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

Abstract

Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Drosophila. Starting from published single-cell transcriptomic data, we report that forkhead (FKH) is endogenously expressed in neurons, whereas forkhead-box-O (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer’s disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify Atg17, a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.

Circadian Gene cry Controls Tumorigenesis through Modulation of Myc Accumulation in Glioblastoma Cells

“…The studies of other groups describe the beneficial effects of haloperidol on cry1 expression in GB cells, but these results obtained in cell culture suggest that the doses required to treat patients might be toxic; in consequence, specific delivery strategies combined with haloperidol are worth of study. In addition, we observed significant effects of cry knockdown in normal glial cells, in line with Bolukbasiet al, who recently described the extension of lifespan by foxo upregulation in glial cells [46]. We observed an effect of cry upregulation in the number of glial cells (Figure 5L).…”

Circadian Gene <em>cry</em> Controls Glioblastoma Tumorigenesis through Modulation of <em>myc</em> Expression

“…But these results obtained in cell culture suggest that the doses required to treat patients might be toxic, in consequence specific delivery strategies combined with haloperidol are worth of study. We have observed significant effects cry knockdown in normal glial cells, in line with Bolukbaso and cols that recently described the extension of lifespan by foxo upregulation in glial cells (Bolukbasi et al 2021). We have observed an effect of cry RNAi expression in the number of glial cells (Figure 5L).…”

Bioorthogonal Imaging Uncovers Sex- and Diet-dependent Lipid Metabolic Changes in Drosophila Brain during Aging

“…Interestingly, CNS-speci c deletion of FoxO3 in 5xFAD mice led to altered brain lipid levels and exacerbation of synaptic loss and Abeta pathology, whereas astrocytespeci c overexpression of FoxO3 reversed these neurodegenerative phenotypes, suggesting a neuroprotective role of FoxO3 (Du et al, 2021). The single-cell RNA-sequencing (RNA-seq) pro ling of the adult Drosophila brain also showed that FOXO is endogenously expressed in glia but not neurons (Bolukbasi et al, 2021;Davie et al, 2018). Our study, together with published data, supports the role of the evolutionarily conserved IIS-FOXO pathway in regulating brain lipid metabolism, organismal health and life span.…”