Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production
Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production
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DOI：
10.1073/pnas.111158898
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发表时间：
2001-06-05
影响因子：
11.1
通讯作者：
Harrison, DE
中科院分区：
文献类型：
--
作者：
Flurkey, K;Papaconstantinou, J;Harrison, DE
延长寿命的单基因突变为探索细胞和组织功能中与年龄相关的变化的分子基础以及年龄依赖性疾病的病理生理学提供了宝贵的工具。我们在这里表明，在Pit 1（斯内尔侏儒）基因座上功能丧失突变的纯合子小鼠在相对长寿的（C3 H/HeJ x DW/J）F-1背景下显示出> 40%的平均和最大寿命增加。突变dw（J）/dw动物显示年龄依赖性胶原交联延迟和免疫系统状态的六个年龄敏感指数延迟。因此，这些发现表明，单个基因可以控制哺乳动物的最大寿命以及细胞和细胞外衰老的时间。将P2P移植到侏儒小鼠中并不逆转寿命效应，这表明该效应不是由于催乳素水平降低，相反，Ghrhr（lit）突变的纯合性，其像Pit 1（dw）突变一样降低血浆生长激素水平，确实导致寿命显著增加。与热量限制的小鼠不同，雄性斯内尔侏儒小鼠在老年时变得肥胖，并表现出相应的高瘦素水平，这表明它们的长寿不仅仅是由于肥胖本身的改变。对Pit 1（dw）突变体和密切相关的长寿Prop-1（df）（艾姆斯侏儒）突变体的进一步研究，将为衰老、长寿和晚年疾病的激素调节提供新的见解。
Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a > 40% increase in mean and maximal longevity on the relatively long-lived (C3H/HeJ x DW/J)F-1 background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels, In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.