Program in mammalian telomere biology

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The ends of mammalian chromosomes contain variable numbers of TTAGGG repeats. In many species this telomeric DNA is lost due to the end replication problem, as normal somatic cells replicate. When cells lose sufficient telomeric DNA, a DNA damage signal is generated, activating the ATM kinase and p53 transcription factor to block the cell cycle and induce cell replicative senescence. Senescence is thought to serve as a barrier to cell immortality and abnormal cell growth since it limits cell replicative capacity. However, short telomeres also result in genetic instability leading to a variety of diseases and large correlational studies have linked short telomeres to high rates of cell transformation. Short telomeres are also associated with early mortality, suggesting that telomere length might contribute to determining lifespan. Studies of monozygotic and dizygotic twins and elderly populations have yielded conflicting results, leaving the question of whether telomere length per se affects life span, controversial.******Use of the best mammalian genetic model, mice, cannot address this issue because the dynamics of rodent telomeres differ significantly from those of most mammals including humans. We previously found that males lose telomere sequence faster than females and that telomere length in children correlates to the age of fathers at conception, providing some clues about how telomere length is set in the human population and why telomere length varies so widely in humans. However, study of human samples has limitations based on genetic and ethical considerations. ******We observed a strong correlation between telomere length and lifespan in a subset of the ~200 inbred dog breeds with average lifespans ranging from 5-14 years (Fick et al, Cell Reports, 2012). Our observations were possible due to the high linkage disequilibrium in dog breeds, and have provided what may be the strongest evidence to date that telomere length contributes to determining lifespan in species where telomere attrition causes cell senescence. This proof-of-principle study in canines has laid the foundation for using primary canine cell strains to test the hypothesis that cells from different breeds will divide a number of times that is proportional to the average breed lifespan, and that factors can be identified that regulate telomere dynamics in normal diploid cells.******Our long-term goals are to use a subset of dog breeds to:***-establish and characterize a set of primary canine cell strains.***-use them to ask if telomere length and replicative lifespan affects organismal lifespan***-identify candidate endogenous factors that regulate telomere length, and***-target these factors to see if they selectively increase or decrease cell replicative lifespan or organismal lifespan.******Once the canine model is established we will make it freely available to others working in the area of cellular aging to accelerate understanding of this area.