The significant increase in the human lifespan during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine the rate of ageing. The sirtuins, and in particular the mammalian member SIRT6, are a family of NAD+ dependent deacetylases that were implicated in ageing and the regulation of metabolism. Much evidence correlates SIRT6 with the regulation of ageing, primarily the manifestation of ageing related pathologies in SIRT6 deficient mice, and the induction of SIRT6 by calorie-restricted diet that delays ageing and reduces its related diseases. Nonetheless, the role of SIRT6 in ageing and the mechanisms by which it might act are still elusive. To explore it at the molecular mechanistic level, SIRAID aims to i) study the role of SIRT6 in glucose and fat metabolism under high fat diet; ii) to determine whether SIRT6 is involved in regulating life span, and to characterise how SIRT6 is activated by calorie restriction; and iii) to perform large scale SILAC-based proteomics screening for SIRT6 substrates. These results will then be used for the development of small activator molecules of SIRT6 that may be used therapeutically for age related metabolic diseases. Taken together, we suggest a multifaceted approach that will allow us to explore the role of SIRT6 in ageing and metabolism, and to translate this knowledge to counter and prevent the medical problems associated with human longevity.
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