Circadian clocks, ageing and age-related diseases: molecular links and therapeutic intervention potentials
Age is the single biggest risk factor for a wide spectrum of diseases. The rapid population ageing calls for 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 our 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 various peripheral clocks in most major body organs and cells. Circadian clocks are the internal timing mechanism that drives endogenous circadian (near 24 hour) rhythms in sleep/wake cycle, hormone release and behaviour. Circadian clocks control ~10% of our transcriptome in a tissue-specific manner. During ageing, our body clocks gradually lose precision. Consequently, this loss of synchrony both with the 24 hour light/dark environment (external misalignment) and with the other organs (internal misalignment) imposes significant risks of developing human conditions and diseases, including skin ageing, musculoskeletal degeneration and cancer. Research in this laboratory aims to 1) Identify mechanisms underlying age-related changes in circadian rhythms in the brain and peripheral organs. 2) Establish functional significance of various tissue clocks in coordinating physiology to local demands. 3) Explore the hypothesis of utilizing body clock mechanisms in order to ameliorate disease progression and improve patient responses to therapies.
Previously, our research has contributed to the understanding of the molecular mechanisms of circadian clock regulation (Neuron 2008; Curr Bio 2010; Nucleic Acids Res 2014; PLoS Genetics 2020; eLife 2022) as well as the pharmacological resetting potentials of clock-acting compounds (J Cell Sci 2008; J Pharmacol Exp Ther 2009; PNAS 2010). Our more recent interest is the interface between circadian biology and extracellular matrix homeostasis in the context ageing and age-related disease, including osteoarthritis (Arthritis & Rheum 2013; Osteoarthritis & Cartilage 2015; J Clin Invest 2016; Nat Rev Rheum 2016; Osteoarthritis & Cartilage 2021; Sci Advances 2022), intervertebral disc degeneration and back pain (Annals Rheum Dis 2017; Annals Rheum Dis 2021), collagen secretion, fibrosis and tendinopathies (Sci Rep 2014; Genes & Dev 2014; Nature Cell Biology 2020) and breast cancer (Nature Comms 2017; J Cell Sci 2018, Breast Cancer Res 2018; J Cell Sci 2019).