"The ageing process is inexplicably linked to bone loss. This skeletal deterioration occurs in both sexes across all ethnic backgrounds and as such represents a major healthcare challenge worldwide. By increasing our understanding of how the ageing process impacts physiological systems, we can begin to develop novel therapeutics for the prevention and treatment of age-related disorders, such as osteoporosis and arthritis. We propose that common factors exist that control both Ageing and Bone and so link increasing age with a generalised decrease in bone mass. The sirtuin family of longevity associated genes regulate lifespan in lower organisms. SIRT1 is the predominant mammalian sirtuin, is strongly linked to cell survival and proliferation and regulates factors common to both ageing and bone. Recently we have made the novel discovery that SIRT1 expression declines with age and mice deficient in the SIRT1 gene have decreased bone mass and strength, similar to that seen in ageing humans. This decreased bone volume was the result of an uncoupling of the equilibrium between osteoclastic resorption and osteoblastic bone formation, a fundamental mechanism in the onset of osteoporosis. Moreover, SIRT1 expression can be induced and age-related bone loss prevented by the use of a strict dietary regime, suggesting common mediators in bone homeostasis and energy metabolism. Our overall hypothesis is that SIRT1 links diet and bone remodeling to preserve bone mass with age and control musculoskeletal deterioration. Specifically, this application will assess the role of SIRT1 in human bone tissue, stem cell commitment, bone cell function and microstructural, compositional properties of the skeleton. In addition, mechanistic studies will explore SIRT1 interactions with target proteins and the effect of dietary regimes will be examined in both human and murine skeletal tissues, to increase SIRT1 and protect against the musculoskeletal damage universally associated with ageing."
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