Aging is a natural process characterized by the progressive decline in tissue and cellular functions, while recent studies indicated the potential reversibility of aging. Gene reprogramming is a typical method that involves cellular reprogramming. The Yamanaka factors, comprising Oct4, Sox2, Klf4, and c-Myc (termed OSKM), have been shown to convert senescent cells into induced pluripotent stem cells and mitigate signs of premature aging in presenile mice. Despite these promising results, the continuous expression of Yamanaka factors induces teratomas and severe mortality, primarily due to the oncogenic properties of c-Myc. It is well-established that c-Myc functions as a key transcription factor for activating the telomerase gene (TERT), and the absence of c-Myc may impede telomere elongation, thereby compromising anti-aging effects. To address these issues, this study employed an optimized Yamanaka factor (Oct4-Sox2-Klf4, OSK) that excludes c-Myc in conjunction with TERT gene therapy. Through a series of experimental validations, we confirmed that the co-expression of the OSK and TERT genes significantly enhanced the expression of genes associated with youth while concurrently reducing the levels of senescence-associated genes. Consequently, this combined gene therapy represents a promising therapeutic strategy for extending lifespan and addressing aging-related diseases.