Cellular senescence is a crucial process of irreversible cell-cycle arrest, in which cells remain alive, but permanently unable to proliferate in response to distinct types of stressors. Accumulating evidence suggests that DNA damage builds over time and triggers DNA damage response signaling, leading to cellular senescence. Cellular senescence serves as a platform for the perpetuation of inflammatory responses and is central to numerous age-related diseases. Defects in DNA repair genes or senescence can cause premature aging disease. Therapeutic approaches limiting DNA damage or senescence contribute to a rescued phenotype of longevity and neuroprotection, thus suggesting a mechanistic interaction between DNA damage and senescence. Here, we offer a unique perspective on the crosstalk between the DNA damage response pathway and senescence as well as their contribution to age-related diseases. We further summarize recent progress on the mechanisms and therapeutics of senescence, address existing challenges, and offering new insights and future directions in the senescence field.