Telomere lengthening to antagonize myocardial aging

Aging is associated with onset and progression of cardiovascular disease resulting from changes at both cellular and molecular levels. Accumulation of senescent cells in the myocardium has been implicated in deterioration of hemodynamic performance and impaired reparative processes. Cellular senescence can be linked to oxidative stress and repeated cellular divisions, both of which lead to telomeric shortening. Telomeres are the distal ends of chromosomes that consist of nucleotide repeats that function to protect important DNA from damage. Cells with critically short telomeres become senescent and are no longer able to divide, making them more likely to undergo apoptosis. Telomeres are protected from shortening by multiple factors that protect the structure as well as regulate access to the telomere by telomerase (TERT), the enzyme responsible for telomere elongation. Maintenance of telomeres depends upon coordination of multi-molecular complexes that can be thought of as regulators of the "cellular clock" defined by telomeric length and tied to the aging phenotype. Myocyte replacement occurs throughout the mammalian lifespan and is thought to be dependent in part upon a cardiac progenitor cell (CPC) pool, the onset of senescence in the CPC population has been postulated to play a role in progressive structural and functional deterioration of the aged myocardium. Our lab has recently identified a serine/ threonine kinase named Pim-1 to be protective in the heart downstream of the nodal kinase Akt¹· ². While investigating the functions of this newly found cardiac kinase we found that cardiomyocytes (CMs) as well as CPCs overexpressing Pim-1 had the ability to repeatedly divide in vitro and in vivo. The increased mitotic activity did not result in genetic instability, the cells maintained the ability to cycle several passages and still differentiate into the appropriate cardiac cell types. The goal of this study was to demonstrate that preservation of telomeres and a more youthful phenotype in CPCs is mediated by the cardioprotective kinase Pim-1. Herein we demonstrate that telomeres are rapidly lengthened with Pim-1 overexpression in CPCs and CMs, which coincides with increased proliferation in CPCs. Mechanistically, we find that Pim-1 dependent telomere lengthening results from interactions with TERT and is also dependent upon c-Myc activity. In vivo telomere length is preserved by Pim-1 activity in response to cardiomyopathic stimuli and is coincident with enhanced TERT activity. Mechanisms maintaining or lengthening telomeres can serve as a "fountain of youth," allowing cells to sustain a young phenotype and fight against the diseases commonly associated with cardiovascular dysfunctio