Evaluating Circadian Rhythms
Some aged animals receiving fetal tissue grafts exhibit an increased lifespan 99 , raising the intriguing possibility that the master clock regulates not only daily rhythms but also longevity. Morphology and neuropeptide expression. There is mixed evidence in both humans and rodents for age-related changes in the structure of the SCN. Some cross-sectional studies indicated a decrease in SCN volume in adults over 80 years of age compared with younger adults, and fewer total cells in the aged SCN , ; however, these findings may have been influenced by the type of cell marker used.
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In rats, decreased SCN volume and cell number have been reported in some studies , but not others A more consistent body of work indicates age-related changes in the neurochemical makeup of the SCN in humans, primates, and rodents. In particular, the expression of arginine vasopressin AVP and vasoactive intestinal polypeptide VIP , each of which follows a circadian rhythm and predominates in the shell and core of the SCN, respectively, is reduced in elderly humans compared with younger and middle-aged adults refs. A similar reduction in AVP and VIP expression has been observed in aged rodents , , whereas in mouse lemurs, a nonhuman primate, the peak of rhythmic AVP and VIP expression in the SCN is shifted, not suppressed, in aged animals compared with younger adults Schematic of possible mechanisms underlying age-related changes in circadian rhythms.
Progressive yellowing and thickening of the lens may reduce sensitivity to light, the strongest zeitgeber. A weaker SCN output signal may in turn reduce the strength of downstream oscillators in central and peripheral tissues, including the cortex, pineal gland, liver, kidney, thyroid, and spleen. Providing other zeitgebers such as scheduled meals green arrows , which act on the circadian system via extra-SCN pathways, may help entrain an aging circadian system.
Although the implications of a reduction in AVP and VIP expression are unclear, there are a number of intriguing correlations between neuropeptide expression and the stability of several rhythms.
In a sample of elderly humans mean age of 90 years , VIP expression in the SCN correlated positively with the amplitude of the locomotor activity rhythm based on actigraphy measures taken within 18 months of death These observations provide an interesting parallel to the effects of fetal SCN tissue grafts into aged rodents, whereby a conditional association was observed between the presence of VIP-expressing transplanted cells and successful restoration of locomotor activity, temperature, and drinking rhythms in aged mice Modeling work by Vasalou and colleagues underscores the impact of even modest reductions in the connectivity of VIP neurons in the SCN, in that elimination of only a small amount of long-range VIPergic connections leads to decreased synchrony among cells in the master clock.
At a synaptic level, studies in mice suggest an age-associated reduction in the density of GABAergic synapses in both the core and shell of the SCN Given the role of GABAergic signaling in regulating the activity of SCN cell firing , this reduction in synapses could have meaningful implications for age-related changes in the timing of the master clock.
Neuronal coupling in the SCN. Perhaps the most consistent changes observed in the aging SCN are related to the rhythm and synchrony of cell firing. Multiunit recordings in rodents indicate that the amplitude of SCN activity decreases with age, and that this decrease may reflect a loss of coherence in firing patterns across SCN cells in aged animals — Farajnia and colleagues identified in aged mice approximately 24 months greater numbers of neurons within the SCN in which peak firing occurred out of phase with the dominant SCN rhythm in comparison with young mice aged 3 months.
Observations that the amplitude of the firing rhythm in SCN neurons diminishes with age, while the oscillation of firing in individual SCN neurons between day and night appears to remain fairly robust in aged animals, suggest an age-related decline in the overall coherence of the output signal from the SCN 91 , This loss of coherence at a network level within the master clock may contribute to the weakening or desynchronization of oscillators downstream of the SCN.
Clock gene expression in the SCN.
Causal links between clock gene expression patterns in the SCN and age-associated changes in circadian rhythms have not been conclusively demonstrated. However, what evidence exists suggests that this relation may be critical. Further experiments within this study suggest that these changes in rhythmic PER2 expression in the SCN arise as a consequence of decreased rhythmic cell firing in the SCN Targeted manipulation of clock genes selectively within the SCN yields changes in rhythms of physiology or behavior that approximate some of those observed during the natural course of aging For example, Bmal1 -null mice develop sarcopenia, cataracts, and slowed hair growth, and exhibit a significantly shorter lifespan compared with wild-type age mates Similarly, null mutation of the Per gene in Drosophila is associated with significantly shorter lifespan, as well as greater accumulation of age- and stress-related oxidative damage, compared with wild-type flies Some criticisms of these findings have been raised, in that clock genes such as Bmal1 have important, noncircadian roles in the development of organisms , As such, a system-wide manipulation of these genes may yield a phenotype that is not exclusively due to disruption of the circadian clock However, these and other associated findings raise the intriguing possibility that changes in clock gene expression may be implicated not only in age-associated changes in circadian rhythms of behavior and physiology, but also more broadly in the processes of aging overall i.
