Morphology of ovaries in laron dwarf mice, with low circulating plasma levels of insulin-like growth factor-1 (IGF-1), and in bovine GH-transgenic mice, with high circulating plasma levels of IGF-1

Abstract

BackgroundIt is well known that somatotrophic/insulin signaling affects lifespan in experimental animals, and one of the signs of aging is progressive gonadal dysfunction.MethodsTo study the effects of insulin-like growth factor-1 (IGF-1) plasma level on ovaries, we analyzed ovaries isolated from 2-year-old growth hormone receptor knockout (GHR-KO) Laron dwarf mice, with low circulating plasma levels of IGF-1, and 6-month-old bovine growth hormone transgenic (bGHTg) mice, with high circulating plasma levels of IGF-1. The ages of the Laron dwarf mutants employed in our studies were selected based on their overall survival (up to ~ 4 years for Laron dwarf mice and ~ 1 year for bGHTg mice).ResultsMorphological analysis of the ovaries of mice that reached ~50% of their maximal life span revealed a lower biological age for the ovaries isolated from 2-year-old Laron dwarf mice than their normal-lifespan wild type littermates. By contrast, the ovarian morphology of increased in size 6 month old bGHTg mice was generally normal.ConclusionOvaries isolated from 2-year-old Laron dwarf mice exhibit a lower biological age compared with ovaries from normal WT littermates at the same age. At the same time, no morphological features of accelerated aging were found in 0.5-year-old bGHTg mice compared with ovaries from normal the same age-matched WT littermates.

Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries

“…Therefore, the increased expression of Amh, Gdf9, and Bmp15 in GHRKO mice suggests that these mice have a larger ovarian reserve than N mice of the same age. This observation confirms previous histological findings that 2-year-old GHRKO mice still have visible ovarian structures (antral follicles and corpora lutea) while N mice of the same age have already completely depleted their ovarian reserve (Sluczanowska-Glabowska et al 2012). Despite that, the expression of Amh, Gdf9, and Bmp15 was not altered by short-term PMA treatment in N mice, indicating that changes observed in the ovarian reserve of GHRKO female mice can be due to chronic suppression of IGF-I signaling.…”

“…A recent study has demonstrated that oocyte expression of a constitutively active form of Foxo3 in a transgenic mouse model is associated with the preservation of the ovarian reserve (Pelosi et al 2013) and, therefore, can be related to an ovarian phenotype characteristic of younger mice as observed in GHRKO mice in the current and previous studies (Sluczanowska- Fig. 1 Expression of Amh, Bmp15, and Gdf9 mRNA in a GHRKO (black bar) and normal mice (white bar), b normal mice treated with PMA (black bar) or DMSO (white bar), and c GHRKO mice treated with PMA (black bar) and DMSO (white bar) Glabowska et al 2012). Studies in other tissues generally indicate that higher FOXO3 mRNA expression predicts also higher level of nuclear FOXO3 (Essaghir et al 2009;Turrel-Davin et al 2010).…”

“…However, treating GHRKO females with IGF-I decreases the number of primordial follicles and increases the number of healthy antral follicles (Slot et al 2006), suggesting that IGF-I-induced signaling promotes primordial follicle activation and antral follicle survival. In addition, previous evidence indicates that GHRKO female mice have a prolonged reproductive lifespan, as indicated by the presence of ovarian activity at a later age (older than 20 months) when N mice have already depleted the ovarian follicular reserves (Sluczanowska-Glabowska et al 2012).…”

Very small embryonic-like stem cells as a novel developmental concept and the hierarchy of the stem cell compartment

“…Specifically, our data on longliving murine strains (e.g., Laron dwarf or Ames dwarf mice) that have very low levels of circulating IGF-1 in peripheral blood have demonstrated that these animals have greater numbers of VSELs than age-matched normal wild type animals. By contrast, shortliving mice with overexpression of growth hormone (GH) and thus high levels of circulating IGF-1 have reduced numbers of VSELs in their tissues [29,30,75,95,96].…”

The somatotropic axis and aging: Benefits of endocrine defects

“…Importantly, in both GH-resistant (GHRKO) and GH-deficient [hypopituitary Ames dwarf (Prop1 df ) and Snell dwarf (Pit1 dw )] mice, extension of average, median and maximal longevity is associated with improved maintenance of physical and cognitive function, resistance to oxidative stress, as well as reduced incidence and/or delayed onset of neoplasms and other age-related pathologies [4–6]. Trade-offs include major decreases in growth rate and adult body size, delayed maturation and reduced fertility [4, 6, 5, 7] which appears to be partially offset by a delay in reproductive aging [8, 9]. …”