Longevity, genes, epigenetics, cancer and disease

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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.

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connie dello buono

Health educator, author and enterpreneur motherhealth@gmail.com or conniedbuono@gmail.com ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at www.clubalthea.com Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at quora.com and posts in this site.

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