Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction.
Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction.
复制标题
DOI：
10.7554/elife.10956
复制
发表时间：
2016-02-16
期刊：
影响因子：
7.7
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Regan JC;Khericha M;Dobson AJ;Bolukbasi E;Rattanavirotkul N;Partridge L
女性平均寿命比男性长，但晚年发病率更高。我们已经发现了果蝇衰老肠道病理上的实质性性别差异。在肠干细胞（ISC）分裂的驱动下，老年女性的肠上皮经历了严重的退化，而男性的ISC活性较低与病理延迟或无病理，以及更好的屏障功能有关，即使在老年。雄性屈服于雌性抵抗的肠道挑战，与较少增殖的ISCs有关，这表明在高度活跃的修复机制和雌性晚年病理之间存在权衡。饮食限制可以减少衰老女性的肠道病理，并且比男性更能延长女性的寿命。通过特定肠道区域的基因性别逆转，我们在男性中诱导了类似女性的衰老病理，与寿命减少有关，但也与饮食限制的寿命增加有关。DOI: http://dx.doi.org/10.7554/eLife.10956.001女性比男性寿命更长，许多与年龄有关的疾病在一种性别中比另一种性别更常见。此外，一些延长实验动物健康寿命的治疗方法对雌性比雄性更有效。其中包括饮食限制，即食物或特定的饮食成分供应不足。干细胞可以帮助修复老化和受损的组织，因为当它们分裂时，它们可以形成一个细胞，可以分化成几种成熟细胞类型中的一种。先前对黑腹果蝇的研究表明，肠道中干细胞的活性会影响雌性果蝇的寿命。现在，Regan等人详细研究了雄性和雌性果蝇随着年龄增长的内脏。这表明，随着果蝇年龄的增长，雌性肠道会恶化，因为肠道中的干细胞分裂更频繁，形成小肿瘤。这些干细胞帮助年轻女性生长和修复她们的肠道，但随着年龄的增长，它们开始与肠道作对。相比之下，男性的内脏保持得很好，不会显示出同样的衰老迹象。吃得少的女性的肠道衰老得更慢，这表明她们在限制饮食的情况下可能会活得更长，因为这能改善她们的肠道健康。Regan等人随后利用一种基因技巧让雄性果蝇拥有雌性的内脏。这些雌性化的雄性比正常的雄性有更多的肠道肿瘤，但它们在限制饮食时也表现出更大的寿命延长，因为它们老化的肠道状况较差，意味着饮食有更多的空间来改善它们的健康。那么，如果肠道恶化不会限制男性寿命，那么男性的死因是什么呢？追求这个问题可能最终帮助我们了解人类寿命如何受到性别差异的影响，并开发出每个人都能从中受益的衰老和与年龄有关的疾病的治疗方法。DOI: http://dx.doi.org/10.7554/eLife.10956.002
Women live on average longer than men but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the aging gut in Drosophila. The intestinal epithelium of the aging female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in aging females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like aging pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction. DOI: http://dx.doi.org/10.7554/eLife.10956.001 Women live longer than men, and many age-related diseases are more common in one sex than the other. In addition, some treatments that extend the healthy lifespan of laboratory animals are more effective in females than in males. These include dietary restrictions, where food or specific dietary constituants are kept in short supply. Stem cells can help to repair old and damaged tissue because, when they divide, they can form a cell that can specialize into one of several mature cell types. Previous studies of the fruit fly Drosophila melanogaster have shown that stem cell activity in the gut affects how long female flies live. Now, Regan et al. have looked in detail at the guts of male and female fruit flies as they age. This revealed that female guts deteriorate as the flies grow old because the stem cells in the gut divide more often and form small tumours. These stem cells help young females to grow and repair their guts, but start to turn against them as they age. In contrast, male guts stay well maintained and do not show the same signs of ageing. Females fed less food had guts that aged more slowly, suggesting they might live longer on a restricted diet because it improves their gut health. Regan et al. then used a genetic trick to make male flies with female guts. These feminized males had more gut tumours than normal males, but they also showed a greater increase in lifespan when placed on a restricted diet, because the poorer condition of their ageing gut meant there was more scope for the diet to improve their health. So if gut deterioration does not limit male lifespan, what do males die of? Pursuing this question may ultimately help us to understand how human lifespans are affected by sex differences and develop treatments for ageing and age-related diseases that everyone can benefit from. DOI: http://dx.doi.org/10.7554/eLife.10956.002