Deactivation of the GATA Transcription Factor ELT-2 Is a Major Driver of Normal Aging in C. elegans

To understand the molecular processes underlying aging, we screened modENCODE ChIP-seq data to identify transcription factors that bind to age-regulated genes in C. elegans. The most significant hit was the GATA transcription factor encoded by elt-2, which is responsible for inducing expression of intestinal genes during embryogenesis. Expression of ELT-2 decreases during aging, beginning in middle age. We identified genes regulated by ELT-2 in the intestine during embryogenesis, and then showed that these developmental genes markedly decrease in expression as worms grow old. Overexpression of elt-2 extends lifespan and slows the rate of gene expression changes that occur during normal aging. Thus, our results identify the developmental regulator ELT-2 as a major driver of normal aging in C. elegans.
Author Summary A central question in aging is to uncover the molecular drivers of the normal aging process. Using the roundworm C. elegans as a model organism, we found that the ELT-2 GATA transcription factor regulates many gene expression changes that occur during aging. During development, elt-2 functions as a key regulator of intestinal development. During aging, the levels of ELT-2 transcription factor decline, which causes expression of its target genes to decline and this limits lifespan. Reduction of elt-2 GATA activity in young worms induces gene expression changes resembling those that normally occur in old age. Overexpression of elt-2 slows down the rate of aging, and extends lifespan by about 25%. This work finds that worm lifespan is limited by the declining expression of a key developmental regulator.