Ratajczak Mariusz Z, Kucia Magda, Liu Rui, Shin Dong-Myung, Bryndza Ewa, Masternak Michal M, Tarnowski Maciej, Ratajczak Janina, Bartke Andrzej
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, KY 40202, USA.
Aging (Albany NY). 2011 Jul;3(7):692-7. doi: 10.18632/aging.100354.
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.
RasGrf1基因缺陷小鼠的寿命延长表明，RasGrf1基因缺陷可促进长寿。有趣的是，RasGrf1是从父源染色体转录的亲本印记基因之一。其印记消除会导致RasGrf1下调，这已在一群多能成体组织来源的非常小的胚胎样干细胞（VSELs）中得到证实，这些干细胞参与组织器官的再生。此外，基于最近的观察结果，即RasGrf1信号分子位于胰岛素（Ins）和胰岛素样生长因子-1（Igf-1）受体的下游，RasGrf1基因敲除小鼠寿命的延长可能支持Ins/Igf-1信号减少对长寿的有益作用。同样，VSELs中RasGrf1的下调使它们对慢性Ins/Igf-1信号具有抗性，并保护它们不被成年组织过早耗尽。因此，对RasGrf1基因敲除小鼠的研究表明，一些印记基因可能在个体发育的长寿中发挥作用，并表明寿命存在性别差异，这种差异起源于基因组水平。所有这些都支持了一个概念，即精子基因组可能对哺乳动物的寿命有不利影响。我们将在基因组印记和VSELs的背景下讨论RasGrf1对寿命的作用。
