Longevity is determined by ETS transcription factors in multiple tissues and diverse species

Abstract

Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila , reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop , an ETS transcriptional repressor, and Foxo , a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo . In combination, Aop can both moderate or synergise with Foxo , dependent on promoter context. Moreover, Foxo and Aop oppose the gene-regulatory activity of Pnt , an ETS transcriptional activator. Directly knocking down Pnt recapitulates aspects of the Aop / Foxo transcriptional programme and is sufficient to extend lifespan. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines expression of metabolic genes, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are often conserved amongst ETS TFs, prompting us to examine whether other Drosophila ETS-coding genes may also affect ageing. We show that five out of eight Drosophila ETS TFs play a role in fly ageing, acting from a range of organs and cells including the intestine, adipose and neurons. We expand the repertoire of lifespan-limiting ETS TFs in C . elegans , confirming their conserved function in ageing and revealing that the roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species.

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

“…Notably, these results are in agreement with other recent studies pointing to the limited expression of FOXO in Drosophila neurons compared with other cell types (54). 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).…”

“…These findings help shed light on an apparent paradox from previous studies on the modulation of lifespan by neurons: While decreased IIS in neurons extends healthy lifespan (29), the Reduced IIS fkh-dependent Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system canonical downstream effect of increased FOXO activity in neurons shortens lifespan (17,20). Based on single-cell transcriptomic data (33) and our immunostaining results from the adult Drosophila brain, we now suggest that the endogenous expression patterns of multiple TFs among different cell types can help inform the interpretation of these results.…”

“…Our results exemplify tapping into publicly available gene expression datasets to extract physiological insights, and highlight the need to shift away from organism-wide approaches and toward cell type-specific strategies to obtain meaningful insights in aging research. (20) and FOXA family members (21). While FOXA family members have been less extensively studied than FOXO downstream of IIS, recent work has shown that IIS activity results in phosphorylation of the Drosophila FOXA ortholog Forkhead (FKH) and that FKH can biochemically interact with both AKT and TOR kinases (21), identifying FKH as a key transcriptional player within the IIS/TOR signaling network.…”

“…Consistent with a prolongevity role for FOXO family members in humans, single-nucleotide polymorphisms in the FOXO3A gene are associated with longevity in large-scale genome-wide association studies ( 18 , 19 ). In addition to FOXO, multiple additional TFs within the IIS pathway modulate healthy lifespan at the level of the whole organism, including ETS family members ( 20 ) and FOXA family members ( 21 ). While FOXA family members have been less extensively studied than FOXO downstream of IIS, recent work has shown that IIS activity results in phosphorylation of the Drosophila FOXA ortholog Forkhead (FKH) and that FKH can biochemically interact with both AKT and TOR kinases ( 21 ), identifying FKH as a key transcriptional player within the IIS/TOR signaling network.…”

Acis-regulatory element promoting increased transcription at low temperature in cultured ectothermicDrosophilacells

“…The apparent growth-promoting role of Ets97D is intriguing in the context of temperature acclimation. Interestingly, Pnt has also been implicated very recently in the control of metabolic gene expression (Dobson et al 2019).…”