Tissue and organ rejuvenation and senescence/aging are closely related to the function of stem cells. Recently, we demonstrated that a population of pluripotent Oct-4+ SSEA-1+Sca-1+Lin-CD45- very small embryonic-like stem cells (VSELs) resides in the adult murine bone marrow (BM) and other murine tissues. We hypothesize that these pluripotent stem cells play an important role in tissue/organ rejuvenation, and have demonstrated that their proliferation and potentially premature depletion is negatively controlled by epigenetic changes of some imprinted genes that regulate insulin factor signaling (Igf2-H19 locus, Igf2R and RasGRF1). Since the attenuation of insulin/insulin growth factor (Ins/Igf) signaling positively correlates with longevity, we propose, based on our experimental data, that gradual decrease in the number of VSELs deposited in adult tissues, which occurs throughout life in an Ins/Igf signaling-dependent manner is an important mechanism of aging. In contrast, a decrease in Ins/Igf stimulation of VSELs that extends the half life of these cells in adult organs would have a beneficial effect on life span. Our preliminary data in long-living Igf-1-signaling-deficient mice show that these animals possess a 3-4 times higher number of VSELs deposited in adult BM, lending support to this novel hypothesis.