Chronological Shifts: How Circadian Rhythm Changes with Age in Mammals

Summary

In the biological context, time is quantified through cycles spanning from milliseconds to years. Circadian rhythms, specifically measuring time over a 24-hour period, are orchestrated by a highly prevalent and extensively studied timing system. At the heart of this temporal mechanism lies a complex molecular process that operates in various tissues across the body. Nevertheless, these autonomous rhythms are regulated by a central clock in the brain, which synchronizes tissue-specific rhythms based on external light cues it receives from the environment. Similar to other physiological systems, the circadian system undergoes degradation with age. The changes in circadian rhythm observed in aging individuals, characterized by reduced activity and functionality, may be associated with the aging of the central clock—the suprachiasmatic nuclei (SCN). In this article, we will explore the physiological processes within the brain that govern regular behaviors aligned with time. Additionally, we will examine three significant changes in circadian rhythm that occur with aging and delve into the underlying reasons for these changes.

Introduction 

In the realm of human circadian rhythms, an unspoken guiding rhythm quietly shapes our daily lives, compelling us to perform similar tasks at predictable intervals each day. Among the various captivating aspects of circadian rhythms, one particularly intriguing and pervasive phenomenon emerges: as individuals age, their daily schedules undergo a noticeable transformation. The transformation often manifests as an earlier awakening in the morning and an earlier retirement to slumber in the evening. This behavioral shift bears a resemblance to the natural course of daylight, as though these seasoned individuals are inclined to follow the sun's trajectory with their own daily routines. What accounts for this shift in behavior among the elderly?

The biological clock situated within mammals is housed in the anterior part of the hypothalamus in the brain, known as the suprachiasmatic nuclei (SCN). It relies on the daily light-dark cycle to govern rhythmic changes in the behavior and physiology of most species. The circadian cycles established by this clock occur throughout nature and have a period of approximately 24 hours [1]. Disruptions in the sleep-wake cycle, fragmented sleep episodes, and reductions in the amplitude of various rhythmic behaviors, such as the hormone excretion (including melatonin and cortisol) and fluctuations in body temperature, are commonly associated with aging in humans and other mammals [2]. This article aims to introduce the definition of circadian rhythm, delve into its fundamental principles, and explore the correlation between changes in circadian rhythm and the aging process.

Circadian Clock in Mammalian System

Characteristics

Circadian rhythms are fundamentally entrained with environmental cues, known as zeitgebers (time-givers), which serve as indicators of astronomical (solar) time [3]. Entrainment differs from “synchronization” which involves adjusting events to occur simultaneously, although both convey temporal coordination of two events. Entrainment, in this context, emphasizes the self-adaptiveness of one oscillation to cooperate with another, signifying that our biological rhythms are self-adjusted to align, on average, with external stimuli [4]. These stimuli encompass zeitgebers such as humidity, temperature, light, and certain social cues [5]. While humans through generations have established a standardized system of time to govern our work and social schedule, it is important to note that our circadian rhythms are inherently attuned to the natural entrainment provided by the sun [6].

However, what makes circadian rhythms truly fascinating is their inherent ability to persist even in the absence of external environmental triggers like light. In the 1700s, the French scientist de Mairan conducted groundbreaking work by publishing a monograph detailing the daily leaf movements of a plant. Notably, he observed that the plant's leaves continued to rise and lower daily, even in the absence of sunlight [1]. It is thereby concluded that molecular oscillations generated by clock genes allow circadian rhythms to persist in the absence of 24 hour signals through various mechanisms, a phenomenon referred to as free-running [7]. The internal ticking of organisms reveals both the harmony with external cues and the resilient rhythm sustained within, highlighting the intricacy of nature's internal clockwork.

Physiology

The mammalian circadian system operates through a hierarchical arrangement of oscillators, spanning from individual cells to tissues and then organs within an organism. At the apex of this hierarchy sits the SCN, functioning as the body's master clock. Through electrical, endocrine, and metabolic signaling pathways, the SCN harmonizes independent peripheral clocks found in nearly every tissue and organ system alongside the central clock [8]. This synchronization ensures a coordinated rhythm at the organismal level  [7]. 

