Age-Associated Loss of Bone Marrow Hematopoietic Cells Is Reversed by GH and Accompanies Thymic Reconstitution

Abstract

Deterioration of the thymus gland during aging is accompanied by a reduction in plasma GH. Here we report gross and microscopic results from 24-month-old Wistar-Furth rats treated with rat GH derived from syngeneic GH3 cells or with recombinant human GH. Histological evaluation of aged rats treated with either rat or human GH displayed clear morphologic evidence of thymic regeneration, reconstitution of hematopoietic cells in the bone marrow, and multiorgan extramedullary hematopoiesis. Quantitative evaluation of formalin-fixed, hematoxylin and eosin-stained sections of bone marrow from aged rats revealed at least a 50% reduction in the number hematopoietic bone marrow cells, compared with that of young 3-month-old rats. This age-associated decline in bone marrow leukocytes, as well as the increase in bone marrow adipocytes, was significantly reversed by in vivo treatment with GH. Restoration of bone marrow cellularity was caused primarily by erythrocytic and granulocytic cells, but all cell lineages were represented and their proportions were similar to those in aged control rats. On a per-cell basis, GH treatment in vivo significantly increased the number of in vitro myeloid colony forming units in both bone marrow and spleen. Morphological evidence of enhanced extramedullary hematopoiesis was observed in the spleen, liver, and adrenal glands from animals treated with GH. These results confirm that GH prevents thymic aging. Furthermore, these data significantly extend earlier findings by establishing that GH dramatically promotes reconstitution of another primary hematopoietic tissue by reversing the accumulation of bone marrow adipocytes and by restoring the number of bone marrow myeloid cells of both the erythrocytic and granulocytic lineages.

Growth hormone receptor signaling is dispensable for HSC function and aging

“…We did not observe changes in myeloid potential reported in earlier studies that used systemic rGh treatment 5,7 suggesting that these previous observations reflect noncell autonomous changes in hematopoietic lineage potential. Together, our results show that exogenous rGh treatment differentially affects lineage potential of young and old HSCs, and induces a more balanced lineage output from aged HSCs.…”

“…1 The importance of cell autonomous regulation of hematopoietic stem cell (HSC) potential throughout aging is well established, although emerging evidence suggests that HSC potential may also be regulated by environmental cues that are subject to age-related variation. 2 Growth hormone (Gh) signaling has been implicated in a variety of age-related hematopoietic phenotypes, [3][4][5] and exogenous Gh can enhance or restore young or aged hematopoietic cellularity and function, respectively. [5][6][7][8][9][10] Studies have proposed that Gh mediates its hematopoietic effects indirectly through nonhematopoietic cells within the bone marrow (BM) 7,11 ; however, as the Gh responsive cell was not identified in these studies, it remains unclear whether Gh directly targets hematopoietic stem/progenitor cells in a cell autonomous manner.…”

Growth hormone enhances thymic function in HIV-1–infected adults

“…Although GH and IGF-1 enhance multilineage hematopoiesis (26,(43)(44)(45)(46), GH treatment did not appear to be associated with substantial changes in circulating hematopoietic cells. The number of circulating CD34 + cells (a population that presumably includes prethymic progenitor cells) was not altered.…”

Ghrelin promotes thymopoiesis during aging

“…Similar pro-thymic effects were observed in 8-month-old C57BL/6 mice upon ghrelin infusion (Supplemental Figure 1C), suggesting that effects of ghrelin on thymic cellularity are not strain dependent. It has been previously reported that activation of the GH-IGF-1 axis can significantly attenuate thymic involution (25) and promote hematopoiesis (26). Ghrelin is also known to be a potent stimulator of the somatotropic axis in the young animals (8); therefore, we next examined the impact of ghrelin infusion on the GH-IGF-1 axis in old mice.…”

“…In addition, recent studies have demonstrated that autologous peripheral blood stem cell transplants in breast cancer patients (20), androgen ablation by castration in old mice (21), and gonadotropin-releasing hormone agonist treatment in both rodents (22,23) and prostate cancer patients (24) can significantly promote thymic renewal. In addition, past studies have demonstrated a thymopoietic and hematopoietic effects for GH (25,26), IGF-1 (27), and GH secretagogues (28) during aging. Here we provide evidence that signaling of the orexigenic peptide hormone ghrelin through GHS-R serves an important biological role in generation of naive T cells and ageassociated thymic involution.…”