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

描述(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。现有的三种衰老理论(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)将通过比较已知的最长寿啮齿动物(裸鼹鼠)和几个具有不同最大寿命潜力(MLSP)的物种的反应来进行评估。我们将比较具有不同MLSP的亲缘关系密切和系统发育不同的物种。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同性、生态位，或者更确切地说，是否明显地反映了长寿生物体的共同衰老机制。我们将使用一种综合比较的方法，采用有机、生化和遗传技术。耐人寻味的初步数据表明，核磁共振是探索衰老速度调节机制的极佳新模型。NMR是小鼠大小(约35克)的啮齿动物，寿命是质量预测的十倍(28.3y)，在他们的一生中继续繁殖，并表现出与年龄相关的生理功能下降。NMR的静息代谢率和峰值代谢率都不会随着年龄的增长而下降，因此与包括人类在内的其他物种相比，裸鼠一生的能量消耗是异常的。因此，这些动物可能暴露在相当大的氧化损伤和血糖应激下，并可能表现出增强的抗衰老防御机制。 虽然NMRS的抗氧化防御能力比寿命较短的小鼠更强，但令人惊讶的是，年轻NMRS的氧化损伤(迄今表明，是通过脂质过氧化)比年轻小鼠大得多。高水平的氧化损伤表明，NMR不会产生较少的活性氧物种，也没有优越的抗氧化防御机制来降低氧化损伤的累积速度，而是可能对氧化应激具有极强的耐受性。核磁共振年龄相对较低，不随年龄变化。到目前为止，微阵列数据显示，核磁共振RNA具有足够的质量用于阵列杂交，并且与小鼠相比，某些基因似乎持续过度表达。核磁共振数据将与其他地下密切相关的鼹鼠和系统发育不同的金色鼹鼠进行比较，此外还将与实验室老鼠和蝙蝠进行比较。这些涉及七个寿命不同的物种的物种间对比将被用来测试近似性衰老理论的普遍性。

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.