Light is processed through the eyes and transmitted through the retinohypothalamic tract to the hypothalamic SCN, which is formed by a group of about 20,000 nerve cells (neurons). Through the neurons’ coupling, these cellular clocks acquire the ability to activate or silence genes throughout the body at the appropriate times to modulate our senses and behavior [9]. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication [10]. However,  the mechanics of synchronization between core neurons and peripheral tissues remain unknown.

The core of the mammalian circadian clock is a negative feedback loop composed of transcription factors that bind specific segments of DNA known as response elements [11]. Once bound, transcription factors can turn downstream genes on or off. In the mammalian circadian clock, the CLOCK (circadian locomotor output cycles kaput) transcription factor dimerizes with another transcription factor named BMAL1 (Brain Muscle ARNT-Like 1). The CLOCK:BMAL1 dimer binds to a subtype of response elements called enhancer boxes, or E-boxes, and promotes the transcription of core clock genes: Cryptochrome (Cry1 and Cry2), Period (Per1, Per2 and Per3), REV-ERB (Rev-erbα and Rev-erbβ) and ROR (Rorα, Rorβ and Rorγ) [12]. Following transcription, Cry and Per are translated in the cytoplasm, where they form a dimer and subsequently return to the nucleus. There, the resulting dimer interacts with the CLOCK:BMAL1 dimer, hindering its ability to stimulate the transcription of Cry and Per genes. Consequently, the production of Cry and Per is halted. As these proteins degrade, the CLOCK:BMAL1 dimer is released, allowing it to once again promote the transcription of Per and Cry [13]. Furthermore, the nuclear receptors Rev-erbα and Rorα are also clock components involved in the regulation of the core clock circuitry [14]. REV-ERBs repress while RORs activate the transcription of BMAL1 (Figure 1). This regulation contributes to the robustness of circadian oscillations, ensuring a synchronized and well-coordinated biological clock. The whole cyclical process forms a negative feedback loop, generating a 24-hour cycle of gene expression. 

Apart from initiating the rhythmic transcription of fundamental clock components, CLOCK:BMAL1 also regulates the rhythmic expression of thousands of clock-controlled genes, creating oscillations in biochemistry, physiology, and behavior. This orchestration plays a pivotal role in governing the rhythmic arrangement of a wide array of biological functions.

Role In Health

Circadian rhythms play a critical role in maintaining overall health and well-being. In mammals, the circadian clock influences nearly all aspects of physiology and behavior including sleep-wake cycles, cardiovascular activity, endocrine system, body temperature, renal activity, physiology of the gastrointestinal tract, and hepatic metabolism [15].

The control of the circadian clock over human pathophysiology is demonstrated in epidemiological studies. For instance, heart attacks are more likely to occur early in the morning, when the level of a hormone called cortisol starts its daily rise. Clinical epidemiology in humans also indicates that pulmonary edema, hypertensive crises, asthma, and allergic rhinitis attacks all peak at certain times during the day [16]. This synchronized phenomenon underscores the circadian rhythm's control over hormone concentrations and various physiological functions, including cardiovascular and respiratory variations, throughout the day.

Disturbing the circadian clock has adverse effects on human health. Travelers often experience jet lag, characterized by symptoms such as fatigue, disorientation, and insomnia. Likewise, shift workers exhibit alterations in nighttime melatonin levels and reproductive hormone profiles, potentially increasing the risk of hormone-related diseases [17]. The disruption of circadian coordination, as seen in shift workers, is also associated with a heightened susceptibility to cancer and the acceleration of malignant growth [18]. These findings highlight the negative impact of circadian rhythm disruption on various physiological processes.

Changes in Circadian Rhythm With Aging

Circadian rhythms do not remain constant throughout one's lifetime; they undergo changes over time, involving shifts in phase and a decrease in amplitude (reduction in the intensity or strength of circadian rhythms). Although numerous factors contribute to these alterations, a growing body of literature suggests that a decline in the central circadian clock within the suprachiasmatic nucleus (SCN) may be a crucial element responsible for age-related changes. 

