Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
What this study shows
The authors asked whether the transcription factor Nrf2 is needed for rapamycin to hold back cellular senescence. In wild-type mouse fibroblasts exposed to hydrogen peroxide, rapamycin raised Nrf2, switched on autophagy and lowered the senescence markers p16 and p21, beta-galactosidase staining and the inflammatory secretory profile (SASP). In Nrf2-knockout cells rapamycin still lowered beta-galactosidase staining and the SASP, but no longer lowered p16 and p21 or activated autophagy; re-expressing Nrf2 restored those effects, and human WI38 cells with Nrf2 knocked out by CRISPR behaved the same way. In Nrf2-knockout mice given rapamycin (4 mg/kg every other day for 6 weeks, 8 mice per group), fat-tissue beta-galactosidase staining and pro-inflammatory cytokines fell while p16 did not, and rapamycin lowered STAT3 phosphorylation in lung tissue and WI38 cells. The study provided evidence that rapamycin's effect on the SASP can be separated from its Nrf2-dependent effect on cell-cycle arrest. Boundary: Mouse and human fibroblasts in culture plus a short 6-week dosing study in young Nrf2-knockout mice; mTOR inhibition was by rapamycin, which was given before and during the senescence trigger, so this is prevention of senescence onset rather than treatment of established senescent cells.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse skin fibroblasts and WT vs Nrf2-knockout MEFs (H2O2- or bleomycin-induced senescence); human WI38 fibroblasts (replicative senescence, CRISPR Nrf2 knockout); WT and Nrf2-knockout mice given rapamycin 4 mg/kg i.p. every other day for 6 weeks) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse skin fibroblasts and WT vs Nrf2-knockout MEFs (H2O2- or bleomycin-induced senescence); human WI38 fibroblasts (replicative senescence, CRISPR Nrf2 knockout); WT and Nrf2-knockout mice given rapamycin 4 mg/kg i.p. every other day for 6 weeks |
| Journal | Aging Cell |
| Year | 2017 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1111/acel.12587 · PMID 28371119 · Free full text (PMC5418203) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Rapamycin (25-250 nM in cells; 4 mg/kg i.p. every other day for 6 weeks in mice), with Nrf2 knockout / re-expression |
| Target | mTOR (via rapamycin); Nrf2 |
| Model | Mouse; human cells |
| Effect | Rapamycin lowers SASP and beta-gal staining independently of Nrf2; lowering of p16/p21 and autophagy activation require Nrf2 |
In the Atlas
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- Spatial coupling of mTOR and autophagy augments secretory phenotypes (2011)
- Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation (2026)
- mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation (2015)
- Therapeutic reversal of cellular senescence: A systematic review of senolytics, senomorphics and anti-ageing therapies in human clinical trials (2026)
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