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SRN-901, a Novel Longevity Drug, Extends Lifespan and Healthspan by Targeting Multiple Aging Pathways
Brett Weiss1, Daniel R Miranda1, Dylan Arrazati1
1Seragon Biosciences, Irvine, CA, USA.
Introduction:
Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.
Results:
SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.
Discussion:
These results highlight SRN-901 as a promising multi-compound candidate for extending lifespan and healthspan by targeting multiple aging pathways.
Insights
A novel drug combination, SRN-901, significantly extended median lifespan by 33% and reduced frailty by 70% in aging mice. This intervention targets multiple aging pathways, offering a promising approach to enhance longevity and healthspan.
Area of Science:
- Gerontology and aging research
- Pharmacology and drug development
- Molecular biology and genetics
Background:
- Aging is a complex process involving multiple interconnected biological systems.
- Existing interventions often target single pathways, limiting their efficacy in extending lifespan and healthspan.
- A combinatorial approach may better address the multifaceted nature of aging.
Purpose of the Study:
- To evaluate the effects of the novel oral drug SRN-901 on lifespan, frailty, and aging-related molecular and metabolic changes.
- To assess SRN-901's impact on gene expression pathways associated with aging and age-related diseases.
- To determine if SRN-901 can mitigate age-related metabolic dysregulation.
Main Methods:
- 18-month-old mice fed a Western diet were treated with SRN-901, a combination of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and SRN-820.
- Lifespan, frailty scores, gene expression (transcriptomics), and metabolic profiles (metabolomics) were analyzed.
- Statistical analyses, including Cox proportional hazards models, were used to assess treatment effects.
Main Results:
- SRN-901 treatment increased median remaining lifespan by 33% (hazard ratio 0.54) and attenuated frailty progression by 70%.
- Transcriptomic analysis revealed modulation of aging-related pathways, including inflammation, apoptosis, DNA repair, and neurodegeneration.
- Metabolic profiling indicated that SRN-901 normalized age-related metabolic shifts, promoting a younger metabolic profile and enhancing glutathione metabolism.
Conclusions:
- SRN-901 demonstrates significant efficacy in extending lifespan and improving healthspan in a mouse model of aging.
- The multi-compound nature of SRN-901 allows it to target diverse aging pathways simultaneously.
- SRN-901 represents a promising therapeutic candidate for interventions aimed at delaying aging and promoting longevity.
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