In a hamster experiment, it was observed that older individuals exhibited reduced circadian activity. Hamsters whose total activity per circadian cycle had declined to less than 10% of the levels observed in young adults were categorized as elderly. These elderly hamsters were identified as potential candidates for transplantation to test whether the aging of SCN is responsible for their reduction in activity. Subsequently, they were allocated to one of the following groups: those receiving viable SCN grafts, control grafts (cortical tissue grafts), sham-operated, or left unoperated (Figure 2). Upon receiving fetal suprachiasmatic implants, the circadian rhythms of the older hamsters were revitalized, exhibiting higher amplitudes. This revitalization resulted in a notable extension of lifespan by up to 4 months compared to the control groups [19]. The results illustrate that, like many physiological processes, circadian timing systems are not immune to the effects of aging. With age, humans will experience decreased duration and quality of sleep as a result of shift in the circadian phase and decrease in circadian amplitude.

Sleep Traits

According to the National Sleep Foundation, sleep duration varies widely across the lifespan and exhibits an inverse relationship with age (Table 1). The sleep-wake cycle undergoes rapid changes during the first year of life, with significant implications for circadian rhythm development [20]. In the initial stage (0–3 months), newborns lack an established circadian rhythm, resulting in sleep being distributed across the entire 24-hour day. However, a notable transition occurs at 10–12 weeks, marked by the emergence of the circadian rhythm. Subsequently, between ages 4 and 12 months, sleep tends to become more nocturnal [21]. These developmental shifts underscore the intricate interplay between circadian rhythm maturation and evolving sleep patterns in early life.

Normal aging is accompanied by changes in the sleep quality, quantity, and architecture [23]. A study encompassing over one thousand randomly selected adults (20–80 years) in São Paulo, aimed to assess sleep structure and duration. Polysomnography results, obtained by monitoring heart rates, oxygen levels, and brain waves during sleep to provide a comprehensive image of sleep traits, consistently revealed age-related alterations. These changes included reductions in total sleep time, sleep efficiency, and slow-wave sleep, along with an increase in WASO (wake after sleep onset) (Figure 3).

Melatonin, predominantly synthesized by the pineal gland, is primarily released during the night, reaching levels approximately tenfold higher than daytime concentrations. Functioning as a chronobiotic that affects the timing or regulation of the circadian rhythm, melatonin influences sleep by either advancing or delaying the sleep-wake cycle, causing an earlier or later onset of sleep. The natural nighttime secretion of melatonin diminishes gradually with age, as noted in research [24]. Given the pivotal role of melatonin in regulating the sleep-wake cycle, this decline in secretion may contribute to diminished sleep efficiency and an elevated occurrence of circadian rhythm sleep disturbances.

Circadian Phase

Numerous elderly individuals undergo a shift in their sleep-wake cycle, leading to early evening sleepiness. Those with advanced sleep phase syndrome (ASPS) typically initiate sleep between 7 to 9 pm and awaken approximately 8 hours later, around 3 to 5 am [26].

A potential explanation for early morning awakening and challenges in maintaining sleep among older individuals would be a shortened free-running period due to aging [27]. In older adults, a shorter circadian period was observed when individuals were allowed to self-select their sleep schedules. The study involved six young adults (ages 23–30) and six older adults (ages 53–70) living under conditions of temporal isolation for three to eight weeks, with comparative measurements of sleep-wake cycles, sleep stages, and rectal temperature rhythms conducted during both entrained and non-entrained (free-running) conditions. The results indicated a reduction in the period of body temperature rhythms during free-running in the older group, while the young group maintained the normal 24-hour cycle [28]. However, some researchers question this finding, since the experiments were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. In another experiment conducted under precisely controlled lighting conditions, a different conclusion emerged. With measuring the periods of the endogenous rhythms of melatonin, core body temperature, and cortisol, both older people and younger ones revealed an average free running period of 24.18 hours [29].

