Reference - Detail
| RRC ID | 88152 |
|---|---|
| Author | Li TY, Gao AW, Yang R, Sun Y, Lei Y, Li X, Chen L, Liu YJ, Arey RN, Morales K, Liu RB, Wang W, Zhou A, Zhao TJ, Li W, Lalou A, Wang Q, Lima T, Houtkooper RH, Auwerx J. |
| Title | A lysosomal surveillance response to stress extends healthspan. |
| Journal | Nat Cell Biol |
| 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. |
| Volume | 27(7) |
| Pages | 1083-1097 |
| Published | 2025-7-1 |
| DOI | 10.1038/s41556-025-01693-y |
| PII | 10.1038/s41556-025-01693-y |
| PMID | 40571723 |
| PMC | PMC12270918 |
| MeSH | Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Disease Models, Animal Humans Longevity* / genetics Lysosomes* / genetics Lysosomes* / metabolism Proteolysis Stress, Physiological* Vacuolar Proton-Translocating ATPases / genetics Vacuolar Proton-Translocating ATPases / metabolism |
| Altmetric score |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 37 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm1978 tm4525 |