Reverse aging is focused on the epigenetic clock, in which biological aging errors are traced through the DNA methylation patterns, switching on senescence and silencing youthful genes, leading to frailty, cognitive, and organ failure. Yamanaka factors: October 4, Sox2, Klf4. Original reprogramming of adult cells into induced pluripotent stem cells (iPSCs) using Yamanaka factors avoids tumors by full activation; partial, transient expression using doxycycline-inducible AAV vectors safely resets epigenomes, restoring vision in mice with advanced age by regenerating optic nerves and enhancing neuromuscular junctions without pluripotency. The ER-100 of Life Biosciences, which is in Phase 1/2 in 2026 to treat glaucoma, is a delivery of OSK (without c-Myc, to reduce cancer risk) to one eye, and preclinical models have shown 20/40 improvement in vision after activation of Muller glia and survival of retinal ganglion, possibly also to macular degeneration. TFEB-mediated lysosomal improvement leads to the elimination of age-related lipofuscin accumulation and progerin in Hutchinson-Gilford progeria fibroblasts, nuclear blebbing is reversed, and proliferation rates are recovered to neonatal levels, and NAD+ precursors such as NR increase sirtuins to repair mitochondrial DNA and prevent inflammaging. Metformin imitates Caloric restriction causing activation of AMPK by diminishing mTOR hyperactivity that propagates senescent cells, and the data of the TAME trial indicated a healthspan increase of 5-8 years in diabetics; rapalogs such as everolimus have comparable senolytic effects in combination therapies. There are still issues: off-target reprogramming may cause arrhythmias in cardiac trials, epigenetic memory suggests full reversal to embryonic states, and multi-hallmark interventions (senolytics + telomerase + klotho) are required to extend the lifespan of 20+ years, with single therapies showing only 10-15% improvements in mice.
MBH/PS