Age-Related Changes in the Circadian System Unmasked by Constant Conditions

Abstract

Circadian timing systems, like most physiological processes, cannot escape the effects of aging. With age, humans experience decreased duration and quality of sleep. Aged mice exhibit decreased amplitude and increased fragmentation of the activity rhythm, and lengthened circadian free-running period in both light-dark (LD) and constant dark (DD) conditions. Several studies have shown that aging impacts neural activity rhythms in the central circadian clock in the suprachiasmatic nucleus (SCN). However, evidence for age-related disruption of circadian oscillations of clock genes in the SCN has been equivocal. We hypothesized that daily exposure to LD cycles masks the full impact of aging on molecular rhythms in the SCN. We performed ex vivo bioluminescent imaging of cultured SCN slices of young and aged PER2::luciferase knock-in (PER2::LUC) mice housed under LD or prolonged DD conditions. Under LD conditions, the amplitude of PER2::LUC rhythms differed only slightly between SCN explants from young and aged animals; under DD conditions, the PER2::LUC rhythms of aged animals showed markedly lower amplitudes and longer circadian periods than those of young animals. Recordings of PER2::LUC rhythms in individual SCN cells using an electron multiplying charge-coupled device camera revealed that aged SCN cells showed longer circadian periods and that the rhythms of individual cells rapidly became desynchronized. These data suggest that aging degrades the SCN circadian ensemble, but that recurrent LD cycles mask these effects. We propose that these changes reflect a decline in pacemaker robustness that could increase vulnerability to environmental challenges, and partly explain age-related sleep and circadian disturbances.

The aging clock: circadian rhythms and later life

“…SCN neurons in aged animals were also less inhibited by GABAergic stimulation, which appears consistent with the loss of GABAergic synapses in the SCN with age (113). 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 (91,119 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 (131), although this may not be the case for adults who are in residential care or nursing facilities (132).…”

“…jci.org Volume 127 Number 2 February 2017 may be critical. In the PER2::LUC mouse, housing in constant dark conditions revealed a dampening of the PER2 rhythm in the SCN with age (13-15 months), as well as a lengthening of the circadian period of expression (91). 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 (91).…”

“…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).…”

“…In the PER2::LUC mouse, housing in constant dark conditions revealed a dampening of the PER2 rhythm in the SCN with age (13-15 months), as well as a lengthening of the circadian period of expression (91). 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 (91). 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 (120).…”

Membrane Currents, Gene Expression, and Circadian Clocks

“…In our own hands, the molecular clockwork in the SCN as measured by PERIOD2 levels was not disrupted in middle-aged mice held in a light -dark (LD) cycle (Nakamura et al 2011). However, when these mice were placed in constant dark (DD) for at least 2 weeks, differences in the bioluminescence rhythms (PER2::LUC) emerged (Nakamura et al 2015). In our view, the reduction in the amplitude of the circadian timing signal produced by the central clock will result in a weakening in the control of peripheral oscillators as well as a decrease in amplitude and precision of daily rhythms in physiology and behavior.…”