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. 2017 Feb 22;13(4):443–453. doi: 10.1007/s12015-017-9728-2

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© The Author(s) 2017

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Fig. 2 — Changes in the methylation state of parentally imprinted genes lead to attenuation of GH/INS/IGF signaling in VSELs. VSELs are deposited in adult tissues as a backup population for tissue-committed stem cells (TCSCs). Due to erasure of paternal imprinting at the Igf2-H19 locus, VSELs do not express endogenous IGF-2 and, through the activity of H19 gene-derived miRNA675, downregulate expression of the IGF-1 and INS receptors, which decreases their sensitivity to the circulating IGF-1, INS and IGF-2 activating GH/INS/IGF signaling axis. At the same time, due to hypermethylation of the DMR at the Igf2R locus by upregulating expression of the non-signaling IGF-2 receptor (which serves as molecular bin for IGF-2), these cells additionally attenuate responsiveness to circulating IGF-2. During aging, gradual hypermethylation at the Igf2-H19 locus is observed, which leads to an increase in expression of autocrine IGF-2 and a decrease in H19-expressed miR675, which leads to an increase in expression of the IGF-1 and INS receptors. This results in age-related increased sensitivity to GH/INS/IGF signaling and age-mediated VSEL depletion. As a consequence, there is a decrease in VSEL-generated TCSCs, which impairs tissue and organ rejuvenation. Moreover, VSELs deposited in adult tissues may, over time, become more quickly depleted by chronically elevated circulating levels of IGF-1 and INS, which engage the IGF1R and INSR expressed by these cells. This mechanism may contribute to accelerated aging observed in situations with high circulating levels of IGF-1 and INS (e.g., high calorie uptake)