Mechanisms of Aging in the Long-lived Naked Mole-Rat

描述（由申请人提供）：通过比较寿命极长的物种和寿命较短的哺乳动物物种的反应，探索延长寿命和延缓衰老的机制。通过比较已知最长寿啮齿动物（裸鼹鼠（NMR）、异头鼠（Heterocephalus glaber））与不同最大寿命潜力（MLSP）物种的反应，将评估现有的三种衰老范式（即氧化损伤理论、晚期糖基化终产物（AGE）理论和长寿基因表达理论）。将比较具有不同MLSP的亲缘关系密切的和系统发育上不同的物种。这种多物种评估将阐明共同特征是否反映了系统发育的共性、生态位，或者更确切地说，长寿生物体中共同的衰老机制是否显而易见。我们将采用综合比较方法，采用有机、生化和遗传技术。有趣的初步数据表明，核磁共振是探索调节衰老速率机制的一个极好的新模型。NMRs是老鼠大小（约35g）的啮齿动物，其寿命是按质量预测的10倍（约28.3岁），在其一生中继续繁殖，并表现出与年龄相关的生理功能下降。nmr的静息率和峰值代谢率都不会随着年龄的增长而下降，因此裸鼹鼠一生的能量消耗与其他物种（包括人类）相比是例外的。因此，这些动物可能暴露于相当大的氧化损伤和血糖应激，并可能表现出增强的抗衰老防御机制。

DESCRIPTION (provided by applicant): 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.