Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila

Abstract

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.

Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila

“…Structural and functional impairments within the intestinal epithelium have been reported in aged mammals (9) and Drosophila (10-13). Moreover, we (13) and others (14)(15)(16) have shown that the intestine represents an important target organ with respect to genetic interventions that promote longevity in both C. elegans and Drosophila (17). One interpretation of these findings is that maintaining intestinal integrity is an important determinant of health and viability at the organismal level; however, given that most assays of intestinal homeostasis are based on imaging techniques that require killing the flies (10-12), it has not been possible to determine how the onset of intestinal degeneration in individual flies relates to other aspects of aging and/or subsequent mortality.…”

Epigenetic regulation of aging stem cells

“…It will be interesting to determine whether the modulation of specific chromatin regulators can restore the proliferative and multipotential properties of stem cells and thereby ameliorate age-dependent tissue decline. Moreover, the relationship between stem cell function and organismal longevity has yet to be rigorously addressed in mammals, although the importance of specific tissue-stem cells (gut stem cells) in organismal longevity has been revealed in invertebrates (Biteau et al, 2010). As the mechanisms underlying agedependent stem cell decline are better understood, studying the effects of manipulating stem cell function on overall organismal lifespan and healthspan will be an attainable goal.…”

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

“…JNK signalling has been shown to counteract the effects of ROS and antagonize Insulin/IGF signalling (IIS) leading to extension of lifespan (Wang et al, 2003) (Wang et al, 2005). Interestingly, balanced levels of JNK or IIS in ISCs contribute favourably to intestinal homeostasis and also increase animal lifespan (Biteau et al, 2010). A similar outcome has been observed upon reduction of Myc-dependent ISC proliferation in hyperplastic fly midguts (Cordero et al, 2012a).…”