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

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.

Age Regulates Drosophila Ovarian Germline Stem Cells via Insulin-Dependent and Independent Mechanisms

“…Nonetheless, insulin signaling does not control the S phase progression of the GSC division cycle that is delayed in aged GSCs; rather, it controls the G2 phase, in agreement with our recent study and a previous report [13,14]. dInr mutant GSCs increase their population by expressing a G2 phase marker (e.g., exclamation point and round fusomes and cyclin B), and dividing at the rate that is onethird that of controls.…”

“…Each GSC carries a unique organelle with a membranous-like structure, called a fusome, which is juxtaposed to the interface between the cap cell and the GSC. During the late G2/M, S, and early G2 phases of the GSC cell cycle, fusomes display a round, elongated, and exclamation point shape, respectively ( Figure 1B) [13,14]. 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 a branched fusome [12].…”

“…In our recent study [14], we investigated how age affects GSCs. We found that both GSC self-renewal and division decrease with age.…”

“…(B) Correlation between GSC fusome morphology during the S, G2, and M phases in GSCs. The G1 phase is omitted, as it is extremely short in the GSC division cycle [14]. mechanisms.…”

“…Systemic aging or GSC intrinsic aging suppresses the S phase of the GSC cell cycle; however, systemic insulin signals predominately control the G2 phase. Panels A-C adopted from Kao et al [14].…”