All biological systems are subject to stochastic variation. In mammals this is obvious from the large individualvariation in life span and patterns of aging-related pathology, even in genetically homogeneous animals.Stochasticity is also apparent at the molecular level. Random molecular fluctuations creating variability ingene expression within a cell population have been demonstrated in bacteria and yeast. To some extent thisis inherent to the nature of the processes of information transfer, especially at small numbers of mRNA orprotein products per cell. However, noise at the molecular level can also have external causes, varying fromrandom damage to the genome to variability in regulatory signals. While sometimes advantageous, i.e., indevelopment and evolution, increased Stochasticity in aging is generally viewed as having detrimental effectson cellular function. The central hypothesis in this proposal is that oxidative stress, a likely cause of aging,increases stochastic variability of gene expression, that it does so by causing both genetic and epigeneticchanges in cells, and that cells and organisms possess a variety of genetic pathways and cellular responsesto mitigate or buffer against unduly large stochastic changes. We will test this hypothesis in two specificaims. First, we will comparatively analyze four different model systems of aging, nematodes, fruit flies, miceand human cells, for mutation accumulation at a similar lacZ reporter construct. We will also investigate howsuch genome level Stochasticity depends on genetic factors known to cause aging-relatedneurodegenerative disease, how it differs between human and mouse cells and how it can be modulated bygenetic factors. Second, we will directly measure transcriptional noise levels in mouse neurons and neuronalstem cells during aging and in model systems for human neurodegenerative diseases. In parallel, we willstudy similar transcriptional noise in human and mouse fibroblasts in different genetic backgrounds andamong individual nematodes during aging. We expect that the proposed study will provide a new dimensionto existing paradigms in the field by defining the role of Stochasticity in aging phenotypes and identifying thegenetic and biochemical mechanisms that influence it.
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