Circadian Rhythmicity and Aging: the Molecular Basis of Oscillatory Gene Expression

Abstract

Circadian rhythmicity in hormone synthesis and secretion is a characteristic feature of a large number of biological systems. These rhythms are essential in the regulation of most physiological functions, and studies over the past several years have started to elucidate the molecular mechanisms governing them. Importantly, there is evidence that fundamental changes occur in the quality of circadian rhythmicity during the aging process. These changes occur via differential adaptation to the environment. The day-night rhythm is translated into hormonal oscillations governing the metabolism of all living organisms. In mammals, circadian synthesis of the hormone melatonin occurs in the pineal gland in response to signals originating from the endogenous clock located in the hypothalamic suprachiasmatic nucleus (SCN). The molecular mechanisms involved in rhythmic synthesis of melatonin involve the CREM (cAMP-responsive element modulator) gene, which encodes transcription factors responsive to activation of the cAMP signalling pathway. ICER (inducible cAMP early repressor) is a product of the CREM gene that is rhythmically expressed and participates in a transcriptional autoregulatory loop. ICER also controls the amplitude of oscillations of serotonin N-acetyl transferase, the rate-limiting enzyme of melatonin synthesis. Thus, processes of transcriptional regulation are central to the physiological mechanisms of oscillatory hormonal production that are known to change during aging.