A Lysosomal Surveillance Response to Stress Extends Healthspan

Authors

Terytty Yang Li
Arwen W Gao
Rendan Yang
Yu Sun
Yuxuan Lei
Xiaoxu Li
Lin Chen
Yasmine J Liu
Rachel N Arey
Kimberly Morales
Raya B Liu
Wenzheng Wang
Ang Zhou
Tong-Jin Zhao
Weisha Li
Amélia Lalou
Qi Wang
Tanes Lima
Riekelt H Houtkooper
Johan Auwerx

Language

English

Publication Date

7-1-2025

Journal

Nature Cell Biology

DOI

10.1038/s41556-025-01693-y

PMID

40571723

PMCID

PMC12270918

PubMedCentral® Posted Date

6-26-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.

Keywords

Lysosomes, Caenorhabditis elegans, Animals, Caenorhabditis elegans Proteins, Longevity, Stress, Physiological, Vacuolar Proton-Translocating ATPases, Humans, Proteolysis, Disease Models, Animal, Lysosomes, Stress signalling, Ageing, Lysosomes

Published Open-Access

yes

Recommended Citation

Li, Terytty Yang; Gao, Arwen W; Yang, Rendan; et al., "A Lysosomal Surveillance Response to Stress Extends Healthspan" (2025). Faculty and Staff Publications. 1899.
https://digitalcommons.library.tmc.edu/baylor_docs/1899