There is considerable interest in identifying molecular and physiological causes aging as these are likely to be risk factors for age-related disease and frailty. The causes of aging remain essentially unknown but we and others have highlighted stress as a principle component. We propose to uncover causes of aging by studying the genetic determinates of the lifespan of a simple animal model, Caenorhabditis elegans. Using this model, we wish to test the general hypothesis that the rate of aging is determined in part by stress response factors counteracting intrinsic stresses. In previous studies, we have extended C. elegans lifespan by genetic mutations and with superoxide dismutase/catalase mimetic drugs. The preliminary studies that have prompted this proposal indicate that an insulin/IGF-like signaling pathway that determines worm lifespan, co-ordinately regulates stress response genes. Our general strategy is to directly alter the levels of stress response proteins and measure the effects on normal lifespan. We will manipulate the expression of stress genes by three interventions. Firstly, we propose to construct transgenic worms that over-express individual molecular chaperone genes (heat shock protein(hsp)-16 and hsp-70) that are known to prevent the accumulation of damaged proteins during an acute stress. Secondly, we shall over-express transcriptional activators, such as heat shock factor, that are the co-ordinate regulators of stress response. Thirdly, we will identify and manipulate the levels of endocrine signals that act downstream of the insulin/IGF signaling pathway to limit lifespan.
Showing the most recent 10 out of 17 publications
