How Senescent Vascular Cells Lose Their Clock Age-Dependent Impairment of Circadian Rhythmicity in Smooth Muscle Cells

Abstract

See related article, pages 532–539 “Oh dear! Oh dear! I shall be too late!” — —Alice’s Adventures in Wonderland, Lewis Carroll In mammals, as well as in flies and even in prokaryotes, circadian rhythmicity is allowed by a genetic clockwork that tightly regulates organisms’ adaptation to daily variations of light, temperature, and other living conditions.1 The master pacemaker of the hierarchically organized cell-autonomous circadian clocks2 is localized in the densely packed 2×104 neurons of the hypothalamic suprachiasmatic nuclei (SCN), which is reset mainly by light signals captured by the retina. Although clocks resident in peripheral tissues, the so-called peripheral clocks, are mainly controlled by the SCN, an abrupt change in feeding time synchronizes these clocks independently of the central clock.3 In fact exogenous (eg, light) or endogenous rhythms can temporally adjust the cellular clocks, whose main characteristics are (1) feedback regulation and (2) 24 hours oscillatory period. At molecular level, circadian rhythms are maintained by the intracellular feedback loop of the clock genes.4 The principal members of this family are the mPer 1 and 2 genes,5 Brain and Muscle RNA-t-like protein ( BMAL-1 ),6 Clock ,7 the 2 Cryptochrome genes ( mCry1 and 2 ),8 Casein Kinase Ie ( CKIe ),9 and the orphan receptor Rev-erbα .10 These genes constitute a well-conserved transcritpion/translation-based negative feedback loop. In mammals, Clock and BMAL-1 proteins are in the positive limb of the loop, whereas mPERs and Cryptochromes are in the negative.2,11 Clock/BMAL-1 heterodimeric complex, …