Mechanisms that enhance longevity and retard senescence are explored by comparing responses of an extremely long-lived species with those of shorter4ived mammalian species. Three existing paradigms of aging (namely the oxidative damage theory, the advanced glycation end product (AGE) theory and the longevity gene expression theory) will be evaluated by comparing responses of the longest-lived rodent known (the naked molerat (NMR), Heterocephalus glaber) with those of several species with disparate maximum life span potential (MLSP). Both closely-related and phylogenetically distinct species with divergent MLSP will be compared. This multi-species assessment will elucidate if shared traits reflect phylogenetic commonality, ecological niche, or rather if common aging mechanisms in long-lived organisms are evident. We will use an integrated comparative approach employing organismic, biochemical and genetic techniques. Intriguing preliminary data suggest that the NMR is an excellent new model for exploring mechanisms regulating the rate of aging. NMRs are mousesized (approximately 35g) rodents that live ten times longer than predicted by mass (>28.3y), continue to breed throughout their lives, and exhibit attenuated age-related declines in physiological function. Neither resting nor peak metabolic rates of NMRs decline with age so that lifetime energy expenditure of naked mole-rats, when compared to other species, including humans, is exceptional. These animals are thus potentially exposed to considerable oxidative damage and glycemic stress and may exhibit enhanced anti-aging defense mechanisms. While antioxidant defense capacity of NMRs is greater than that of shorter-lived mice, surprisingly oxidative damage (as indicated, to date, by lipid peroxidation), is considerably greater in young NMRs compared to young mice. High levels of oxidative damage infer that NMRs do not generate smaller amounts of reactive oxygen species, nor do they have superior anti-oxidant defense mechanisms to reduce the rate of oxidative damage accrual, but rather they may be extremely tolerant of oxidative stress. NMR AGEs are comparatively low and do not change with age. Microarray data, to date, reveal that NMR RNA is of sufficient quality for array hybridization, and that certain genes appear to be consistently over-expressed compared to mice. NMR data will be compared with other subterranean closely-related mole-rats and phylogenetically distinct golden moles in addition to laboratory mice and bats. These inter-species contrasts involving seven species with varying longevity will be used to test the ubiquity of proximate theories of aging.
Showing the most recent 10 out of 38 publications
