Biological clocks regulate organism physiology and behavior. The circadian clocks are one class of such clocks, which generate 24 hr rhythms in order to adapt to 24-hour light/dark cycle. It was known for years that the circadian system controls many behavioral processes such as daily locomotor activity and sleep/wake cycle. What was emerging over last years is that the circadian clock is key regulator of metabolism, cardiovascular physiology, immune and stress response systems.Our laboratory was instrumental in establishing a connection between the circadian clock and aging.
We have reported that knockout of the key circadian protein BMAL1 results in syndrome of early aging in mice - the significantly reduced life span (9 months for knockout vs. 28 months for wild type animals) and the development of multiple age-related pathologies (such as sarcopenia, osteoporosis, reduction of subcutaneous adipose tissue, decreased hair growth, cataracts, cornea inflammation, etc.).
Being a transcriptional factor, BMAL1 may orchestrate or influence many metabolic pathways in the organism. Therefore, different mechanisms may be responsible for aging and for the development of particular pathologies in BMAL1 deficient animals. Currently we have several projects related to the study the role of BMAL1 and circadian clock in the regulation of aging. One direction is study of aging associated signaling pathways such as TOR signaling pathways, Sirtuin signaling pathway and insulin-like growth factor/insulin-like growth factor receptor (IGF/IGFR) pathway. All these pathways play important role in cell metabolism and proliferation and organism response to nutrients and stress. These pathways are tightly regulated and disruption of the regulation is the major determinant of aging and age-related pathologies.
Another interest of the laboratory is circadian clock dependent mechanisms of dietary restriction. Dietary restriction and calorie restriction particularly is one of the most powerful interventions, which extend longevity in different organisms including mammals. We found that calorie restriction significantly affect circadian rhythms in gene expression and that functional circadian clock is necessary for lifespan extension by calorie restriction.
Stem cell homeostasis is implicated in the control of aging. We are concentrated on circadian clock mechanisms in mesenchymal stem cells and, specifically, on the role of clock proteins in osteoblast differentiation. This research will help to establish involvement of the circadian clock in such age associated pathology as osteoporosis.