FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-Wide Proteostasis During Aging

Abstract

The progressive loss of muscle strength during aging is a common degenerative event of unclear pathogenesis. Although muscle functional decline precedes age-related changes in other tissues, its contribution to systemic aging is unknown. Here, we show that muscle aging is characterized in Drosophila by the progressive accumulation of protein aggregates that associate with impaired muscle function. The transcription factor FOXO and its target 4E-BP remove damaged proteins at least in part via the autophagy/lysosome system, while foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend lifespan. Moreover, FOXO/4E-BP signaling in muscles decreases feeding behavior and the release of Insulin from producing cells, which in turn delays the age-related accumulation of protein aggregates in other tissues. These findings reveal an organism-wide regulation of proteostasis in response to muscle aging, and a key role of FOXO/4E-BP signaling in the coordination of organismal and tissue aging.