produce phase-dependent effects on the circadian system, meaning that the effect depends on the phase (or circadian time) at which they are applied; both can delay or advance the timing of the circadian system depending on the timing of administration. Thus, appropriately timed treatment is critical for inducing the desired effect.

CIRCADIAN RHYTHM CHANGES WITH HEALTHY AGING

One of the most noticeable age-related changes in circadian rhythms is a change in chronotype, one’s preference for the timing of sleep and wakefulness [7]. Older adults are more likely to consider themselves as morning types and typically go to bed earlier and wake up earlier compared to young adults. This phase advance is seen not only in sleep-wake timing but also in the timing of core body temperature, melatonin, and cortisol rhythms [7, 8]. In addition to the phase advance, sleep also occurs at an earlier biological time relative to their core body temperature and melatonin rhythm [9, 10]. Older adults typically experience fragmentation of the rest-activity rhythms as evidenced by more napping during the day and fragmented sleep at night [13], although excessive daytime sleepiness is not normal in healthy older adults [14, 15]. Finally, older adults also report poorer sleep quality, characterized by shorter sleep duration, more frequent awakenings, lower sleep efficiency, less slow-wave sleep, and prolonged sleep latency (For reviews, see [11, 12]). Many of these changes are due to a combination of age-related changes in both the circadian system and the sleep homeostat.

Aging can also be associated with decreased sensitivity to light, the primary zeitgeber for the human circadian system, because of changes in the lens of the eye, the retina, and the visual cortex. The lens increases in thickness and yellows with age, reducing both overall light transmission to the retina as well as transmission of shorter wavelengths of light [16]. Finally, the density of ipRGCs in the retina decreases, as do the number of cells in the visual cortex. Together, these changes can reduce the effectiveness of light at synchronizing the circadian system to the external light-dark cycle and may likely also disrupt downstream processes that would maintain healthy rhythms [17].

Despite the evidence that light transmission changes with aging, findings are mixed regarding whether older adults show a decreased response to light compared to young adults [17, 18]. Several studies tested the phase-delaying effects of bright (2,000–10,000 lux) light stimulus and found no difference between young and older adults [18–20]; however, there is some evidence that older adults might show reduced phase advance response [21]. Another study found that older adults had a reduced circadian phase shifting response to moderate (~50–1,000 lux) levels of nighttime light exposure [22]. Other studies have also investigated whether older adults respond differently to light stimuli of different wavelengths. One study tested a shorter wavelength blue light and a longer wavelength green light stimulus on melatonin suppression and found significant differences between young and older adults in response to blue light but not in response to green light [23], while another study did not find significant age differences in the phase-advance response to blue and green light [24]. A study by Najjar et al. found a shift in peak sensitivity to longer wavelengths in older adults compared to younger adults, but no change in melatonin suppression [25]. More research is needed to clarify whether responses to light change with aging.

As humans age, some neurodegeneration occurs in the SCN. Studies suggest that the SCN decreases in volume and undergoes a reduction in the overall number of neurons [26, 27]. In addition, evidence suggests that there is a reduction in the expression of rhythmic neuropeptides such as arginine vasopressin and vasoactive intestinal polypeptide in the SCN [27, 28]. While human SCN activity exhibits diurnal variation [29], the amplitude of the firing rhythm of the SCN neurons has been shown to decrease with aging [27], reflective of an age-related loss of coherence among neurons in the SCN [8]. Finally, some evidence suggests that there may be age-related changes in clock gene expression [8]. These changes may underlie the weakening of the output signal of the SCN which is observed with aging.

One of the ways in which this weakened output of the circadian system manifests is a reduced amplitude of circadian rhythms in older adults compared to young adults (for review, see [7]). Core body temperature typically peaks in the evening and reaches a nadir in the early morning; while this rhythm persists in older adults, the amplitude is significantly reduced because the temperature nadir does not fall as low as in young adults. Similarly, melatonin levels in some older adults are reduced. Cortisol levels normally peak within an hour of habitual wake time and are low during the night. With aging, the amplitude of the cortisol rhythm is reduced due to higher nighttime cortisol levels. Other rhythms in which age-related dampening of amplitude can be observed include the rest-activity rhythm and some metabolic and gene expression rhythms [7, 30]. For example, we found that the amplitude of both total and low-density lipoprotein cholesterol circadian rhythm was significantly lower in older adults compared to younger adults [31]. Similarly, a study that examined the plasma lipidome also reported that older adults had a reduced amplitude in the circadian rhythm of lipids [32]. Unlike amplitude and phase, the period of the human circadian system appears to remain relatively stable with age [33, 34].

