Systemic genotoxic stress is expected to generate senescent cells and accelerate aging. Surprisingly, mice subjected to lethal dose of total body irradiation and rescued by bone marrow transplantation (TBIBMT) showed neither gain of aging-related frailty nor increase in senescence markers. Mesenchymal cells in various tissues of TBIBMT mice do not undergo senescence and stay dormant with unrepaired DNA breaks during the entire life of the animal and activate senescence program only after they are forced into cell divisions ex vivo or in vivo. Accumulation of such dormant senescence-prone cells (DSPC) has no physiological effects under normal life conditions but is associated with impaired wound healing, decelerated tumor growth due to inefficient scaring and stroma formation and rapid increase in frailty and death after placement on a high-fat diet suggesting the involvement of DSPC accumulation in obesity-induced health decline in cancer survivors following genotoxic treatments.