A component of this relation between clock genes and aging in physiology may be via sirtuin 1 SIRT1 , an NAD-dependent protein deacetylase that appears to mediate the effects of caloric restriction on longevity Furthermore, Sirt1 knockouts display a premature aging phenotype, including disrupted activity rhythms comparable to those in aged 19—22 months wild-type mice , , as well as shortened lifespan and increased levels of proinflammatory markers in blood In contrast, overexpression of Sirt1 in the mouse brain is associated with elevated Bmal1 and Per2 mRNA in the SCN, and a shorter free-run period than in wild-type littermates Taken together, these findings suggest a role for an age-dependent decrease in SIRT1 in mediating changes in the molecular circadian clockwork Given the importance of time cues, or zeitgebers, in resetting the circadian system on a daily basis, reduced sensitivity to zeitgebers from the environment could contribute to circadian changes in later life.
Several avenues of research have examined this possibility with respect to light, the most powerful zeitgeber. Humans exert considerable control over their exposure to light in their environment. In general, previous research does not suggest that older adults are exposed to less light during the day relative to younger adults , although this may not be the case for adults who are in residential care or nursing facilities Important differences may arise, however, in the transmission of light through younger versus older eyes.
This yellowing has a selectively stronger effect on shorter wavelengths of light, which are preferentially absorbed by intrinsically photosensitive retinal ganglion cells ipRGCs that transmit time-of-day information to the SCN , , and degree of lens yellowing is associated with reported sleep disturbances in older adults Pupil size and responsiveness of ipRGCs to blue light may diminish with age, although not all findings are consistent , Cataracts have also been associated with impaired sleep quality, and removal can exert a beneficial effect on sleep efficiency and the amplitude of the melatonin rhythm in older adults — However, the magnitude of this effect appears limited and transient, and may be most pronounced in individuals who have particularly poor sleep quality , However, evidence to date has not indicated clear effects of such lenses on measures of sleep efficiency, activity, or melatonin release Metabolic cues.
Although light is the most potent zeitgeber for the circadian system, other cues such as metabolic signals play a powerful role in regulating the circadian clock Research examining the potency of restricted food delivery as a zeitgeber across the lifespan suggests that responsiveness to this nonphotic time cue may only be modestly affected by age. For example, similarly to young rats, older rats approximately 24 months will still develop anticipatory bouts of activity for food presentation on a restricted schedule , Given that timed food delivery is a highly potent zeitgeber and does not exert its entrainment effects via the SCN , it is possible that timed food delivery could serve as an effective means of resynchronizing circadian timing in older individuals reviewed in ref.
For example, Walcott and Tate reported that low-amplitude, fragmented activity rhythms in aged rats 13—18 months became more consolidated after a day period of food restriction. Interestingly, recent work in Drosophila indicates that the lifespan-extending effects of chronic dietary restriction are mediated by increased expression of several clock genes in peripheral tissues, which regulate fat metabolism These and other related findings imply that limited, timed food access may be an avenue through which age-associated pathologies involving the circadian system, such as neurodegenerative diseases, could be mitigated Desynchronization of downstream oscillators from the master clock.
Another possible mechanism underlying circadian disruption with aging pertains to the relative synchrony between SCN and oscillators in central and peripheral tissues. In Drosophila , downstream clock gene oscillation in peripheral tissues and behavioral rhythms decrease in amplitude and become fragmented with increasing age 58 days 83 , despite robust Per expression rhythms persisting in neurons. These findings may suggest that a dampening of rhythmic output from the master clock with age may lead to a desynchronization between central and peripheral oscillators, and consequently misalign peripheral oscillators with external temporal cues Similarly, in rodents lacking a functional master clock, restricted feeding schedules are sufficient to synchronize rhythmic clock gene expression across several peripheral oscillators , The functioning of the biological clock is intimately linked to healthy development across the lifespan.
With this change comes a dramatic imbalance of not only neurotransmitters but endocrine hormones thyroid hormone, insulin , which can lead to drastic changes in mood and concentration. This syndrome is commonly called jet lag Hirshfield, There is evidence that jet lag produces temporal lobe atrophy amnesia and spatial cognitive deficits location errors and disorientation Cho, Typically problems occur when the circadian period is phase shifted lengthened or shortened as it is in a trip from west to east i. Jet Lag Therapy.
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Boulos et al. Jet lag treatment is especially effective when used in conjunction with exogenous melatonin Arendt, ; Arendt et al. Melatonin, the body's natural endogenous sleep aid, is a tryptophan metabolite synthesized from serotonin by N-acetyl transferase NAT in the dark Moore and Klein, In the presence of visible light, NAT is inhibited and melatonin production is shut down.
Under normal circadian conditions, there is a small peak of melatonin production every afternoon at about 4 pm, and a much larger peak that occurs later in the evening between approximately 10 pm and 3 am. This pathway can be modified by a combination of light and exogenous melatonin treatment. Internal melatonin can be enhanced by taking melatonin pills 0.
