Old flies have a robust central oscillator but weaker behavioral rhythms that can be improved by genetic and environmental manipulations

Abstract

Summary Sleep:wake cycles break down with age, but the causes of this degeneration are not clear. Using a Drosophila model we addressed the contribution of circadian mechanisms to this aged-induced deterioration. We found that in old flies free-running circadian rhythms (behavioral rhythms assayed in constant darkness) have a longer period and an unstable phase before they eventually degenerate. Surprisingly, rhythms are weaker in light:dark cycles and the circadian-regulated morning peak of activity is diminished under these conditions. On a molecular level, aging results in reduced amplitude of circadian clock gene expression in peripheral tissues. However, oscillations of the clock protein PERIOD (PER) are robust and synchronized among different clock neurons, even in very old, arrhythmic flies. To improve rhythms in old flies, we manipulated environmental conditions, which can have direct effects on behavior, and also tested a role for molecules that act downstream of the clock. Coupling temperature cycles with a light:dark schedule or reducing expression of protein kinase A (PKA) improved behavioral rhythms and consolidated sleep. Our data demonstrate that a robust molecular time-keeping mechanism persists in the central pacemaker of aged flies, and reducing PKA can strengthen behavioral rhythms.

The aging clock: circadian rhythms and later life

“…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 (151). In support of this idea, manipulations intended to align peripheral oscillators with the master clock, such as imposing an environmental temperature rhythm that is synchronized with the light/dark cycle, have yielded improvements in sleep and activity rhythms in aged Drosophila (83). Similarly, in rodents lacking a functional master clock, restricted feeding schedules are sufficient to synchronize rhythmic clock gene expression across several peripheral oscillators (121,152).…”

“…Many metabolic rhythms exhibit progressive dampening with age (76,81,82). These changes are underscored by evidence of age-related decreases in the amplitude of clock gene expression rhythms in clocks outside of the master pacemaker (83,84). Dampening of these rhythms is suspected to contribute to the increased risk in older adults of metabolic diseases such as diabetes, dyslipidemia, and hypertension (12,85).…”

“…In tissues such as the lungs, the rhythm of Per1 expression seen in young rats (2 months) was absent in old animals (24-26 months) (84). In Drosophila, the amplitude of clock gene expression and protein rhythms in head and body tissues decreased in aged flies (58 days old), despite the persistence of a robust PER2 rhythm in brain clock neurons (83). These declines in peripheral clocks may have important implications for the susceptibility of aged animals to various disease states, given evidence demonstrating links between loss of rhythmic clock gene expression and the development of metabolic disease states and cancers (94,95).…”

“…Using the PER2::LUC mouse model, Sellix and colleagues (151) demonstrated that peripheral clocks in esophagus, lung, and thymus gland in older mice (22-28 months) were slower to entrain to a 6-hour phase advance of the light/dark schedule, in comparison with younger (3-6 months) mice. 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 (151).…”

Casein Kinase 1 Promotes Synchrony of the Circadian Clock Network

“…Daily cycling of Clk and cry expression is abol- ished, with intermediate levels of both transcripts throughout the day. As in the case of the Western blot analysis described above, these RNA assays of adult heads largely report clock gene expression in the compound eye (37,38), which constitutes a peripheral oscillator. We infer that the peripheral clock in the eye is dampened in dbt EY02910 mutants.…”