Sex Differences in Age-related Circadian Rhythm Changes

Women on average have a slightly shorter circadian period than men [34], which may partially contribute to women generally having an earlier chronotype than men. Interestingly, this clear chronotype difference between men and women diminishes with age, as men experience a more pronounced phase advance later in life in the transition to earlier chronotypes [35]. Older women also tend to report sleeping less and having more sleep complaints than men, including higher rates of insomnia [36]. Restless leg syndrome, which has a strong circadian component and increases in prevalence and severity with age, is estimated to be twice as prevalent in women compared to men [37]. Similarly, some studies report an increase in periodic limb movements of sleep (PLMS) periodicity index in older women and not older men, although others report no difference or the opposite [38]. Some of these sex differences have been attributed to hormonal changes that occur with menopause, while other potential causes could be psychological factors such as higher levels of stress, anxiety, and depression among women, or societal and lifestyle factors that differ between men and women.

CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS IN OLDER ADULTS

Circadian rhythm sleep-wake disorders (CRSWD) refer specifically to disorders related to the timing of sleep and wakefulness and are characterized primarily by an inability to initiate, maintain, or terminate sleep at the desired time. They may be caused by misalignment between the internal circadian system and the external environment, or by problems with the internal circadian system. Survey data suggest that these disorders are relatively rare and impact 3% or less of the adult population, although they may be underreported due to the challenges associated with differentiating CRSWD symptoms from primary insomnia [39–41]. CRSWD subtypes that are more prevalent in older adults compared to young adults include advanced sleep-wake phase disorder (earlier sleep timing than desired) and irregular sleep-wake rhythm disorder (irregular sleep timing, typically characterized by multiple short sleep bouts). Additionally, non-24-hour sleep-wake rhythm disorder, where sleep timing moves progressively later (or rarely, earlier) each night due to reduced ability to synchronize the internal circadian system with the 24-hour external environment, is most common in blind individuals; possibly because of the greater prevalence of vision loss or impairment in older adults, it is also more common in older adults compared to young adults [42]. Older adults also have greater difficulty sleeping at an adverse circadian phase (i.e. biological time), making them more vulnerable to CRSWDs such as shiftwork disorder and jetlag disorder [42]. Finally, delayed sleep-wake phase disorder is normally more prevalent among adolescent and young adults, but when it occurs in older adults, it tends to be associated with other disease states such as Alzheimer’s Disease (AD) [42, 43].

CIRCADIAN RHYTHM CHANGES IN AGING-RELATED DEMENTIA AND NEURODEGENERATIVE DISEASES

Compared to the general population and to healthy older adults, patients with dementia are more likely to exhibit disturbances in sleep and rest-activity rhythms. Prevalence rates vary by disease, with estimates ranging from 25–50% in AD (depending on disease severity) and up to 90% of patients with Lewy body or Parkinson’s Disease (PD) [44–47]. These sleep and circadian disturbances often manifest years before a clinical diagnosis of dementia is made, and one longitudinal study found that increased severity of insomnia over time was associated with 41–72% higher risk of memory decline and 45–58% higher risk of dementia diagnosis in older adults [48]. Typically, these disturbances include fragmented sleep and insomnia, less robust rest-activity rhythms, more daytime napping or excessive daytime sleepiness, and increased prevalence of sleep and circadian rhythm disorders. Although similar to the changes seen in healthy aging, they tend to be more severe in magnitude. One of the most prominent circadian-related symptom is the phenomenon known as “sundowning”, in which patients in the middle-to-late stages of dementia experience increased agitation, confusion, and activity in the late afternoon and early evening [49]. These symptoms are typically associated with difficulty initiating and maintaining nighttime sleep.