Consuming foods that contain protein high in tryptophan, i.
Light and biological rhythms.
In contrast, high-protein food, such as meat that is rich in tyrosine and low in carbohydrates, can increase excitatory neurotransmitters and enhance wakefulness Wurtman et al. In summary, by judicious exposure to daylight or circadian blue light and with careful timing of meals and intake of a low dose of melatonin, it is possible to resynchronize circadian rhythms and reduce symptoms of jet lag. Brown, ; Arendt, ; Arendt et al. Shift Work. Jet lag, while unpleasant, is usually an infrequent occurrence.
Shift work, which requires employees to constantly change their waking and sleeping hours, is a much more common occurrence. Constant changes in work shift lead to a loss of alertness, productivity and increase in accidents. Night work and alternating patterns of shift work are the most injurious to human health, and can lead to chronic and even lethal diseases Straif et al.
Exposure to visible light at night deregulates the circadian gene, Per2, which is involved in human breast and endometrial cancer development Chen, Visible light at night, whether from nighttime shift work or inadvertent light trespass, suppresses the natural production of melatonin, decreasing its natural killer-cell antitumor activity Irwin et al.
In addition to an increased risk of cancer and autoimmune disorders, shift workers have higher risk of cardiovascular disease Knutsson and Boggild, and metabolic disorders including Type 2 diabetes Spiegel et al. Besides physical dysfunction, there are mental and emotional problems associated with shift work, including depression Sookoian et al. Learning and memory are also impeded by shift work and sleep deprivation Harrison and Horne, ; Vandewalle et al.
Shift Work Therapy.
The aging clock: circadian rhythms and later life
Treatment for the physical and emotional problems associated with shift work is complex. These strategies have recently been reviewed Arendt, ; Stevens et al. As with jet lag, diet tyrosine containing foods for alertness and tryptophan containing foods for sleep , may aid in rebalancing shift work circadian disruption Wurtman et al. Sleep Disruption. Human sleep is complex and is controlled by both endogenous homeostatic and circadian hormone secretion Cardinali and Pandi-Perumal, It can be categorized into three components: Non-sleep wakefulness ; REM rapid-eye-movement sleep the brain, eyes, and body muscles are active-dreaming ; and Slow-wave sleep , which is further classified as either theta light sleep or drowsiness or delta deep sleep.
The level of alertness or sleepiness may be quantitatively measured by noting the changes in the electroencephalographic EEG power spectrum. In general the lower the number Hz the slower the brain pattern and vice versa [Table 3]. The endogenous homeostatic control of sleep is related to how long someone has been awake and the subsequent depth of their sleep. Circadian modification of sleep is influenced by age, with onset delayed in adolescents Tarokh and Carskadon, and a reduction in Slow-Wave sleep in the elderly Cajochen et al. Each cycle of sleep induces a different neuroendocrine change, which affects all aspects of human physiology Carcinali and Esquifio, Delta sleep is the deepest sleep, and is restorative.
During this cycle there is a decrease in stress related hormones, lowering of blood pressure and heart and respiration rate, and an increase in growth hormone. REM sleep is a state of brain activation that increases heart rate and blood pressure and induces irregular respiration. Although REM sleep and total duration of sleep are relatively stable with increasing age, the duration of Slow-Wave, in general and delta sleep in particular, decreases with each decade of life Dijk and Duffy, The inability to get sufficient delta sleep in the daytime may explain some of the health hazards associated with shift work Arendt, Sleep research has benefitted from recent discoveries of the chemical, physiological and biophysical contributions of visible light control to human circadian response Provencio et al.
As sleep research has become an interdisciplinary study, integrating neuroscience, endocrinology, circadian rhythm, photobiology, and sleep physiology, a more precise understanding of the molecular mechanisms involved in human sleep and wakefulness have begun to be defined.
Sleep Disorder Treatments. Appropriate circadian blue light nm Brainard et al. A cooler room temperature Van Someren, c , evening diet containing food such as milk, that is enhanced with the precursor of melatonin, tryptophan Wurtman et al. Taking these simple steps is often sufficient to overcome most mild sleep disorders. Additional procedures may be necessary to overcome the sleep disturbances that accompany old age and dementia. The elderly are particularly susceptible to sleep disturbances Cajochen et al.
Alzheimer's disease is known to damage the cholinergic pathways and the circadian pacemaker in the suprachiasmatic nucleus which can also contribute to sleep disruption. Dementia is often associated with difficulty in falling asleep sleep latency , and frequent nighttime awakenings. There is also a decrease in slow-wave sleep, rapid eye movement sleep, and total sleep time, and an increase in daytime napping.
Cyclic agitation episodes sundowning , nightmares or hallucinations, sleep attacks, and nocturnal behavioral outbursts are often associated with specific dementia syndromes McCurry and Ancoli-Israel, Modifying the exposure to circadian blue light in the late afternoon and evening Van Someren, ; Dowling et al.