RasGrf1: genomic imprinting, VSELs, and aging.

Increase in life span in RasGrf1-deficient mice revealed that RasGrf1 deficiency promotes longevity. Interestingly, RasGrf1 is one of parentally imprinted genes transcribed from paternally-derived chromosome. Erasure of its imprinting results in RasGrf1 downregulation and has been demonstrated in a population of pluripotent adult tissues-derived very small embryonic like stem cells (VSELs), stem cells involved in tissue organ rejuvenation. Furthermore, based on recent observation that RasGrf1 signaling molecule is located downstream from insulin (Ins) and insulin like growth factor-1 (Igf-1) receptors, the extended life-span of RasGrf1-/- mice may support beneficial effect of reduced Ins/Igf-1 signaling on longevity. Similarly, downregulation of RasGrf1 in VSELs renders them resistant to chronic Ins/Igf-1 signaling and protects from premature depletion from adult tissues. Thus, the studies in RasGrf1-/- mice indicate that some of the imprinted genes may play a role in ontogenetic longevity and suggest that there are sex differences in life span that originate at the genome level. All this in toto supports a concept that the sperm genome may have a detrimental effect on longevity in mammals. We will discuss a role of RasGrf1 on life span in context of genomic imprinting and VSELs.