Potential mechanisms

The relationship between dementia, sleep disturbances and circadian rhythm disruption is highly complex and most likely bidirectional, as there is evidence that poor sleep contributes to cognitive decline and risk of dementia [47, 50, 51], while the brain atrophy observed with neurodegenerative diseases can impair the circadian and sleep systems [52]. In general, the severity of sleep and circadian disturbances appears to increase with disease progression.

In addition to being an independent risk factor for dementia [47, 53], sleep disturbances also have a bidirectional relationship with many other risk factors for dementia. Sleep disturbances increase the risk of cardiovascular disease (for review, see [54, 55]), which itself is a significant risk factor for dementia. Reduced slow wave sleep and impairments in the glymphatic system, which relies on the vascular system to facilitate metabolic waste clearance from the brain, have also been implicated in neurodegenerative disease [56–60]. Hypoxia and sleep loss resulting from sleep-disordered breathing have been shown to accelerate many processes associated with dementia such as amyloid beta plaque formation, tau protein accumulation, and increase oxidative stress and neuroinflammation leading to apoptosis [53, 61]. Sleep loss and circadian disruption both have adverse effects on metabolism including increased insulin resistance [62], which has been associated with worse cognitive functioning and may subsequently lead to the development of dementia such as AD [63].

Physiological changes that occur with age also appear to be pronounced in patients with neurodegenerative diseases. Although the majority of work has been conducted in rodents, some human studies have demonstrated that both healthy older adults and patients with AD exhibit impaired glymphatic drainage which may contribute to the accumulation of amyloid-beta and phosphor-tau [64–66]. Similarly, average ipRGC density in the retina decreases after age 70 [67], but is even more severe in patients with AD or PD [68]. Reduced melatonin levels and reduced expression of melatonin receptors are well-documented in neurodegenerative diseases such as AD and PD [69, 70], and other studies have found significant associations between melatonin levels and cognitive impairment [71]. Interestingly, a 6-year longitudinal study found no reduction in melatonin secretion in healthy elderly individuals [72], leading to speculation that some of the age-related changes considered to be a normal part of healthy aging may be pathological in nature [8]. However, studies have found phase advances or delays, disrupted rhythms, increased interindividual variability in melatonin peak timing, and reduced or absent nocturnal melatonin peaks in AD patients compared to controls [73]. Additionally, changes in pineal gland volume and morphology have been described in AD patients [73].

The well-documented fragmentation of sleep and rest-activity rhythms seen in dementia may be related to the age-related loss of neurons in the SCN [26], which is more pronounced in AD patients compared to healthy older adults [27, 74]. Impaired functional connectivity due to brain atrophy may also contribute to the sleep disruptions and loss of rhythmicity observed in patients with dementia [43, 75]. Finally, there is evidence suggesting a role for the sleep-wake neuropeptide orexin in modulating sleep in AD; increased orexin levels are associated with disrupted sleep and cognitive impairment in AD patients while orexin receptor antagonists promote sleep and thus offer a potential therapeutic target for improving sleep in AD [76].

Sleep and Circadian Disturbances in Alzheimer’s Disease

Profound disturbances in circadian rhythms and sleep are universally reported in patients with AD. However, some longitudinal studies have found that changes in sleep and circadian rest-activity rhythms manifest years before a clinical diagnosis of AD [43, 77–79], and that individuals with high sleep fragmentation at baseline had significantly higher risk of developing AD [80]. Additionally, poor sleep quality and short sleep duration has been associated with greater accumulation of amyloid beta and tau even in older people without dementia [51, 81, 82].

The discovery that the glymphatic system clears metabolic waste from the brain during sleep laid the foundation for its study as a potential mechanism by which sleep disturbances could contribute to the development of AD [57, 83]. Given that glymphatic drainage occurs primarily during deep sleep [83] and that deep sleep is significantly reduced in patients with AD [84], it is possible that this underlies the correlation between increased severity of sleep disturbances and dementia progression [56].

