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Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans
Iman Man Hu1,2, Ana Serna1, Stacia Everts1
1Laboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Abstract:
Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways related to longevity in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO, the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, including the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPRmt) regulator afts-1 to be crucial for both improved healthspan and extended lifespan upon amonafide treatment. Moreover, healthspan was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4. We further examined the potential of amonafide in age-related disease. Treating a C. elegans model for Parkinson's disease with amonafide improved mobility. In conclusion, we identified amonafide as a novel geroprotector, which activates mitochondrial-, pathogen-, and xenobiotic-associated defense responses that-though more studies are needed-may serve as a candidate for Parkinson's disease therapy.
Insights
Amonafide, a topoisomerase inhibitor, extends healthspan and lifespan in C. elegans by activating defense pathways. This novel geroprotector shows promise for age-related diseases like Parkinson's.
Area of Science:
- Gerontology and Pharmaceutical Science
- Molecular Biology and Genetics
- Neuroscience and Aging
Background:
- Aging is a significant risk factor for numerous diseases, driving the need for interventions to enhance healthspan and longevity.
- The AKT1 signaling pathway is implicated in longevity, with reduced AKT1 levels associated with extended lifespan in model organisms.
Purpose of the Study:
- To identify small molecules that mimic the longevity effects of AKT1 knockdown.
- To evaluate the therapeutic potential of identified compounds, particularly topoisomerase inhibitors, in promoting healthspan and lifespan.
- To investigate the molecular mechanisms underlying the observed longevity effects of amonafide.
Main Methods:
- In silico drug screening to identify small molecules targeting the AKT1 pathway.
- Pharmacological evaluation of topoisomerase inhibitors, specifically amonafide, in the model organism C. elegans.
- RNA sequencing (RNA-seq) to analyze transcriptional changes induced by amonafide treatment.
- Genetic analysis to determine the role of specific pathways (e.g., DAF-16/FOXO, UPRmt, integrated stress response) in amonafide's effects.
- Assessment of amonafide in a C. elegans model of Parkinson's disease.
Main Results:
- Amonafide, a topoisomerase inhibitor, significantly improved healthspan and lifespan in C. elegans.
- The longevity effects of amonafide were not solely dependent on the canonical DAF-16/FOXO pathway.
- Amonafide treatment induced a youthful transcriptional signature, activating diverse defense pathways including the mitochondrial unfolded protein response (UPRmt) via afts-1.
- Healthspan extension was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4.
- Amonafide treatment improved motor function in a C. elegans model of Parkinson's disease.
Conclusions:
- Amonafide is identified as a novel geroprotector with significant benefits for healthspan and lifespan.
- Amonafide activates mitochondrial, pathogen, and xenobiotic defense responses, contributing to its longevity effects.
- Amonafide demonstrates potential as a therapeutic candidate for age-related diseases, including Parkinson's disease.
