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Genotoxic Stress Meets Mitochondria: Integrating Aging Mechanisms

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Air date: Wednesday, September 14, 2011, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
Views: Total views: 389 * This only includes stats from October 2011 and forward.
Category: WALS - Wednesday Afternoon Lectures
Runtime: 01:08:08
Description: The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signaling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders. Exploiting the experimental merits of the mouse, we have shown that telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues.

The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of PGC-1α and PGC-1β and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. This telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

The NIH Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.

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NLM Title: Genotoxic stress meets mitochondria : integrating aging mechanisms [electronic resource] / Ron DePinho.
Series: NIH Wednesday afternoon lecture series
Author: De Pinho, Ronald A.
National Institutes of Health (U.S.)
Publisher:
Other Title(s): NIH Wednesday afternoon lecture series
Abstract: (CIT): The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signaling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders. Exploiting the experimental merits of the mouse, we have shown that telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of PGC-1[alpha] and PGC-1[beta] and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1[alpha] and PGC-1[beta] promoters, thereby forging a direct link between telomere and mitochondrial biology. This telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
Subjects: Aging--genetics
Mitochondria--genetics
Neoplasms--genetics
Telomere--metabolism
Publication Types: Lectures
Webcasts
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Caption Text: Download Caption File
NLM Classification: QU 470
NLM ID: 101571682
CIT Live ID: 10501
Permanent link: https://videocast.nih.gov/launch.asp?16856

 

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