Telomeres shorten with age in rat cerebellum and cortex in vivo

Abstract

Normal somatic cells have a finite replicative capacity. With each cell division, telomeres, the ends of linear chromosomes, progressively shorten until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell type in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. Previous research in our laboratory has found that telomeres shorten in rat microglia with increasing time in vitro. Our current hypothesis is that telomeres shorten in rat brain in vivo with increasing age. Tissue samples of cerebellum and cortex were obtained from Sprague-Dawley rats of various ages. Genomic DNA and total protein was isolated from each sample for telomere length measurement via Southern blot analysis (up to 5 months) and telomerase activity measurement via TRAP analysis (up to 6 months), respectively. Telomere shortening occurs in vivo in both rat cerebellum and cortex from day 21 to approximately 5 months of age. Cortex samples possessed shorter telomeres than did cerebellum samples. The longest telomeres undergo the most dramatic shortening, while the shortest telomeres exhibit only slight attrition. Telomerase activity slowly increases from day 21 to approximately 6 months of age, with the cerebellum exhibiting higher activity than cortex in all instances. These results indicate that telomere shortening occurs in rat brain in vivo with increasing age, and that the low levels of telomerase activity present may be preferentially recruited to maintain the shortest telomeres while allowing the longer ones to shorten more rapidly. Since microglia are thought to be the only mature cells of the postnatal CNS undergoing appreciable cell division, we propose that the telomere shortening occurring in the adult rat brain with age can be largely attributed to microglial cell division. Our findings provide an impetus to further investigate the pattern of telomere length and telomerase activity that emerges with further aging in the rat brain.