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：
6804442
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）：通过将极其长寿命的物种与较短的哺乳动物物种的反应进行比较，可以探索增强寿命和衰老衰老的机制。 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).将比较与MLSP发散的密切相关和系统发育不同的物种。这种多种种类评估将阐明共享特征是否反映了系统发育共同点，生态位，或者是否明显看出了长寿生物的常见衰老机制。我们将采用采用生物化学，生化和遗传技术的综合比较方法。有趣的初步数据表明，NMR是探索调节衰老率的机制的绝佳新模型。 NMR是慕斯（约35克）的啮齿动物，其寿命比质量（> 28.3岁）的预测长10倍，在生理功能上继续繁殖，并表现出与年龄相关的减弱。 NMR的休息和峰值代谢率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mole鼠的寿命能量消耗是例外。因此，这些动物可能会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。尽管NMR的抗氧化剂防御能力大于较短的小鼠的抗氧化能力，但与年轻小鼠相比，年轻的NMR中令人惊讶的是氧化损伤（迄今为止通过脂质过氧化）的抗氧化损伤（如迄今为止所示）要大得多。高水平的氧化损伤推断，NMR不会产生较小量的活性氧，也没有具有优质的抗氧化剂防御机制来降低应计的氧化损伤速率，而是对氧化应激的耐受性可能极为耐受。 NMR年龄相对较低，并且不会随着年龄的增长而变化。迄今为止，微阵列数据表明，NMR RNA具有足够的质量用于阵列杂交，并且与小鼠相比，某些基因似乎始终如一地表达。除实验室小鼠和蝙蝠外，还将将NMR数据与其他地下密切相关的痣和系统发育不同的金痣进行比较。这些涉及七个具有不同寿命的物种的种间对比将用于检验衰老的近端理论的普遍性。