Local non-pituitary growth hormone is induced with aging and facilitates epithelial damage

Abstract

SUMMARY Microenvironmental factors modulating age-related DNA damage are unclear. Non-pituitary growth hormone (npGH) is induced in human colon, non-transformed human colon cells, and fibroblasts, and in 3-dimensional intestinal organoids with age-associated DNA damage. Autocrine/paracrine npGH suppresses p53 and attenuates DNA damage response (DDR) by inducing TRIM29 and reducing ATM phosphorylation, leading to reduced DNA repair and DNA damage accumulation. Organoids cultured up to 4 months exhibit aging markers, p16, and SA-β-galactosidase and decreased telomere length, as well as DNA damage accumulation, with increased npGH, suppressed p53, and attenuated DDR. Suppressing GH in aged organoids increases p53 and decreases DNA damage. WT mice exhibit age-dependent colon DNA damage accumulation, while in aged mice devoid of colon GH signaling, DNA damage remains low, with elevated p53. As age-associated npGH induction enables a pro-proliferative microenvironment, abrogating npGH signaling could be targeted as anti-aging therapy by impeding DNA damage and age-related pathologies.

Cellular reprogramming as a tool to model human aging in a dish

“…Recent studies have used organoids to study cellular aging 14 , 102 , 103 and to identify treatments to ameliorate age-related diseases 104 , 105 . For example, brain organoids generated from iPSCs isolated from patients suffering from ataxia-telangiectasia (carrying a mutation in the ataxia-telangiectasia-mutated (ATM) gene that encodes the ATM kinase) have been used to investigate the impact of ATM kinase absence in the nervous system 14 .…”

“…In a separate study, brain organoids generated from AD iPSC-derived cells or γ-irradiated brain organoids generated from wild-type cells, have been also used to screen drugs 104 , 105 . Moreover, aged colon organoids were obtained from human iPSCs to investigate whether DNA damage response was inversely correlated with an increase in the production of growth hormone 102 . Cellular aging was confirmed by an increase of p16, DNA damage, decrease of telomere length, increase in senescence-associated β-galactosidase activity and expression.…”

A narrative review of organoids for investigating organ aging: opportunities and challenges

“…[140] Age-associated increase in non-pituitary growth hormone (npGH) and p16 levels and decrease in telomere length are observed in intestinal organoids cultured for up to 4 months. [141] Moreover, investigations of age-induced changes in niche-stem cell communications reveal that the induction of notum in aged Paneth cells, the niche cells supporting the intestinal stem cells, inhibits WNT signaling in stem cells and abrogates their regenerative potentials. [87] Based on many research models, many intervention strategies have been exploited to delay aging.…”

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

“…Melmed and colleagues have elegantly described a critical role of peripheral/non-pituitary GH in the aging colon in abetting a tumor supportive microenvironment ( 13 ). An increasing mutational burden due to age or external mutagens in normal cells trigger p53 production, and GH was found to be a p53 target ( 14 – 16 ). In turn, GH suppresses p53 production by a negative feedback loop, suppresses DNA damage repair (DDR) pathways ( 16 , 17 ), as well as causes an extensive remodeling of the extracellular matrix (ECM) in direct support of tumor progression ( 13 ).…”

“…An increasing mutational burden due to age or external mutagens in normal cells trigger p53 production, and GH was found to be a p53 target ( 14 – 16 ). In turn, GH suppresses p53 production by a negative feedback loop, suppresses DNA damage repair (DDR) pathways ( 16 , 17 ), as well as causes an extensive remodeling of the extracellular matrix (ECM) in direct support of tumor progression ( 13 ). Additionally, Lobie and colleagues have described in much detail, the anti-apoptotic and cancer stem cell-inducing actions of autocrine GH in breast, liver, endometrial and colorectal cancers ( 18 – 27 ).…”