Convergent Longevity Mechanisms Across Phylogenetically Distant Species: From Evolutionary Patterns to Translational Opportunities

Abstract The quest to understand the mechanisms underlying longevity has long captivated scientists, particularly those interested in translating findings from model organisms to humans. This review examines the convergent longevity mechanismsacross phylogenetically distant species and their potential for human translation through a systematic review of published literature. Key findings indicate that long-lived mammals have evolved enhanced DNA repair and tumor suppression mechanisms, primarily through increased copy numbers of caretaker and tumor suppressor genes. Notably, CREBBP, PIK3R1, HELLS, and FOXM1 show convergent gene duplication across long-lived mammals (naked mole rat, greater mouse-eared bat) with strong correlation to longevity quotients, and these genes are simultaneously druggable, CRISPR-editable, and possess validated human orthologs representing the highest-priority targets for human translation. The iTARGET algorithm outperforms traditional epigenetic clocks in identifying age-related CpG sites and can distinguish causal mechanisms from age-correlated biomarkers, enabling cross-species validation of conserved epigenetic signatures at orthologous aging-associated gene loci including FOXO3, SIRT1, mTOR, IGF1R, CDKN2A, and HOXC cluster. FOXO3 represents a validated dual-modality therapeutic target that can be modulated through both small molecules (targeting its DNA-binding domain) and CRISPR-based epigenetic editing (using dCas9-DNMT3A fusion constructs), demonstrating mechanism modality matching for longevity interventions with conserved function across species. Additionally, MnSOD-mediated lifespan extension involves a conserved network of genes affecting metabolic and stress response pathways. Epigenetic studies, advanced by sophisticated algorithms and sequencing techniques, have identified key age-related CpG sites and age-specific changes in aging rates. The BALL nanoparticle delivery system achieves effective in vivo gene editing with improved bioavailability and serum stability, providing a validated delivery mechanism for targeting human orthologs of convergent longevity genes. Convergent evolution accounts for over 80% of longevity-related trait evolution, with copy number expansions in DNA repair pathway genes representing a universal mechanism across both animal and plant kingdoms, and geometric methods and convergence-divergence models providing quantitative frameworks for prioritizing mechanisms by phylogenetic convergence strength. Functional conservation of longevity genes in human orthologs, such as FOXO3, highlights promising targets for therapeutic intervention. While no major contradictions were identified, significant knowledge gaps remain. In conclusion, this review synthesizes key findings on convergent longevity mechanisms, emphasizing those with functionally conserved human orthologs and the most promising candidates for therapeutic intervention. The review also assessed the diverse datasets used in aging research, ranging from genomics to metabolomics, and highlighted the importance of integrative analysis for robust conclusions. Additionally, the literature surveyed emphasized the role of epigenetic modifications in age-related gene expression changes, with a focus on methods capturing dynamic epigenetic patterns over time.