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

长寿裸鼹鼠的衰老机制

基本信息

批准号：
6944709
负责人：
ROCHELLE BUFFENSTEIN
金额：
$ 28.58万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2008-08-31
项目状态：
已结题

项目摘要

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.

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，探索延长寿命和延缓衰老的机制。将通过比较已知最长寿啮齿动物（裸鼹鼠（NMR）、异头鼹鼠）的反应来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） glaber）与具有不同最大寿命潜力（MLSP）的几个物种的物种。将比较具有不同 MLSP 的密切相关和系统发育不同的物种。这种多物种评估将阐明共同的特征是否反映了系统发育的共性、生态位，或者更确切地说，长寿生物体中的共同衰老机制是否明显。我们将采用有机、生物化学和遗传技术的综合比较方法。有趣的初步数据表明，核磁共振是探索衰老速率调节机制的绝佳新模型。 NMR 是小鼠大小（约 35 克）的啮齿动物，其寿命比预期寿命长十倍（> 28.3 年），在一生中持续繁殖，并表现出与年龄相关的生理功能衰退。核磁共振的静息代谢率和峰值代谢率均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，裸鼹鼠一生的能量消耗是异常的。因此，这些动物可能面临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 的抗氧化防御能力高于寿命较短的小鼠，但令人惊讶的是，与年轻小鼠相比，年轻 NMR 的氧化损伤（迄今为止表明，由脂质过氧化引起）要大得多。高水平的氧化损伤表明核磁共振不会产生少量的活性氧，也不具有卓越的抗氧化防御机制来降低氧化损伤的发生率，但它们可能对氧化应激具有极强的耐受性。 NMR AGE 相对较低，并且不随年龄变化。迄今为止的微阵列数据表明，NMR RNA 的质量足以进行阵列杂交，并且与小鼠相比，某些基因似乎始终过度表达。除了实验室小鼠和蝙蝠之外，核磁共振数据还将与其他地下密切相关的鼹鼠和系统发育上不同的金鼹鼠进行比较。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衰老的近似理论的普遍性。