Stochastic aspects of aging (5 of 11)

Project: Research project

Project Details


All biological systems are subject to stochastic variation. In mammals this is obvious from the large individual
variation 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 in
gene expression within a cell population have been demonstrated in bacteria and yeast. To some extent this
is inherent to the nature of the processes of information transfer, especially at small numbers of mRNA or
protein products per cell. However, noise at the molecular level can also have external causes, varying from
random damage to the genome to variability in regulatory signals. While sometimes advantageous, i.e., in
development and evolution, increased Stochasticity in aging is generally viewed as having detrimental effects
on 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 epigenetic
changes in cells, and that cells and organisms possess a variety of genetic pathways and cellular responses
to mitigate or buffer against unduly large stochastic changes. We will test this hypothesis in two specific
aims. First, we will comparatively analyze four different model systems of aging, nematodes, fruit flies, mice
and human cells, for mutation accumulation at a similar lacZ reporter construct. We will also investigate how
such genome level Stochasticity depends on genetic factors known to cause aging-related
neurodegenerative disease, how it differs between human and mouse cells and how it can be modulated by
genetic factors. Second, we will directly measure transcriptional noise levels in mouse neurons and neuronal
stem cells during aging and in model systems for human neurodegenerative diseases. In parallel, we will
study similar transcriptional noise in human and mouse fibroblasts in different genetic backgrounds and
among individual nematodes during aging. We expect that the proposed study will provide a new dimension
to existing paradigms in the field by defining the role of Stochasticity in aging phenotypes and identifying the
genetic and biochemical mechanisms that influence it.
Effective start/end date9/30/076/30/12


  • Genetics
  • Molecular Biology
  • Statistics and Probability


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