This chapter surveys three longevity strategies that aim for durable, system‑level rejuvenation rather than short-term metabolic benefits. It first examines senolytics, including genetic and small‑molecule approaches for identifying and clearing senescent cells, from plasmid‑based iCasp9 systems delivered by lipid nanoparticles to widely used combinations such as dasatinib, quercetin, and fisetin. It then explores epigenetic reprogramming, detailing how transient expression of Yamanaka-type factors or newer single-factor systems like SB000 can reset aged cells toward youthful methylation profiles, while highlighting energy‑related constraints in older organisms. Finally, it reviews the biology of telomere shortening, the limitations of telomerase‑based lifespan extension, and emerging methods—such as telomerase‑activating compounds and potential mRNA delivery of hTERT—to restore telomere length when clinically needed. Together, these interventions outline some of the leading longer-term strategies under development for mitigating or reversing cellular aging.