Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling

Abstract

Background The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. Results We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. Conclusions These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system

“…S1 B ). In addition, and consistent with previous studies examining the effects of reduced IIS in glia ( 31 ), we observed no change in fecundity for flies overexpressing FOXO in glia ( SI Appendix , Fig. S1 C ).…”

“…Our results also place glial cells alongside the fat body ( 24 ) and some gut cell populations ( 20 ) as Drosophila cell types in which FOXO can mediate similar effects. Our results also complement our recent findings that glia-specific IIS inhibition can extend healthy lifespan in a FOXO-dependent manner ( 31 ). Finally, our results do not exclude the possibility that other TFs downstream of IIS in the nervous system can modulate longevity; indeed, recent studies have shown that knockdown of the ETS family TF Eip74EF in neurons can extend healthy lifespan ( 20 ), and other TFs are likely to play additional roles in nervous system aging.…”

“…In mice, IGF1 receptor deletion extends lifespan when restricted to the nervous system using the nestin-Cre driver line, which expresses in both neurons and glia (the nonneuronal cells of the nervous system) ( 28 ). In flies, IIS inhibition in either neurons ( 29 , 30 ) or glia ( 31 ) alone is sufficient to extend healthy lifespan, with neuron-specific interventions able to preserve youthful electrical transmission in neuronal circuits with age ( 32 ). However, studies to date have not identified which of the TFs downstream of IIS can extend healthy lifespan in the nervous system.…”

FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology

“…However, it remained unclear whether it is mediated by the loss of Irs2 in neurons or astrocytes or both. A recent study used genetic manipulations of the IIS pathway in different glial subtypes in the Drosophila brain and found that reduced insulin/PI3K signaling specifically in astrocyte‐like glia, but not in other glial subtypes, extends lifespan without delaying development and this effect is FoxO3 dependent (Woodling et al, 2020 ). Our result that the subcellular localization of FoxO3 in astrocytes is highly sensitive to insulin/PI3K signaling is in keeping with this idea and supports a conserved astrocytic insulin/PI3K/FoxO3 pathway in metabolism and lifespan regulation.…”

“…Key to the regulation of aging and metabolism are the Forkhead box O (FoxO) transcription factors, which act downstream of the insulin/insulin‐like growth factor signaling (IIS) pathway to mediate critical organismal processes, including growth control, reproduction, and lifespan regulation, and cellular responses such as energy utilization, metabolic homeostasis, autophagy, and stress resistance (Barthel et al, 2005 ; Brown & Webb, 2018 ; Gross et al, 2008 ; Martins et al, 2016 ). In both Caenorhabditis elegans and Drosophila melanogaster , reduction of IIS signaling leads to extended lifespan, and this effect requires FoxO/DAF16 and dFOXO, respectively (Friedman & Johnson, 1988 ; Friedman & Johnson, 1988 ; Kenyon et al, 1993 ; Woodling et al, 2020 ). This pathway is well‐conserved as FoxO3, the most prominent FoxO member in the mammalian system, is implicated in lifespan extension in caloric‐restricted mice (Shimokawa et al, 2015 ).…”