Combinatorial interventions in aging

Insight on the underlying mechanisms of aging will advance our ability to extend healthspan, treat age-related pathology and improve quality of life. Multiple genetic and pharmacological manipulations extend longevity in different species, yet monotherapy may be relatively inefficient, and we have limited data on the effect of combined interventions. Here we summarize interactions between age-related pathways and discuss strategies to simultaneously retard these in different organisms. In some cases, combined manipulations additively increase their impact on common hallmarks of aging and lifespan, suggesting they quantitatively participate within the same pathway. In other cases, interactions affect different hallmarks, suggesting their joint manipulation may independently maximize their effects on lifespan and healthy aging. While most interaction studies have been conducted with invertebrates and show varying levels of translatability, the conservation of pro-longevity pathways offers an opportunity to identify 'druggable' targets relevant to multiple human age-associated pathologies. Parkhitko et al. discuss combinatorial approaches targeting underlying mechanisms of aging across species and describe frameworks to analyze these interactions and their cross-species translational potential.