GH and Senescence: A New Understanding of Adult GH Action

Author:

Chesnokova Vera1,Melmed Shlomo1ORCID

Affiliation:

1. Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

Abstract

Abstract Replicative senescence occurs due to an inability to repair DNA damage and activation of p53/p21 and p16INK4 pathways. It is considered a preventive mechanism for arresting proliferation of DNA-damaged cells. Stably senescent cells are characterized by a senescence-associated secretory phenotype (SASP), which produces and secretes cytokines, chemokines, and/or matrix metalloproteinases depending on the cell type. SASP proteins may increase cell proliferation, facilitating conversion of premalignant to malignant tumor cells, triggering DNA damage, and altering the tissue microenvironment. Further, senescent cells accumulate with age, thereby aggravating age-related tissue damage. Here, we review a heretofore unappreciated role for growth hormone (GH) as a SASP component, acting in an autocrine and paracrine fashion. In senescent cells, GH is activated by DNA-damage-induced p53 and inhibits phosphorylation of DNA repair proteins ATM, Chk2, p53, and H2AX. Somatotroph adenomas containing abundant intracellular GH exhibit increased somatic copy number alterations, indicative of DNA damage, and are associated with induced p53/p21. As this pathway restrains proliferation of DNA-damaged cells, these mechanisms may underlie the senescent phenotype and benign nature of slowly proliferating pituitary somatotroph adenomas. In highly proliferative cells, such as colon epithelial cells, GH induced in response to DNA damage suppresses p53, thereby triggering senescent cell proliferation. As senescent cells harbor unrepaired DNA damage, GH may enable senescent cells to evade senescence and reenter the cell cycle, resulting in acquisition of harmful mutations. These mechanisms, at least in part, may underlie pro-aging effects of GH observed in animal models and in patients with chronically elevated GH levels.

Funder

National Institutes of Health

Publisher

The Endocrine Society

Subject

Endocrinology, Diabetes and Metabolism

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