Mechanisms of aging in the naked mole-rat: The case for programmed aging

Abstract

Maximum lifespan is an important species trait that generally scales with body size. Never the less there are many mammals that deviate from this allometric relationship and live more than double the expected lifespan predicted on the basis of body size. These exceptionally long-lived species appear to defy the expected rate of aging and provide powerful tools with which to elucidate if maximum species lifespan is indeed encoded in the genome; determine possible biological clocks and their downstream molecular mechanisms that may abrogate or regulate rates of aging. One such mammal is the naked mole-rat [NMR]. This, the longest-lived rodent known, lives 8.6-times longer than similar-sized mice, yet it maintains cancer-free, good health for more than 85% of its astonishing 30-year lifespan. NMRs, like other long-lived species, show pronounced resistance to most cellular stressors. This may be due to enhanced cellular protection and/or better maintenance of somatic integrity. In contrast, short-lived species generally direct many of their resources into rapid growth and early reproduction rather than fend off threats to their soma. Although the mechanisms facilitating this species divergence in somatic maintenance are poorly understood, these most likely represent an evolutionary trade-off between partitioning energy and resources into somatic maintenance (thereby contributing to the survival of the individual) versus investments in growth and reproduction and ensuring the rapid attainment of sexual maturity and the long-termsurvival of the species. This species-specific difference in resource and somatic management must be encoded in the genome, thus enabling cells and the organism to mount the appropriate level of cytoprotection, commensurate with their expected longevity. We explore this premise by reevaluating the various theories of aging in the light of what is known from the biology of the longest-living rodent, the naked mole-rat.