The genetic and molecular analysis of aging in model systems has made exceptional strides. Certain themes have emerged that appear to have broad applicability. In addition, the participation of mitochondria in aging has taken on new dimensions, and the realization that organelle integrity and cross-talk play a role in cellular aging, likely including stem cell aging, is becoming evident. The long-term objective of the proposed research is to exploit the yeast model system for a better understanding of these emerging insights, with the goal of ameliorating aging decline in humans. The pathway that signals mitochondrial dysfunction to the nucleus, called the retrograde response, will be examined in detail in terms of its activation during normal aging. This will include an analysis of the requirements of the retrograde response genes for the maintenance of life span as cells age. The association of the main branches of the retrograde response with extended life span will be examined. The interaction between retrograde and Ras2 signaling will be dissected at the molecular level, and the signal proximal to mitochondria that triggers the retrograde response will be identified. The mechanisms underlying mitochondria-based age asymmetry between mother and daughter cells will be characterized by studying partition of newly-synthesized mitochondrial material and organelle turnover. The effects of these mechanisms on life span will be determined. The novel cross-talk between mitochondria and peroxisomes, which plays a role in age asymmetry will be examined at the molecular level, and the extent to which additional features of age asymmetry operate will be examined using a genetic approach.
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