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与寿命较短的哺乳动物物种的反应，探讨了延长寿命和延缓衰老的机制。三个现有的范式老化（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）将进行评估，通过比较已知的最长寿的啮齿动物（裸molerat（NMR），Heterocephalus glaber）与不同的最大寿命潜力（MLSP）的几个物种的反应。将比较具有不同MLSP的密切相关和遗传学上不同的物种。这种多物种评估将阐明，如果共享的特征反映系统发育的共性，生态位，或者更确切地说，如果共同的衰老机制在长寿的生物体是显而易见的。我们将使用一个综合的比较方法，采用器官，生物化学和遗传技术。有趣的初步数据表明，核磁共振是一个很好的新模型，用于探索调节衰老速度的机制。NMR是小鼠大小（约35 g）的啮齿动物，其寿命比按质量预测的寿命长10倍（> 28.3年），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减弱。无论是静息还是峰值代谢率的NMR下降随着年龄的增长，使裸鼹鼠的一生的能量消耗相比，其他物种，包括人类，是例外。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。 虽然NMR的抗氧化防御能力大于寿命较短的小鼠，但令人惊讶的是，与年轻小鼠相比，年轻NMR中的氧化损伤（如迄今为止通过脂质过氧化所示）要大得多。高水平的氧化损伤推断NMR不产生较少量的活性氧物质，也不具有上级抗氧化防御机制来降低氧化损伤累积速率，而是它们可能对氧化应激极其耐受。NMR AGEs相对较低，不随年龄变化。迄今为止，微阵列数据显示，NMR RNA具有足够的质量用于阵列杂交，并且与小鼠相比，某些基因似乎始终过表达。核磁共振数据将与其他地下密切相关的鼹鼠和遗传学上不同的金鼹鼠以及实验室小鼠和蝙蝠进行比较。这些物种间的对比涉及七个寿命不同的物种，将被用来测试衰老的近似理论的普遍性。

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.