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IIS levels affect life cycle of VSELs in adult tissues
53rd ASH Annual Meeting
SAN DIEGO — A decrease in insulin/insulin growth factor signaling caused by caloric restriction that lowers plasma insulin-like growth factor I levels may delay the age-dependent elimination of pluripotent very small embryonic-like stem cells from adult tissues in mice, according to results presented here.
In contrast, chronic insulin/insulin growth factor signaling (IIS) due to chronic high caloric intake and the resulting elevated plasma growth hormone and insulin-like growth factor I (IGF-I) levels prematurely depletes very small embryonic-like stem cells (VSELs) residing in adult organs. Such VSELs in bone marrow leads to a decrease in the number of long-term hematopoietic stem cells (HSCs).
“We believe our data shed new light on the relationships between senescence, plasma growth hormone/IGF-I level, prolonged IIS, and number of VSELs and long-term HSCs,” said Magda Kucia, PhD, with the Stem Cell Institute at the University of Louisville’s James Graham Brown Cancer Center. “This study also indicates that [growth hormone]-based anti-aging therapies need careful re-evaluation of their potentially uncontrolled stimulation of VSELs in [bone marrow] that may lead to development of hematological malignancies. In support of this, elevated [growth hormone] and IIS lead to hematological malignancies, while, by contrast, Laron dwarf mice and Laron dwarf patients, which have a low plasma IGF-I level, do not develop leukemias.”
Researchers determined the number of VSELs and HSCs in long-living murine strains with inborn low level of circulating IGF-I in Laron and Ames dwarf mice, as well as in short-living mice with high levels of circulating IGF-I. They then isolated and evaluated the epigenetic status of genes regulating pluripotency, as well as imprinted genes regulating IIS in those VSELs.
Kucia and colleagues found that the number of VSELs and HSCs residing in bone marrow inversely correlates with plasma growth hormone/IGF-I level. Thus, Laron and Ames dwarf mice, which have low levels of circulating plasma IGF-I, have higher numbers of VSELs and HSCs in their bone marrow. Unlike their aged-matched normal littermates, levels of VSELs and HSCs in these mice remained high even into advanced age. Analysis of the molecular signature of VSELs in these animals showed that prolonged retention of hypomethylation in the differentially methylated regions within the Igf2-H19 and Rasgrf1 loci, which attenuates IIS in these cells.
The number of VSELs decreased in these animals after prolonged treatment with growth hormone or recombinant IGF-I.
Conversely, mice with elevated IGF-I levels in plasma due to expression of the growth hormone transgene or normal wild-type mice injected for a sustained period with recombinant growth hormone both exhibit significant decreases in the number of VSELs and HSCs in bone marrow compared with control animals. Researchers observed attendant epigenetic changes in Igf2-H19 and Rasgrf1 loci, wherein the differentially methylated regions became hypermethylated over time.
The changes in methylation caused increases in IGF-II and Rasgrf1 expression and may explain why plasma growth factor transgenic mice have an increase in IIS that leads to a shorter life span, Kucia said. – by Jason Harris
Disclosure: Dr. Kucia reported no relevant financial disclosures.
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This set of experiments suggests that obese individuals and those with high levels of IGF-I would have less long-lived HSCs. This might impact quality of HSCs collected from overweight and obese individuals. We do know that older donors have less robust HSC, and the National Marrow Donor Program does not allow individuals older than 60 years of age to serve as unrelated donors due to falloff in the quality and quantity of HSCs. It would be an interesting study to examine the weight of individuals donating stem cells, the number of stem cells obtained and the quality of engraftment in recipients. This would have to be carefully analyzed due to the age effect, but it would be interesting to see if there is a correlation. A paper recently published in the journal Obesity showed a decrease in bone marrow endothelial cells due to the inflammation caused by obesity, but it is not quite that straightforward, as a reciprocal relationship with IGF-I levels and metabolic syndrome (obese type2 diabetics) has been described in humans. So, with more caveats, the findings in this abstract support the notion of caloric restriction and longevity of the whole organism, including the HSCs. Yet another reason to stay in shape.
Philip McCarthy Jr., MD
Director of the
Blood & Marrow Transplant Program
Roswell Park Cancer Institute,
Buffalo, N.Y.
Disclosure: Dr. McCarthy reports no relevant financial disclosures.
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