Because of the potential bidirectional relationship between sleep/circadian rhythms and development of AD, some recent promising treatments include pharmaceuticals as well as tailored lighting, lifestyle, and other interventions to improve circadian rhythms and sleep in patients. A phase 2 clinical trial in AD patients found that 4 weeks of treatment with Lemborexant, a dual orexin receptor antagonist, significantly improved rest-activity rhythms, although no change was seen in cognitive function [85]. An ongoing randomized crossover trial is investigating the use of trazodone to improve slow wave sleep in early AD patients with sleep complaints, with the hopes that this could slow AD-related cognitive decline [86]. A prospective study of AD patients with sleep disturbances found that treatment with eszopiclone improved sleep quality, rhythm disturbances, and cognitive function [87]. Although these pharmaceutical studies are promising, the use of hypnotics in dementia patients increases the risk of falls and side effects and so must be carefully considered. Moreover, several studies have reported an increased risk of dementia associated with the use of hypnotics [88, 89], although others have not found this association (For review, see [90]. Thus, there is currently insufficient evidence to determine whether pharmacotherapy for sleep disturbances in patients with dementia provides an overall benefit that outweighs the potential harm [91].

Several non-pharmaceutical interventions to improve sleep in AD patients have also been explored. A phase 1 pilot study found that phase-locked 40-dB pink noise was able to increase the amount of slow wave sleep in adults with mild to moderate AD [92]. A different pilot study used repetitive transcranial magnetic stimulation in AD patients with sleep disorders and found improvements in both sleep quality and cognitive performance [93]. Several studies are also investigating the use of sensory stimulation to improve sleep and circadian rhythms in AD patients by counteracting the decreased brain gamma activity associated with cognitive decline. One study found that 6 months of daily visual and auditory 40 Hz stimulation in mild to moderate AD patients successfully reduced nighttime active periods and arrested cognitive decline compared to the sham control group [94]. A phase 2 study in mild AD patients found that 3 months of daily visual and auditory 40 Hz stimulation was able to improve daily rest activity rhythms [95]. Other studies using 40 Hz stimulation have found small changes in brain morphology [96] and increased synchrony in the default mode network [97].

Many studies have also examined lighting and lifestyle interventions to improve sleep and circadian rhythms (for reviews, see [98–100]). As mentioned earlier, light is the most powerful synchronizer of the human circadian system. However, an individual’s history of light exposure has been shown to significantly impact their subsequent sensitivity to light. For example, participants exposed to bright light during the day experienced a much smaller phase shift to subsequent evening light exposure compared to participants who were previously kept under dim light [101], as well as significantly lower suppression of melatonin secretion [102]. Critically, patients in long-term care facilities and especially patients with dementia are typically exposed to very low levels of light during the day [103, 104], making them susceptible to sleep disturbances and circadian disruption when later exposed to light in the evening [105]. Thus, many lighting interventions for nursing homes seek to increase light levels during the day and reduce levels at night with tuned ambient lighting [106] and novel light fixtures [107] that can incorporate appropriate light exposure into the environment. Several randomized clinical trials in AD patients living in long-term care facilities have found that long-term tailored lighting interventions consisting of bright daytime light and dim nighttime light exposures can improve sleep quality, daily rhythms, mood, and behavior [107, 108], as well as reduce risk of falls [109].

Lifestyle interventions typically include ways to improve sleep hygiene and behavior in addition to strengthening circadian rhythms by managing light exposure and day-to-day regularity of sleep and light exposure timing. A phase 3 randomized controlled trial tested an educational program for caretakers of patients with dementia that included strategies for improving the patients’ sleep using zeitgebers and behavioral routines and found that it successfully improved sleep and reduced caregiver burden due to sleep-related behaviors [110]. Another study found that a multimodal lifestyle intervention consisting of 24 weeks of bright light therapy, physical activity, and good sleep hygiene improved subjective sleep quality but not objectively measured sleep in older adults with mild cognitive impairment [111]. While these interventions show promise, more research is needed to understand how and when to implement them most effectively.

