Enhanced longevity associated with altered ribosome function

2012 senior Scholar Award in aging

The use of simple model organisms for aging such as yeast, worms and flies has driven the aging field forward and been instrumental for the identification of cellular pathways that modulate the aging process. From work in my lab and many others, a set of conserved aging genes have been identified, whose reduced expression leads to lifespan extension across unrelated species. Recently this has been shown for ribosomal protein genes in worms and yeast, with similar data starting to emerge in flies. Ribosomal proteins participate in translation, the critical process by which RNA is made into proteins that are responsible for most cellular functions. Our data indicate that yeast cells with reduced levels of certain ribosomal proteins have enhanced lifespan through altered translation of key regulatory proteins. Similarly, reduced levels of an overlapping subset of ribosomal proteins leads to lifespan extension in worms. This is exciting because protein translation is also controlled by two of the major pathways linked to aging: the insulin/IGF and mTOR pathways. Rapamycin, a drug that inhibits mTOR, extends lifespan and healthspan (the healthy and chronic disease-free period of life) in mice. In this proposal, we seek to understand the mechanisms by which these proteins control aging and to study mouse models that we have generated to test if this mechanism of longevity regulation occurs in mammals. We will test whether mouse mutants with reduced levels of related ribosomal protein genes are long-lived and if they are resistant to age-related chronic diseases. If this proves to be the case, it may be possible to develop therapeutic modulation of ribosome composition or function in a manner that extends healthspan and/or delays the progression of age-related chronic disease states.

Brian Kennedy Ph.D.
Buck Institute for Research on Aging