Date Published: June , 2012
Publisher: Blackwell Publishing Ltd
Author(s): Wenyu Luo, Wen-Feng Chen, Zhifeng Yue, Dechun Chen, Mallory Sowcik, Amita Sehgal, Xiangzhong Zheng.
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 age-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 timekeeping mechanism persists in the central pacemaker of aged flies, and reducing PKA can strengthen behavioral rhythms.
A prominent problem among the elderly is that of disrupted sleep–wake cycles (Duffy & Czeisler, 2002). The mechanisms underlying this disruption are not understood, although decrements in circadian clock function are a distinct possibility. While there is no age-related loss of neurons in the central pacemaker, the suprachiasmatic nucleus (SCN) in hypothalamus (Madeira et al., 1995), the amplitude of the electrical activity rhythm is reduced in older animals (Satinoff et al., 1993; Watanabe et al., 1995; Aujard et al., 2001). This weakening of rhythm strength is thought to arise from decreased amplitude of individual SCN neurons and increased variability among neurons (Aujard et al., 2001). Transplantation of a fetal SCN into aged animals restored circadian rhythms in levels of hypothalamic corticotrophin-releasing hormone (CRH) mRNA, supporting the idea that the central pacemaker is a target of the aging process (Cai et al., 1997). However, the effect of aging on the molecular clock within SCN neurons is unclear. Some studies reported reduced expression of specific clock genes in the aged SCN, although the genes affected may vary by species (Weinert et al., 2001; Kolker et al., 2003), but other studies found robust cycling of circadian clock gene transcription (Asai et al., 2001). In addition, expression of a per1-luciferase reporter is robust in the aged rat SCN although the free-running period is significantly shorter (Yamazaki et al., 2002), while per2-luciferase reporter cycling is dampened in the SCN of middle-aged mice (Nakamura et al., 2011). At the protein level, age affects the amplitude and/or phase of expression of the CLOCK and BMAL1 clock proteins in several extra-SCN regions, but not in the mouse SCN (Wyse & Coogan, 2010). A recent study found minor deficits of PER2 expression in the SCN of middle-aged mice (Nakamura et al., 2011).