Sleep and Circadian Disturbances in Parkinson’s Disease Dementia and Lewy Body Dementia

Like in AD, problems with sleep and circadian rhythms manifest during the prodromal stage of PD [112]. Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) has an extremely high conversion rate to PD, with some studies estimating that over 80% of RBD patients go on to develop PD or similar neurodegenerative disease [113]. Other sleep disturbances such as insomnia, daytime napping, and excessive daytime sleepiness increasingly appear to be prodromal symptoms of PD [112]. Patients with obstructive sleep apnea (OSA) have also been reported to have a higher risk of developing PD than those without OSA. Many of these sleep disturbances continue and/or worsen in patients with PD, for whom sleep disorders constitute the second most frequent complaint among non-motor symptoms [114]. Prevalence rates of RBD range from 30–50% of PD patients [115], while studies estimate that up to 45% of PD patients have OSA [116]. Excessive daytime sleepiness has also been reported in as many as 90% of patients with PD or Lewy body dementia (LBD) depending on disease severity [44, 117], and estimates of insomnia prevalence in PD patients range from 30–80% [44].

Patients with PD have also been found to exhibit aberrations in circadian rhythms, as well as diurnal patterns in the severity of motor and non-motor symptoms which worsen during the later part of the day [44]. A cohort study found that the risk of incident PD was significantly higher in elderly individuals with circadian abnormalities compared to those who maintained robust rest activity rhythms [118]. In healthy individuals, blood pressure typically falls during the night and is higher during the day; in PD patients, this pattern is inverted [119]. The amplitude of the core body temperature rhythm, as well as mean body temperature, is reduced in patients with PD compared to healthy controls [43], and some evidence suggests this pattern is particularly evident in PD patients with RBD [120]. PD patients also exhibit an overall reduction in circulating melatonin levels [121] (but see also Bolitho et al. who reported a 3-fold increase in melatonin secretion [122]), while serum cortisol levels are elevated [121, 123]. Amplitude reductions in circadian rest activity rhythms have also been reported in patients with PD [118], along with more fragmented rhythms characterized by increased motor activity at night and decreased activity during the day [44].

The stability of rest activity rhythms has been associated with the degree of cognitive impairment in PD patients independent of sleep [124], and a recent actigraphy study comparing PD patients to healthy older controls found that late-stage PD patients also exhibited a phase advance [125]. Post-mortem studies in advanced PD revealed Lewy body pathology in the SCN and pineal gland of some patients, suggesting that pathological changes to the SCN and circuits by which it controls locomotor activity may underlie some of the circadian rhythm disturbances in PD [52]. PD patients also exhibit a compromised pupillary light reflex, possibly due to degeneration of ipRGCs, which may impact their ability to align behavior to the light dark cycle [126, 127].

Recently, interest in targeted chronotherapeutic approaches to managing PD has emerged. These therapies mainly consist of bright light exposure or melatonin administration to improve sleep and quality of life in PD patients. Studies suggest that bright light therapy has overall positive effects on sleep impairment in PD, although further research is needed due to the considerable variability among studies in the timing, exposure, and method of administration. For example, one study found that PD patients exposed to 12 weeks of daily evening bright light therapy exhibited a circadian phase delay following treatment [128]. In a recent randomized controlled trial, participants exposed to 4 weeks of daily light therapy personalized to the individual patient’s chronotype experienced improvements in sleep [129]. Other studies have tested treatment durations ranging from 10 days to several years, with morning and/or evening light exposure 1–2 times per day [130]. Similarly, treatment with exogenous melatonin or melatonin agonists seemed to have positive effects on sleep quality as well as some motor symptoms in PD patients [131], but again, more research is needed to refine the timing and dosage needed for optimal treatment. Individual differences in underlying patient chronotypes may mask the true efficacy of light or melatonin therapies; thus, better stratification of patients into groups likely to respond to treatment is needed [52].

CONCLUSIONS

Sleep and the circadian timing system undergo changes with both healthy and pathological aging, including neurodegenerative disease. More research is needed to fully understand the bidirectional relationship between sleep, circadian rhythms, and neurodegenerative diseases (especially in pre-clinical stages) so that appropriately targeted interventions can be developed. Moreover, considering the many individual differences in circadian rhythms and disease trajectories and how lifestyle interacts with these, developing individually tailored therapies may be critical to effectively treating circadian timing problems associated with age and age-related disease.