Resetting of central and peripheral circadian oscillators in aged rats

Abstract

The mammalian circadian timing system is affected by aging. Analysis of the suprachiasmatic nucleus (SCN) and of other circadian oscillators reveals age-related changes which are most profound in extra-SCN tissues. Some extra-SCN oscillators appear to stop oscillating in vivo or display altered phase relationships. To determine whether the dynamic behavior of circadian oscillators is also affected by aging we studied the resetting behavior of the Period1 transcriptional rhythm of peripheral and central oscillators in response to a 6 hr advance or delay in the light schedule. We employed a transgenic rat with a luciferase reporter to allow for real-time measurements of transcriptional rhythmicity. While phase-resetting in the SCN following an advance or a delay of the light cycle appears nearly normal in 2-year old rats, resynchronization of the liver was seriously disrupted. In addition, the arcuate nucleus and pineal gland exhibited faster resetting in aged rats relative to 4-8 month-old controls. The consequences of these deficits are unknown, but may contribute to organ and brain diseases in the aged as well as the health problems that are common in older shift-workers.

Aging in the circadian system: Considerations for health, disease prevention and longevity

“…In addition to the core clock genes responsible for circadian function at the cellular level, subordinate clock-controlled genes (CCGs) represent important output and local coordination systems. The stability of this hierarchical arrangement is disrupted with advancing age (Davidson et al, 2008).…”

“…With advancing age, the circadian system exhibits loss of temporal precision (Benloucif et al, 1997;Davidson et al, 2008;Li and Satinoff, 1995;Valentinuzzi et al, 1997;Weinert and Waterhouse, 1999), contributing to a variety of age-related pathologies. Such age-related changes cannot be explained by cell death or atrophy in the SCN, as aging does not decrease cell size or numbers in the master pacemaker (Madeira et al, 1995).…”

“…Because Per1 transcription is rapidly induced by light and is required for entrainment (Wakamatsu et al, 2001), the induction of Per1 makes a convenient assay for investigating the response of the SCN to a phase-resetting light pulse. In aged animals, Per1 expression following an entraining light stimulus is markedly reduced with a significantly longer delay to resynchronization (Davidson et al, 2008;Kolker et al, 2003). In young animals, disruption of the Period genes leads to aging-like declines in sensitivity to light (Asai et al, 2001;Weinert et al, 2001).…”

“…With advancing age, animals exhibit numerous circadian disruptions (Benloucif et al, 1997;Davidson et al, 2008;Li and Satinoff, 1995;Valentinuzzi et al, 1997;Weinert and Waterhouse, 1999) that contribute to poor health consequences and hastened senescence. In fact, longevity is diminished by circadian perturbations and decelerated by restoration of youthful circadian behavior by transplantation of a fetal clock into the brains of aged animals (Hurd and Ralph, 1998).…”

Age-related changes in neurochemical components and retinal projections of rat intergeniculate leaflet

“…Moreover, SCN have a reduced expression of two major neurochemical constituents, vasoactive intestinal polypeptide (Chee et al 1988;Krajnak et al 1998), and vasopressin (Roozendaal et al 1987;Cayetanot et al 2005), which accounts to a weakening of SCN interconnections, therefore affecting the circadian clock functionality (Engelberth et al 2013). Current data, however, are focused solely on the aging effects on SCN, which brings a limitation to understand the whole process of aging in CTS (Yamazaki et al 2002;Davidson et al 2008). In view of this absence of data concerning effects of aging in IGL, we documented neurochemical and retinal afferent changes in IGL between young, adult, and aged rats based on GAD, ENK, NPY, and CTb immunoreactivity.…”