Air date: Wednesday, September 14, 2011, 3:00:00 PM Timedisplayed is Eastern Time, Washington DC Local Category: Wednesday Afternoon Lectures 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 ...

• published: 20 Sep 2011
• views: 2741
• author: nihvcast