Lifespan extension by preserving proliferative homeostasis in Drosophila.
Lifespan extension by preserving proliferative homeostasis in Drosophila.
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DOI：
10.1371/journal.pgen.1001159
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发表时间：
2010-10-14
期刊：
影响因子：
4.5
通讯作者：
Jasper H
中科院分区：
文献类型：
--
作者：
Biteau B;Karpac J;Supoyo S;Degennaro M;Lehmann R;Jasper H
再生过程对于维持高周转组织中的组织稳态至关重要。同时，必须仔细控制干细胞和祖细胞的增殖，以防止过度增殖性疾病。确保这种平衡的机制，从而促进增殖的稳态，预计是在后生动物的长寿的关键。果蝇的肠上皮提供了一个可访问的模型来测试这一预测。在衰老的果蝇中，由于肠干细胞（ISC）的过度增殖和ISC子细胞的错误分化，导致肠上皮退化，导致肠发育不良。在这里，我们表明，损害组织更新的条件导致寿命缩短，而基因操作，提高增殖稳态延长寿命。这些包括胰岛素/IGF或Jun-N-末端激酶（JNK）信号传导活性降低，以及体干细胞谱系中应激保护基因的过度表达。有趣的是，在一系列基因型中，老化肠上皮细胞的增殖活性与寿命相关，当肠增殖减少但未完全抑制时，寿命最长。我们的研究结果强调了再生过程和预防过度增殖性疾病的策略之间的平衡的重要性，并表明促进衰老后生动物的增殖稳态是延长寿命的可行策略。体细胞干细胞对于许多组织的再生至关重要，从而确保组织功能的长期维持。然而，必须限制干细胞和祖细胞的增殖，以防止衰老动物的过度增殖性疾病和癌症。对干细胞增殖潜力的需求和癌症预防之间的这种冲突损害了包括人类在内的衰老动物的许多高周转组织的再生。它仍然有待建立是否以及如何增殖稳态可以优化，以积极影响寿命。我们的工作解决了这个问题，使用果蝇作为模型，利用最近发现的再生过程中的成年苍蝇。在老年果蝇中，肠干细胞（ISCs）过度增殖，导致错误分化的子细胞（称为肠发育不良的表型）的积累。我们表明，该组织的再生和发育不良之间的平衡显着影响寿命。当ISC增殖率降低，但没有完全抑制，发育异常是有限的，寿命增加。这可以通过适度减少胰岛素和应激信号传导活动以及通过在体干细胞谱系中表达保护性蛋白来实现。我们的研究结果表明，优化高周转组织中的增殖稳态（即限制发育不良，但允许充分再生）是延长寿命的有效策略。
Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan. Somatic stem cells are critical for regeneration of many tissues, thus ensuring long-term maintenance of tissue function. Proliferation of stem and progenitor cells has to be limited, however, to prevent hyperproliferative diseases and cancer in aging animals. This conflict between the need for stem cell proliferative potential and cancer prevention compromises regeneration in many high-turnover tissues of aging animals, including humans. It remains to be established whether and how proliferative homeostasis can be optimized to positively influence lifespan. Our work addresses this question using fruitflies as a model, taking advantage of the recent discovery of regenerative processes in adult flies. In old flies, intestinal stem cells (ISCs) hyperproliferate, causing an accumulation of mis-differentiated daughter cells (a phenotype termed intestinal dysplasia). We show that the balance between regeneration and dysplasia in this tissue significantly influences lifespan. When ISC proliferation rates are reduced, but not completely inhibited, dysplasia is limited and lifespan is increased. This can be achieved by moderately reducing insulin and stress signaling activities, as well as by expressing protective proteins in somatic stem cell lineages. Our results show that optimizing proliferative homeostasis (i.e. limiting dysplasia, but allowing sufficient regeneration) in high-turnover tissues is an efficient strategy to extend lifespan.
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