# Lack of T04C9.1, the Homologue of Mammalian APPL2, Leads to Premature Ageing and Shortens Lifespan in Caenorhabditis elegans

## TL;DR

This study shows that a protein related to aging in worms and mice is linked to premature aging and shortened lifespan when missing.

## Contribution

The study identifies T04C9.1/APPL2 as a key link between autophagy decline and aging in C. elegans and mice.

## Key findings

- Reduced APPL2 in aged mouse organs and T04C9.1 in C. elegans causes premature aging and shortened lifespan.
- Lack of T04C9.1 leads to decreased autophagy, slow movements, and stress resistance in C. elegans.
- Activating autophagy reverses age-related changes caused by T04C9.1 deficiency in C. elegans.

## Abstract

Ageing has been identified as an independent risk factor for various diseases; however, the physiological basis and molecular changes related to ageing are still largely unknown. Here, we show that the level of APPL2, an adaptor protein, is significantly reduced in the major organs of aged mice. Knocking down APPL2 causes premature ageing of human umbilical vein endothelial cells (HUVECs). We find that a lack of T04C9.1, the homologue of mammalian APPL2, leads to premature ageing, slow movements, lipid deposition, decreased resistance to stresses, and shortened lifespan in Caenorhabditis elegans (C. elegans), which are associated with decreased autophagy. Activating autophagy by rapamycin or inhibition of let-363 suppresses the age-related alternations, impaired motility, and shortened lifespan of C. elegans, which are reversed by knocking down autophagy-related genes. Our work provides evidence that APPL2 and its C. elegans homologue T04C9.1 decrease with age and reveals that a lack of T04C9.1 bridges autophagy decline and ageing in C. elegans.