Transatlantic Alliance Award

Shlomo Melmed

Transatlantic Alliance Award

Presented to an international leader for advancements through collaboration in the USA and Europe

Growth hormone: an adult endocrine misnomer

Growth hormone (GH), secreted by the anterior pituitary gland, elicits profound effects on skeletal growth, metabolism and body composition. Most growth-promoting actions are mediated by induced production of hepatic and local tissue insulin-like growth factor-1 (IGF1) levels. GH also exerts direct effects, independent of IGF1.

The GH receptor (GHR) is expressed in multiple tissues, and may be activated by the GH ligand derived from the pituitary, or from local tissue autocrine/paracrine/intracrine GH synthesis. Local, non-pituitary GH (npGH) signals on peripheral tissue GHR to induce cell proliferation by suppressing p53, thereby releasing epithelial cells from proliferative restraint. Furthermore, npGH increases with ageing, blocks repair of age-associated DNA damage, and is a component of the senescence-associated secretory phenotype, enabling a pro-proliferative epithelial field change. Blocking GHR signalling also increases p53, which restrains proliferation.

These mechanisms may underlie the known protective effects of both GH deficiency and GHR signalling disruption on age-associated pathologies, including cancer. Once final adult height has been achieved, GH actions appear to mediate maintenance of symmetrical homeostasis and body composition. With ageing, a switch occurs whereby GH leads to accumulated DNA damage, thereby exacerbating adverse ageing-related diseases.

Elucidation of these mechanisms cautions against inappropriate GH abuse by adults, and also points to the potential for blocking GH action to enable extended lifespan. These postulates highlight adult GH as a regulator of the cellular microenvironment by suppressing age-associated DNA damage repair, rather than functioning exclusively as a promoter of skeletal height.

(Text prepared with my colleagues Vera Chesnokova and Svetlana Zonis.)

‘With ageing, a switch occurs whereby GH leads to accumulated DNA damage, thereby exacerbating adverse ageing-related diseases.’