Aging and insulin signaling differentially control normal and tumorous germline stem cells

Shih‐Han Kao,Chen‐Yuan Tseng,Yu‐Han Su,Haiwei Pi,Chih‐Ling Wan,Hwei‐Jan Hsu,Chang‐Che Hsieh

doi:10.1111/acel.12288

Abstract

Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC–male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging.

Highlights

Stem cells undergo self-renewal to maintain tissues with rapid turnover, regenerate damaged tissues, and ensure optimal tissue and organ function
We show that aging controls GSC division at S phase, in a process distinct from the dietary effect mediated by insulin signaling
Half of the germaria in 56- and 63-day-old ovaries were degenerated. These results agree with previous reports that the number of GSCs significantly declines with age (Pan et al, 2007; Zhao et al, 2008) and is consistent with the observation that Drosophila testicular GSCs undergo an age-related decline in number (Wallenfang et al, 2006)

Summary

Introduction

Stem cells undergo self-renewal to maintain tissues with rapid turnover, regenerate damaged tissues, and ensure optimal tissue and organ function. Drosophila is a small organism with a short lifespan; such properties, combined with the availability of powerful genetic approaches, facilitate the use of Drosophila in investigations of cellular responses at different physiological ages. The GSCs in the Drosophila ovary are well characterized (Fig. 1A; Kirilly et al, 2005), making it an excellent model in which to study how stem cells respond to aging. One Drosophila ovary is composed of 16–20 functional units, named ovarioles, which produce eggs (Spradling, 1993). A single GSC division gives rise to a cystoblast, which undergoes four rounds of incomplete division to form a 16-cell cyst; the cells of the cyst are interconnected with branched fusomes (Spradling, 1993). The 16-cell cyst is surrounded by a layer of follicle cells, and the entire structure buds off from the germarium and develops into a mature egg

Results

Discussion

Conclusion