The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs).
It is well known that attenuated insulin/insulin-like growth factor signaling (IIS) has a positive effect on longevity in several animal species, including mice. Here, we demonstrate that a population of murine pluripotent very small embryonic-like stem cells (VSELs) that reside in bone marrow (BM) is protected from premature depletion during aging by intrinsic parental gene imprinting mechanisms and the level of circulating insulin-like growth factor-I (IGF-I). Accordingly, an increase in the circulating level of IGF-I, as seen in short-lived bovine growth hormone (bGH)-expressing transgenic mice, which age prematurely, as well as in wild-type animals injected for 2 months with bGH, leads to accelerated depletion of VSELs from bone marrow (BM). In contrast, long-living GHR-null or Ames dwarf mice, which have very low levels of circulating IGF-I, exhibit a significantly higher number of VSELs in BM than their littermates at the same age. However, the number of VSELs in these animals decreases after GH or IGF-I treatment. These changes in the level of plasma-circulating IGF-I corroborate with changes in the genomic imprinting status of crucial genes involved in IIS, such as Igf-2-H19, RasGRF1, and Ig2R. Thus, we propose that a chronic increase in IIS contributes to aging by premature depletion of pluripotent VSELs in adult tissues.
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Louisville, KY 40202, USA.
Magda
M
Kucia
Michal
M
Masternak
Riu
R
Liu
Dong-Myung
DM
Shin
Janina
J
Ratajczak
Katarzyna
K
Mierzejewska
Adam
A
Spong
John J
JJ
Kopchick
Andrzej
A
Bartke
Mariusz Z
MZ
Ratajczak
D000375:Aging / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D048429:Cell Size; D018392:Genomic Imprinting / Q000235:genetics*; D013006:Growth Hormone / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C073294:growth hormone, bovine; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone