The survival of populations in developed nations into extreme old age is a remarkable phenomenon in human history. This change has come about largely through improved public hygiene, decreased child mortality and a decrease in infectious diseases. However, the steady increases in the average age of the population have resulted in an ever increasing burden of the degenerative diseases of aging, such as osteoporosis, Alzheimer's disease, diabetes and cancer. Currently, there are several mutually non-exclusive models to explain the mechanisms behind these degenerative aging processes. One theory is centered on the idea that replicative senescence of cells limits their proliferative capacity and hence tissue renewal. Other models suggest that accumulation of genetic and/or epigenetic (chromatin) damage with age eventually impairs cell and tissue function. In this application, we test a hypothesis that links two of these ideas - cellular senescence and epigenetics - to a pathway that has not previously been considered to be a major regulator of aging, namely, Wnt signaling. Although not widely viewed as a regulator of aging, the Wnt signaling pathway is well documented to be an evolutionarily conserved determinant of tissue and organismal development, and later in life, adult tissue homeostasis. The research proposed here is based on recent and exciting discoveries in the two collaborating laboratories. First, the work of Peter D. Adams (PDA) has implicated Wnt signaling in the regulation of cellular senescence by showing that in vitro - human fibroblast cell culture - repression of Wnt signaling triggers extensive heterochromatinization and cellular senescence. Second, the in vivo studies of John M. Sedivy (JMS) have found that a marked expansion of facultative heterochromatin occurs in association with cellular senescence and aging in mouse and primate tissues. Based on these results we propose that a Wnt-Chromatin-Senescence signaling axis is an important determinant of organismal aging. We propose here a series of experiments to initiate the investigation of this novel signaling axis, the mechanisms of its operation, and its role in organismal aging.
Aim 1 will perform high resolution, genome-wide mapping of senescence-associated changes in chromatin structure that are triggered by reduced Wnt signaling in vitro.
Aim 2 will investigate the links between Wnt signaling, heterochromatinization, cellular senescence and aging in vivo, using mouse, primate and human models.
Aim 3 will assess cellular senescence and genome- wide chromatin changes in mice harboring hypomorphic Wnt pathway mutations. Our goal is to use a discovery-based approach to reveal epigenome-wide characteristics of aging processes, functionally connect these with Wnt signaling pathways, and ultimately open the road to new pharmaceutical targets.
Aging is a fundamental biological process with a profound impact on society. An important aspect of aging is believed to be biological structures that are inherently difficult to maintain. Our genomes, which are compacted into a complex network of DNA and protein referred to as chromatin, are likely to be one such structure. This proposal will perform a global analysis of age-associated chromatin modifications and remodelling in mammalian organisms. These discoveries will advance our understanding of the basic processes of aging, as well as potentially uncover targets for pharmaceutical intervention to ameliorate age-related disorders.
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