Hence, an alternative hypothesis for the shift in the sleep-wake cycle timing in older adults is associated with age-related alterations in either light exposure or the circadian clock's responsiveness to light, since light is the primary zeitgeber for circadian timing system [30]. The daily light exposure is significantly diminished in older populations, particularly among individuals with disabilities. Furthermore, with age, there is a decline in the functioning of the eyes. This is compounded by an increase in lens pigmentation, leading to a further decrease in the transmission of short-wavelength light to the retina [31]. It has been tested in individuals with dementia; research indicates a positive correlation between the level of light exposure and the stability of the rest-activity rhythm, as well as with sleep consolidation [32]. 

Circadian Amplitude 

The aging process is linked to a decrease in the magnitude of various circadian rhythms in older individuals such as core body temperature, melatonin and cortisol secretion, activity, and sleep [33]. The circadian rhythm of temperature serves as an effective illustration of the entire circadian clock. This is attributed to a rhythm in heat production, influenced by daily variations in hormone secretions, enzymatic activities, and the rhythmic activity of hypothalamic thermosensitive neurons [34]. Baerensprung first found out the amplitude of human body temperature reached a maximum during early childhood and declined thereafter to about 50% of this value during one’s twenties [35].

The initial research on animals documenting a decline in diurnal body temperature oscillation was conducted by Slonaker in 1912. In a study examining the entire lifespan of rats, he observed that not only did the activity rhythm diminish, but it also became more fragmented [36]. The following experiment focuses on recording the core body temperatures of ten healthy young adults and eight healthy aged men. Elderly participants exhibited significantly higher temperatures at the nadir of the temperature curve compared to the younger participants. The result graph (Figure 4) indicated that, although the data from all subjects significantly conformed to an idealized cosine function with a 24-hour periodicity, the peak-to-trough amplitude of the rhythm was notably lower in the aged group.

These reductions in circadian amplitude observed in aging individuals could be attributed to changes within the aged SCN, the central circadian clock itself. In this context, the aged SCN may exhibit an altered circadian rhythm, potentially influenced by a diminished number of relatively normal neurons and/or weakened coupling between them. These structural and functional changes within the SCN may contribute to the lower amplitude and partially aberrant rhythmic output associated with aging [37].

The disruption of circadian rhythms in older organisms, attributed to an aging SCN, was further supported by experiments transplanting fetal SCN grafts into old rats. These transplants successfully restored circadian rhythms in body temperature, locomotor activity, and/or drinking behavior in intact old rats [38].

Conclusions 

The circadian rhythm is not merely responding to 24-hour changes in the physical environment dictated by the Earth's rotation on its axis; rather, it also originates from an internal timekeeping system within the organism. This internal system is a negative feedback loop that maintains the orderly recruitment of clock proteins to promoters [40]. Changes in circadian rhythm during aging include shortened sleeping duration, an advanced circadian phase, and a decreased circadian amplitude. All of these changes originate in the aged SCN, which exhibits reduced power for dynamics or a lack of responsiveness over time to stimuli.

The initial scientific observation of circadian rhythms dates back to 1729 when the French astronomer Jean Jacques d'Ortous de Mairan placed the mimosa plant in a light-tight dark room. He observed that the plant continued to unfold its leaves in the morning and close them in the evening [41]. Over the decades, our comprehension of circadian rhythms has advanced. Nonetheless, certain aspects, such as the synchronization of the main clock with peripheral clocks across the body or the potential shortening of the free-running period in mammals with aging, still pose challenges for understanding. The impact of circadian rhythm on lifespan is also a complex and fascinating area of study, with potential implications for extending lifespan. Continued research in these areas will not only deepen our understanding of circadian rhythms but may also lead to new insights and interventions in aging and lifespan extension.

About the Author: Xiaoxi Cui

 I authored this term paper for HDE 117 under the guidance of Professor Carey. My interest in this topic stemmed from the observation that older individuals seem to experience a different biological clock. Inspired by the lifestyle of my grandparents, who appear to lead a notably "healthy" life, I questioned whether this observation reflects physiological factors or behavioral choices among all elderly individuals. Therefore, I initiated research on circadian rhythms, and based on my study, I find it to be a significant factor worthy of exploration in the study of aging. My research delves into the mechanisms behind circadian rhythm and its aging. I hope my work encourages readers to consider the profound implications of circadian rhythms on longevity.

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