Gregg, Siobhan
(2012)
Endogenous DNA damage drives cellular senescence and promotes aging.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Global populations are shifting, and the number of individuals over the age of 60 is rapidly increasing. People of advanced age (>60 years old) are at risk for several chronic degenerative diseases. In order to improve the quality of life for the elderly living with age-associated diseases, and to minimize medical costs associated with an aging global population, it is critical to understand the molecular mechanisms that underlie aging.
Aging is characterized as the loss of tissue function and the decreased ability to maintain homeostasis, which leads to an increased risk of morbidity and mortality. The time-dependent accumulation of damage to cellular macromolecules is hypothesized to contribute to age-related decline. However, there is no consensus about the type(s) of damage that drive aging. There is evidence to support the hypothesis that DNA damage plays a causative role in aging. This includes mice and humans with defective DNA repair that exhibit symptoms of accelerated aging. Additionally, DNA damage can induce cellular senescence, and senescent cells are thought to contribute to age-associated functional decline. However, direct causal relationships between senescence and aging, and DNA damage and aging have yet to be established.
The overall goal of this thesis was to address these gaps in knowledge. This required the testing of two hypotheses. First, that the accelerated aging seen as a consequence of defects in DNA repair is similar to normal aging at the molecular, cellular and whole tissue level. Second, that spontaneous DNA damage that occurs in cells is sufficient to drive cellular senescence. To test these hypotheses, I employed a genetic approach, utilizing mice and primary cells that were engineered to be defective in the DNA repair endonuclease, ERCC1-XPF. Hence, mice and cells with reduced expression of ERCC1-XPF accumulate a variety of DNA lesions compared to wild type mice and cells. This thesis is divided into two main sections, which take an in vivo and in vitro approach to testing the hypothesis that endogenous DNA damage can promote aging.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
6 January 2012 |
| Date Type: |
Publication |
| Defense Date: |
4 November 2011 |
| Approval Date: |
6 January 2012 |
| Submission Date: |
6 January 2012 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
123 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cell Biology and Molecular Physiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cell biology, aging, DNA damage |
| Date Deposited: |
06 Jan 2012 14:01 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10876 |
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