Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination

Abstract

Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do / do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres / telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic / cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence of telomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging.

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…From an evolutionary point of view, short telomeres and repressed telomerase (as in human somatic tissues) have been suggested to co‐evolve with homeothermy and replicative aging in mammals (Gomes et al ., 2011), while p66SHC with the metabolic adaptation to harsh energetic environments (i.e., food deprivation and cold temperature) (Giorgio et al ., 2012). In this view, the relative healthier aging of TERC −/− p66SHC −/− compared to TERC −/− p66SHC +/+ mice suggests that the cost to pay for having a plastic metabolism (as ensured by p66SHC) is to amplify the negative effect of telomere erosion on body size and fertility.…”

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

“…Based on telomere length, the use of mouse models for studying physiological aging particularly in regard to the role of telomeres in aging is a matter of debate (Wright & Shay, 2000; Gomes et al ., 2011). Age‐related telomere shortening and its consequences cannot be studied effectively in normal aging mice.…”

The Regulation of Telomerase by Alternative Splicing of TERT

“…In rodents telomerase activity inversely correlates with body mass (Gorbunova & Seluanov, 2009). Recently, an exhaustive analysis of telomerase activity and telomere length in mammals has been reported (Gomes et al, 2011). This analysis revealed striking differences among major mammalian groups.…”

“…However, species can be divided into two groups according to their telomere length, one group with the average telomere length below and the second above 20 kb (Gomes et al, 2011). The average length of telomeres in quail, chicken, and duck was determined and compared to human and mouse by terminal restriction fragment (TRF) analysis (Fig.…”