SRN-901 Combo Drug Extends Mouse Lifespan 33% and Slashes Frailty in Late-Life Trial
A five-compound oral drug targeting mTOR, autophagy, NAD+, and senescence extended median lifespan 33% and cut frailty progression 70% in aged mice.
Summary
SRN-901, a novel oral combination drug containing urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's proprietary SRN-820, was tested in 18-month-old C57BL/6 mice on a Western diet until natural death. Treated mice showed a 33% increase in median remaining lifespan versus placebo (hazard ratio 0.54, representing a 46% reduction in death risk). Frailty progression was attenuated by 70%. Transcriptomic analyses showed beneficial modulation of inflammation, apoptosis, DNA repair, and Alzheimer's-related gene sets. Metabolomic profiling revealed a blood metabolite profile more resembling younger mice, with upregulation of glutathione metabolism. Rapamycin also extended lifespan, but NMN and NR alone did not reach significance, suggesting combination targeting outperforms single-compound NAD+ precursor approaches.
Detailed Summary
Aging is driven by multiple interconnected biological processes—chronic inflammation, mitochondrial dysfunction, cellular senescence, NAD+ depletion, and impaired autophagy—none of which is adequately addressed by single-target interventions. SRN-901 was designed explicitly to hit several of these pathways simultaneously, combining a PI3K/Akt/mTOR pathway modulator (SRN-820), the mitophagy activator urolithin A, the senolytic and anti-inflammatory flavonoid quercetin, the NAD+ precursor nicotinamide riboside (NR), and the antioxidant alpha-lipoic acid into a single oral formulation.
The study enrolled 160 C57BL/6 mice (80 male, 80 female) at 15 months, aged them to 18 months to model late-life intervention, then randomized them to SRN-901 (n=44), placebo (n=44), rapamycin (n=24), NMN (n=24), or NR (n=24). All gavage groups received treatment six days per week. Animals were maintained on a high-fat Western diet (45% kcal from fat) to model human metabolic conditions. The primary endpoint was age at natural death or humane euthanasia. Secondary endpoints included frailty index (24-parameter validated scoring), whole-blood transcriptomics (RNA-seq; NovaSeq 6000; n=24/group), and untargeted metabolomics (UPLC-TripleTOF; n=12/group).
SRN-901-treated mice achieved a 33% increase in median remaining lifespan relative to placebo (Cox HR=0.54; p<0.001). Rapamycin also extended lifespan significantly, while neither NMN nor NR alone reached significance—a finding the authors interpret as evidence that multi-pathway targeting is superior to single NAD+ precursor supplementation at these doses. Frailty index scores, normalized to pre-treatment baseline, rose to 1.17 in SRN-901 mice versus 1.57 in controls by day 128, representing a 70% attenuation of frailty progression (p<0.001). Tumor incidence was also recorded at necropsy across groups.
Transcriptomic analysis using DESeq2 and edgeR identified differentially expressed genes (|log2FC|>1, BH-adjusted p<0.05) enriched in pathways linked to inflammation, apoptosis, DNA repair, and longevity regulation (KEGG mmu04211). GSEA against MSigDB Hallmark gene sets and cross-referencing with GenAge, SynergyAge, and Aging Atlas databases confirmed aging-relevant signatures. Notably, gene sets associated with Alzheimer's disease pathology were modulated—raising the possibility of neurodegeneration-related benefits. Metabolomic profiling identified age-related metabolic shifts that were attenuated by SRN-901, with treated animals displaying a metabolite profile more closely resembling younger mice. Upregulation of glutathione biosynthesis and related antioxidant pathways was a prominent finding, consistent with the inclusion of alpha-lipoic acid and urolithin A.
The results position SRN-901 as a compelling multi-target longevity candidate, though important caveats apply: the study is mouse-only, was funded entirely by Seragon (the drug's developer), SRN-820's precise identity and mechanism remain proprietary, and the Western diet context—while clinically relevant—may not generalize to all dietary backgrounds. Human translation will require independent replication, pharmacokinetic bridging studies, and randomized controlled trials.
Key Findings
- SRN-901 extended median remaining lifespan by 33% in aged Western-diet-fed mice (HR=0.54, 46% reduced death risk).
- Frailty progression was attenuated by 70% over 128 days of treatment versus placebo (p<0.001).
- Rapamycin extended lifespan; NMN and NR alone did not reach significance, supporting multi-pathway combination strategies.
- Transcriptomics showed beneficial modulation of inflammation, apoptosis, DNA repair, and Alzheimer's-related gene sets.
- Metabolomic profiling revealed glutathione pathway upregulation and a blood metabolite profile resembling younger mice.
Methodology
160 C57BL/6 mice randomized at 18 months to SRN-901, placebo, rapamycin, NMN, or NR on a high-fat Western diet until natural death; frailty assessed via 24-parameter index; whole-blood RNA-seq (DESeq2/edgeR) and untargeted UPLC-MS metabolomics performed on subsets. Investigators performing frailty scoring and lifespan analysis were blinded to treatment allocation.
Study Limitations
The study is conducted entirely in mice and funded by Seragon, the drug's developer, introducing potential conflicts of interest. The proprietary SRN-820 component is not fully characterized publicly, limiting reproducibility. Western diet context and the specific C57BL/6 strain may not generalize to diverse human populations or dietary patterns.
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