Paternal genome effects on aging: evidence for a role of Rasgrf1 in longevity determination?

A recent study by Kawahara and Kono (2010) reports that mice artificially produced with two sets of female genomes have an increased average lifespan of 28%. Moreover, these animals exhibit a smaller body size, a trait also observed in several other long-lived mouse models. One hypothesis is that alterations in the expression of paternally methylated imprinted genes are responsible for the life-extension of bi-maternal mice. Considering the similarities in postnatal growth retardation between mice with mutations in the Rasgrf1 imprinted gene and bi-maternal mice, Rasgrf1 is the most likely culprit for the low body weight and extended lifespan of bi-maternal mice. Rasgrf1 is a neuronal guanine-nucleotide exchange factor that induces Ras signaling in a calcium-dependent manner and has been implicated in learning and memory. Like other long-lived mouse strains, Rasgrf1 mutants are known to have low growth hormone and IGF-1 levels and the Rasgrf1 yeast homolog CDC25 had been previously associated with lifespan. Therefore, although the evidence is not conclusive, it does point towards the involvement of Rasgrf1 in the regulation of longevity, hypothetically through a mechanism similar to that observed in other long-lived mice of low GH/IGF-1 signaling causing a low body weight and life-extension.