Circadian clocks, ageing and age-related diseases: molecular links and therapeutic intervention
Age is the single biggest risk factor for a wide spectrum of diseases. The rapid population ageing needs better understanding of the various biological processes underlying age-related pathologies. Among these are circadian rhythms, the endogenous 24 hour cycles governing nearly all aspects of physiology and behaviour. In mammals (including humans), this rhythm is generated by the master clock (suprachiasmatic nucleus, SCN) in the brain, which entrains to the light/dark environment and co-ordinates the peripheral clocks in most major body organs and cells. Circadian clocks control ~10% of our transcriptome in a tissue-specific manner and disrupted circadian rhythms correlate with various pathologies. Mutations in core clock genes lead to metabolic syndrome, obesity, diabetes, premature ageing, and increased tumorigenesis.
Body clocks are the internal timing mechanism that drives endogenous circadian (near 24 hour) rhythms in sleep/wake cycle, hormone release and behaviour. During ageing, our body clocks gradually lose precision. Consequently, this loss of synchrony with the 24 hour light/dark environment imposes significant risks of developing human diseases, such as metabolic syndrome, obesity, diabetes, cardiovascular diseases and cancer. Research in this laboratory aims to 1) Identify mechanisms underlying age-related changes in circadian rhythms in both brain and peripheral organs. 2) Establish functional significance of various tissue clocks in coordinating local physiology. 3) Explore the hypothesis of targeting body clocks in order to ameliorate disease development or progression.
My research has contributed to the understanding of the molecular mechanisms of circadain clock regulation (Neuron 2008; Nucleic Acids Res 2014; PLoS Genetics 2020) as well as the pharmacological resetting potentials of the circadian clock using compounds targeting various pathways (J Cell Sci 2008; J Pharmacol Exp Ther 2009; PNAS 2010). My more recent interest is the interface between ageing and circadian biology. In the long term, outcomes from this work could aid therapeutic drug design against age-related ailments, such as osteoarthritis (Arthritis & Rheum 2013; Osteoarthritis & Cartilage 2015; J Clin Invest 2016; Nat Rev Rheum 2016), spinal disc degeneration (Annals Rheum Dis 2017), pulmonary fibrosis (Genes & Dev 2014), collagen secretion and tendinopathies (Sci Rep 2014; Nature Cell Biology 2020) and breast cancer (Nature Comms 2017; JCS 2018, Breast Cancer Res 2018; JCS 2019).