Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging

Abstract

The dream of slowing down the aging process has always inspired mankind. Since stem cells are responsible for tissue and organ rejuvenation, it is logical that we should search for encoded mechanisms affecting life span in these cells. However, in adult life the hierarchy within the stem cell compartment is still not very well defined, and evidence has accumulated that adult tissues contain rare stem cells that possess a broad trans-germ layer differentiation potential. These most-primitive stem cells—those endowed with pluripotent or multipotent differentiation ability and that give rise to other cells more restricted in differentiation, known as tissue-committed stem cells (TCSCs) - are of particular interest. In this review we present the concept supported by accumulating evidence that a population of so-called very small embryonic-like stem cells (VSELs) residing in adult tissues positively impacts the overall survival of mammals, including humans. These unique cells are prevented in vertebrates from premature depletion by decreased sensitivity to growth hormone (GH), insulin (INS), and insulin-like growth factor (IGF) signaling, due to epigenetic changes in paternally imprinted genes that regulate their resistance to these factors. In this context, we can envision nutrient response GH/INS/IGF signaling pathway as a lethal factor for these most primitive stem cells and an important culprit in aging.

The effects of growth hormone on therapy resistance in cancer

“…diabetic nephropathy [56][57][58] , and multi-organ failures leading to a significantly reduced lifespan [59] . Mouse models of GH excess -mice transgenic for bovine GH (bGH) -corroborate the above human data [2,42,[60][61][62] . These pleiotropic effects of GH action positions GH as a truly enigmatic biomolecule and a topic of intense research in human health for the last century.…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…Additional factors that lead to the GHRKO mice being the longest-lived mouse in the world include the following -(i) increased stress resistance resulting from superior redox homeostasis due to upregulated expression and activity of glutaredoxin and thioredoxin detoxification systems (214,215,216,217) rather than changes in free-radical scavenging(218), (ii) reduced activity of TORC1 kinase complex (219, 220, 221), (iii) resistance to neoplastic incidence and growth(24, 97), (iv) suppressed hypothalamic inflammation(222) -an end-goal of anti-ageing drugs(223), (v) an anti-inflammatory adipokine profile, inverted liver-WAT lipid distribution and reduced senescent cell burden in WAT(62, 68, 70, 72), (vi) increased markers of mitochondrial biogenesis including higher levels of AMPK, SIRT1, and SIRT3 in heart and increased eNOS and PGC1α levels in skeletal muscle and kidney (224), (vii) detrimental effects of GH/IGF axis on very small embryonic-like stem cell pools in adult tissues (225,226) where age-related changes in DNA methylation patterns lead to increased sensitivity to circulating GH, IGF-1 and insulin with age with concomitant depletion of stem-cell pool and impaired tissue regeneration(225), (viii) resistance to diabetogenic effects of a HF diet (14), and (ix) improved insulin sensitivity(15).…”

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways that Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

“…Speci cally, maternal diabetes and HF diet caused down regulation of a well-known glucose and insulin signaling pathway, FGRF2/PI3K/AKT, as well as a concomitant upregulation of fatty acid regulated PGC1α [52]. Both pathways sense nutrient supply to in uence cellular metabolism as well as growth, development and aging [39,40,53].…”

“…We previously demonstrated that combination exposed offspring (P1) are exposed to high levels of circulating maternal glucose and lipids which incite insulin and C-peptide overproduction in the offspring [26][27][28][29]37]. This triad of maternal hyperglycemia and hyperlipidemia and fetal hyperinsulinemia causes insulin resistance with attendant downregulation of growth hormone receptors and less PI3K/AKT activation to drive a glycolysis-to-gluconeogenesis switch [29,[38][39][40]. Informed by the observed disruption in the gene regulatory network in the present study, circulating insulin, c-peptide, and the cardiac Fgfr2 gene and FGFR2 protein expression were assessed.…”