Molecular Basis for Developing Single Molecule Based Anti-Aging Therapies to Prevent Aging Related Diseases in Humans

Overview

Objectives/Goals Aging-delaying interventions often prevent multiple aging-related diseases (ARDs). My recent studies have characterized EZH2-mediated H3K27me3 as the first evolutionarily conserved epigenetic mechanism underlying transgenerational inheritance of early-life nutritional programming of longevity, supporting translational studies in humans [1,2], and identified a longevity-extending EZH2-selective inhibitor (EPZ-6438) to prevent heart disease, type 2 diabetes and aging-related memory loss in aged flies, providing the first-ever proof-of-concept of single molecule-based long-lasting epigenetic therapies for simultaneous prevention of multiple ARDs (unpublished results). Excitingly, dietary restriction has very recently been extended to human participants for safe and effective alleviation of cardiovascular disease, diabetes and cancers simultaneously [3]. My current study was to identify the shared nutrition-mediated molecular and epigenetic mechanisms among aging and ARDs, and further validate EPZ-6438 as a promising nutrition-responsive broad-spectrum therapy for human diseases. Methods/Materials Integrative methods were employed for public data mining, bioinformatic analyses, RNA-seq with human H9 ESCs (embryonic stem cells) and disease characterization with aged flies after treatment of EPZ-6438. Results My results have (i) revealed the Sirt1-EZH2-p53 pathway as a shared mechanism among aging and ARDs, and 12 related druggable targets, providing the molecular basis for developing novel anti-aging therapies to simultaneously prevent multiple ARDs, (ii) identified 868 EPZ-6438-impacted genes enriched in multiple pathways and various biological processes involved with cardiovascular diseases, diabetes, dementia and cancers, validating the drug as a promising multi-disease therapy in humans, (iii) further identified Klf4 and Sox21, suggesting a possible mechanistic connection between EPZ-6438-mediated H3K27me3 inhibition and Nobel Prize-winning Yamanaka factors to delay aging and ARDs [4]. Conclusions/Discussion My research has thus validated the emerging concept of delaying aging through epigenetic reprogramming, and demonstrated that single molecule-based, nutrition-responsive, multi-disease therapies may be developed and delivered to delay aging and various ARDs in humans, opening up novel avenues for aging research and drug development.

Awards (1)

• Honorable Mention

Competition history

• CSEF 2017 Biochemistry/ Molecular Biology · Entry S0527

Resources

• CSEF project summary ↗

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