DAF‐16 stabilizes the aging transcriptome and is activated in mid‐aged Caenorhabditis elegans to cope with internal stress

Abstract

The roles and regulatory mechanisms of transcriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age‐associated down‐regulation of transcription factors. In this study, we characterized the role of a transcription factor DAF‐16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF‐16 translocates into the nucleus in aged wild‐type worms and activates the expression of hundreds of genes in response to age‐associated cellular stress. Most of the age‐dependent DAF‐16 targets are different from the canonical DAF‐16 targets downstream of insulin signaling. This and other evidence suggest that activation of DAF‐16 during aging is distinct from activation of DAF‐16 due to reduced signaling from DAF‐2. Further analysis showed that it is due in part to a loss of proteostasis during aging. We also found that without daf‐16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF‐16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation during aging.

DAF-16 and SMK-1 contribute to innate immunity during adulthood inCaenorhabditis elegans

“…5). Putative negative regulation of the IIS pathway with age is likely to occur 802 downstream of the DAF-2 receptor since the transcript levels of its agonists do not 803 decline over time (Li et al 2019). 804…”

“…For a gene to be 301 considered as either up-or downregulated, the difference in its expression levels 302 between the L4 larval stage and Day 6 of adulthood had to be greater than 2-fold, but 303 for this study we considered only those genes whose expression changed by 5-fold for 304 more. To generate a complete catalog DAF-16 transcriptional targets, we created a 305 composite list of non-duplicate entries for genes that are both positively-and negatively 306 regulated by DAF-16 reported in three different studies (Tepper et al 2013;Chen et al 307 2015; Li et al 2019). The catalog was then compared to our filtered comprehensive lists 308 of genes differentially regulated during aging.…”

“…S2). Genes downregulated at Day 6 were predominantly associated with metabolic 478 processes, including those that take place in the mitochondria ( catalog was derived from a recent report that identified genes whose dynamic 485 expression over time requires DAF-16 (Li et al 2019). We designated these as "DAF-16 486 aging up" or "DAF-16 aging down" to indicate genes that are temporally up-and 487 downregulated by DAF-16, respectively.…”

The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 during aging and confers resistance to environmental stress in postreproductive adultC. elegans

“…During adulthood, the expression levels of the daf-16a isoform, and to an even greater extent the daf-16d isoform progressively increase (8). This is coupled to increased expression of a subset of DAF-16 transcriptional targets in adults as compared to in larvae, suggesting that DAF-16 is activated as C. elegans age (9). How DAF-16 activity might be regulated in an age-dependent manner and whether that regulatory mechanism is unique to aging is not known.…”

“…PPTR-1 associates with AKT-1 but not DAF-16 in worms, and overexpression of PPTR-1 reduces the levels of phosho-AKT-1. Since as a whole the expression levels of insulin-like peptides considered to be agonists of DAF-2 either remain constant or increase during adulthood, the presence of a sustained inhibitory signal through the IIS pathway that persists in adult animals seems likely (9). A regulator that can counteract this signal is therefore an attractive candidate for functioning to modulate the activity of DAF-16 during aging, and this is what led us to develop the hypothesis that phosphoprotein phosphatases modulate DAF-16 transcriptional activity in an age-dependent manner.…”