A multi‐level assessment of the bidirectional relationship between aging and the circadian clock

Abstract

The daily temporal order of physiological processes and behavior contribute to the wellbeing of many organisms including humans. The central circadian clock, which coordinates the timing within our body, is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Like in other parts of the brain, aging impairs the SCN function, which in turn promotes the development and progression of aging‐related diseases. We here review the impact of aging on the different levels of the circadian clock machinery—from molecules to organs—with a focus on the role of the SCN. We find that the molecular clock is less effected by aging compared to other cellular components of the clock. Proper rhythmic regulation of intracellular signaling, ion channels and neuronal excitability of SCN neurons are greatly disturbed in aging. This suggests a disconnection between the molecular clock and the electrophysiology of these cells. The neuronal network of the SCN is able to compensate for some of these cellular deficits. However, it still results in a clear reduction in the amplitude of the SCN electrical rhythm, suggesting a weakening of the output timing signal. Consequently, other brain areas and organs not only show aging‐related deficits in their own local clocks, but also receive a weaker systemic timing signal. The negative spiral completes with the weakening of positive feedback from the periphery to the SCN. Consequently, chronotherapeutic interventions should aim at strengthening overall synchrony in the circadian system using life‐style and/or pharmacological approaches.

Age-Related Unstructured Spike Patterns and Molecular Localization in Drosophila Circadian Neurons

“…Several reports have investigated the activity patterns of clock neurons during aging ( Buijink and Michel, 2021 ). For example, in aged hamsters, SCN neuronal activity deteriorated ( Watanabe et al, 1995 ).…”

“…A number of studies in Drosophila and mammals examined how aging, from molecules to behavior, affects the circadian clock machinery ( Kondratova and Kondratov, 2012 ). In mammals, the circadian clock network shows age-related electrophysiological changes, including membrane currents and spiking activity, in the suprachiasmatic nucleus (SCN) ( Biello, 2009 ; Farajnia et al, 2014 ; Buijink and Michel, 2021 ). However, the mechanistic relationships between core-clock molecular signaling and electrophysiological function are unclear.…”

Development of Nanocrystal Compressed Minitablets for Chronotherapeutic Drug Delivery

“…Some cardiovascular incidents can often appear in days and manifest diurnal habits [ 16 , 17 ]. A high rush of blood pressure at early hours in the morning was noted to have an association with the development of hemorrhagic stroke and sudden cardiac deaths [ 18 , 19 ]. The increased activity of plasma renin and noradrenaline hormones in the morning hours can cause vasoconstriction in the coronary artery, thus leading to greater risk [ 20 ].…”

Chronic Exposure to Dim Light at Night or Irregular Lighting Conditions Impact Circadian Behavior, Motor Coordination, and Neuronal Morphology

“…Human and rodent studies have shown that aging affects the circadian system ( Buijink and Michel, 2021 ). While there is an age-related reduction in light sensitivity ( Lupi et al, 2012 ), melanopsin-mediated responses appear to be retained in older animals even in the absence of rods and cones ( Semo et al, 2003 ).…”

“…While there is an age-related reduction in light sensitivity ( Lupi et al, 2012 ), melanopsin-mediated responses appear to be retained in older animals even in the absence of rods and cones ( Semo et al, 2003 ). Age-related changes have been widely reported in circadian rhythms and sleep, although there are conflicting reports as to the phenotypic effects of aging on the central clock itself ( Buijink and Michel, 2021 ). Interestingly, the circadian clock itself also affects aging: transplanting the SCN of young mice into old mice resulted not only in increased robustness of circadian rhythms ( Van Reeth et al, 1994 ), but also in an increase in life expectancy ( Hurd and Ralph, 1998 ).…”