RasGrf1: genomic imprinting, VSELs, and aging

Mariusz Z Ratajczak,Janina Ratajczak,Andrzej Bartke,Magda Kucia,Michal M Masternak,Rui Liu,Dong-Myung Shin,Ewa Bryndza,Maciej Tarnowski

doi:10.18632/aging.100354

Abstract

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.

Highlights

In the March issue of Aging, Borras et al reported that RasGrf1 deficiency delays aging in mice, with the lifespan of RasGrf1–/– animals increased by ~20% [1]
As we have demonstrated in BM, very small embryonic like stem cells (VSELs) are precursor cells for hematopoietic stem cells (HSCs)
This mechanism is based on the epigenetic changes in selected somatic-imprinted genes (i.e., Igf-2-H19, RasGRF1, and IGF-2 receptor (IGF-2R)) that are involved in insulin (Ins) and insulin-like growth factor signaling (IGF-1 and insulin-like growth factor-2 (IGF-2))

Summary

Introduction

In the March issue of Aging, Borras et al reported that RasGrf1 deficiency delays aging in mice, with the lifespan of RasGrf1–/– animals increased by ~20% [1]. These bimaternal mice were artificially produced with two sets of female genomes by modulating expression of two paternally imprinted loci: insulin-like growth factor-2 (IGF-2)-H19 and Dlk1Gtl2, located on chromosomes 7 and 12, respectively. There are ~80 imprinted genes in mice (expressed from maternal or paternal chromosomes only) that play a important role in embryonic development.

Results

Conclusion