AGING REPROGRAMS CIRCADIAN METABOLIC AND TRANSCRIPTIONAL RHYTHMS

As human lifespan increasingly exceeds the period of good health in one’s life, ameliorating the detriments associated with age-related decline is of the upmost importance. As individuals age, sleep:wake patterns degrade, hormonal release dysregulates, and metabolic dysfunction and neurodegenerative disease become prevalent. Pathways associated with all these are subject to circadian regulation, raising the question of the extent to which circadian disruption contributes to age-related pathology. With age, the molecular mechanism of the central clock in the brain remains largely intact, but signaling from the central clock neurons is disrupted. Clocks in peripheral tissues are affected by age in different ways, but whether the changes are tissue-autonomous or driven by extrinsic cues is not known. This thesis reviews the breakdown of circadian rhythms across species with age, from both a behavioral and a molecular perspective (Chapter 1), and then addresses the questions raised above. Chapter 2 describes our research with a Drosophila model to investigate age-related changes in the circadian metabolome. We found that the metabolites and lipids that cycle in young flies are different from those that cycle with advanced age. In particular, we found that the Pentose Phosphate Pathway loses rhythmicity with age, and is associated with changes in sleep:wake cycles. Chapter 3 investigates the contribution of systemic signals to age-related changes in peripheral tissues by comparing the ability of serum from young and old human subjects to entrain peripheral clocks in fibroblast cell cultures. The results demonstrate that the circadian transcriptome depends upon the age of the serum, such that a significant number of transcripts become arrhythmic or cycle differently following entrainment with aged serum. Pathway analyses of these age-altered circadian transcripts provide insight into age-related changes, as well as potential targets for anti-aging therapy. Chapter 4 highlights the circadian reprograming that occurs with age in the metabolome and the transcriptome and discusses potential underlying mechanisms as well as relevance of age-related circadian reprogramming.