title: Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans.
abstract: Alzheimer's disease (AD) is an age-associated disease. Mutations in the amyloid precursor protein (APP) may be causative or protective of AD. The presence of two functionally redundant APP-like genes (APLP1/2) has made it difficult to unravel the biological function of APP during aging. The nematode Caenorhabditis elegans contains a single APP family member, apl-1. Here, we assessed the function of APL-1 on C. elegans' lifespan and found tissue-specific effects on lifespan by overexpression of APL-1. Overexpression of APL-1 in neurons causes lifespan reduction, whereas overexpression of APL-1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN-14 to preserve youthfulness. APL-1 lifespan extension also requires signaling through the FOXO transcription factor DAF-16, heat-shock factor HSF-1, and vitamin D-like nuclear hormone receptor DAF-12. We propose that reinforcing APL-1 expression in the hypodermis preserves the regulation of heterochronic lin-14 gene network to improve maintenance of somatic tissues via DAF-16/FOXO and HSF-1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved APP-related protein modulates aging.
authors.affiliation: Graduate Center, City University of New York, New York, NY, USA.|Department of Biology, City College of New York, New York, NY, USA.
authors.forename: Collin Y
authors.initials: CY
authors.lastname: Ewald
authors.affiliation: Department of Biology, City College of New York, New York, NY, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marfil
authors.affiliation: Graduate Center, City University of New York, New York, NY, USA.|Department of Biology, City College of New York, New York, NY, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Li
keywords: 
  APP
  ; APL-1; Alzheimer's disease; FOXO transcription factor DAF-16; heat-shock factor HSF-1; heterochronic gene LIN-14; lifespan; vitamin D-like nuclear hormone receptor DAF-12