Blocking NRF1 Slows Cellular Aging and Extends Lifespan in Mice

Inflammaging — the chronic, low-grade sterile inflammation that accumulates with age — is widely recognized as a key driver of age-related disease, but the precise molecular switches that connect DNA damage, innate immunity, and the senescence-associated secretory phenotype (SASP) have remained poorly defined. This study from Nankai University's Center for Aging and Regeneration, published in Nature Communications (December 2025), identifies nuclear respiratory factor 1 (NRF1) as a critical transcriptional hub linking these processes, and demonstrates that suppressing NRF1 can meaningfully delay aging across multiple biological scales.

The research team first established that NRF1 expression correlates positively with established senescence markers in human tissue data (GTEx) across the heart, liver, kidney, muscle, blood, and stomach, and in mouse organ datasets (GSE132040). In primary mouse embryonic fibroblasts (Primary MEFs), NRF1 protein — but not mRNA — rose progressively following senescence induction with etoposide, doxorubicin, or H₂O₂, paralleling increases in P16, P21, P53, and γH2AX. Ionizing radiation (7.5 Gy) in 8-week-old C57BL/6J mice similarly elevated NRF1 protein in heart, liver, and kidney tissues, confirming the pattern in vivo.

Functionally, siRNA-mediated NRF1 knockdown in Primary MEFs dramatically reduced etoposide-induced SA-β-galactosidase staining, suppressed senescent markers (P53, P21, P16, γH2AX), restored EdU incorporation and Ki67 positivity (indicating resumed proliferation), and decreased SASP gene expression including Il-6, Cxcl1, and Mmp13 (all p < 0.05 by two-way ANOVA with Tukey correction, n = 3–6 independent experiments). Cell-cycle analysis showed NRF1 knockout increased G2/M-phase cells and attenuated the etoposide-induced S-phase block. These effects were reproduced with two independent siRNA sequences and extended to MEF cell lines.

Mechanistically, chromatin immunoprecipitation (ChIP) and transcriptomic analyses revealed that NRF1 directly binds and transcriptionally activates the promoters of Tbk1 and Irf3 — two central nodes in the innate immune pathway required for type I interferon production and SASP amplification. NRF1 deficiency suppressed TBK1 and IRF3 expression, blunted downstream IRF3 phosphorylation, and reduced type I IFN and pro-inflammatory cytokine secretion. The team further showed that DNA damage activates ATM kinase, which phosphorylates NRF1 specifically at Serine 393. This phosphorylation event promotes NRF1 oligomerization and enhances its DNA-binding affinity at Tbk1/Irf3 promoters, creating a feed-forward loop that amplifies SASP during genotoxic stress.

In aged mice, systemic NRF1 knockdown via siRNA-lipid nanoparticle delivery reduced multi-organ aging phenotypes including SA-β-gal positivity, inflammatory cytokine levels, and tissue fibrosis markers. Critically, treated aged mice showed extended lifespan compared to controls, though the exact magnitude of lifespan extension requires verification in larger cohorts. The authors propose that targeting the ATM–NRF1–TBK1/IRF3–type I IFN axis represents a senomorphic strategy — suppressing SASP without killing senescent cells — thereby potentially avoiding the wound-healing impairment associated with senolytic agents. NRF1's context-dependent role (previously linked to mitochondrial biogenesis) adds complexity, and tissue-specific delivery strategies will be needed for translational applications.