Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

Abstract

We previously reported that insulin-like growth factor 1 (IGF1) was involved in coregulating female sexual maturation and longevity. To understand the underlying genetic mechanisms, based on the strain survey assays of development and aging traits, we crossed two mouse strains, KK/HIJ and PL/J, and produced 307 female F2 mice. We observed the age of vaginal patency (AVP) and the life span of these females. We also measured circulating IGF1 level at 7, 16, 24, 52, and 76 weeks. IGF1 level at 7 weeks significantly correlated with AVP. IGF1 levels at ages of 52 and 76 weeks negatively correlated with longevity (p ≤ .05). A gene mapping study found 22, 4 ,and 3 quantitative trait loci for IGF1, AVP, and life span, respectively. Importantly, the colocalization of IGF1, AVP, and life span quantitative trait loci in the distal region of chromosome 2 suggests this locus carries gene(s) that could regulate IGF1, AVP, and life span. In this region, proprotein convertase subtilisin/kexin type 2 has been found to be associated with female sexual maturation in a human genome-wide association study. We verified the roles of proprotein convertase subtilisin/kexin type 2 in regulating IGF1 and AVP by showing that depletion of proprotein convertase subtilisin/kexin type 2 significantly reduced IGF1 and delayed AVP in mice, suggesting that it also might be involved in the regulation of aging.Key Words: Female sexual maturation-Life span-Genetics-Mouse-Pcsk2. Decision Editor: Rafael de Cabo, PhDThe evolutionary theory of aging predicts the existence of pleiotropic genes that mediate female sexual maturation (FSM) and life span (1,2). Several lines of evidence support this hypothesis. In the invertebrates, researchers found that allowing only older female Drosophila to reproduce resulted in decreased female fecundity and increased life span in later generations (3,4). In wild mammalian species, ranging from mice to elephants show that the later the initial age of reproduction, the longer the life span (5). The tradeoff holds within species as well. For example, opossums living on a predator-free island in Virginia matured later and aged more slowly than opossums on the "more dangerous" mainland (6). Mice trapped in the wild had delayed FSM and greater female reproduction life span and longevity compared with laboratory mice (7,8). However, the underlying genetic and molecular mechanisms have yet to be clarified.Our previous studies systematically measured age of FSM and longevity in more than 30 mouse inbred strains (9,10). The age of

Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice

“…Additionally, it has been shown before that lower GH/IGF levels correlate with increased lifespan and delayed sexual maturation in different strains of mice, which also indicates the existence of a tradeoff between growth rate, sexual maturation and longevity (Yuan et al, 2012; Yuan et al, 2015). The FoxO transcription factor can be a central player in this regulation, since its increased activation is linked to accelerated aging in several model organisms (Kenyon, 2010).…”

GH and ageing: Pitfalls and new insights

“…Importantly, this relationship was also shown in individual mice from a genetically heterogeneous population produced by crossing inbred animals [107]. Furthermore, in a study of multiple mouse strains, longevity was negatively related to circulating IGF-1 levels [108]. The same study provided evidence that female sexual maturation is occurring later in mice from longer living strains, thus resembling the findings in long-lived GH-related mutants [109, 110].…”

“…This is in spite of the fact that the bulk of information gathered from studies in various animal species (including humans) is in general agreement. To reiterate some of the key findings discussed earlier in this article: In laboratory mice, GH-deficiency or resistance is associated with extension of healthspan, delayed onset and reduced incidence of age-related disease and a remarkable extension of longevity [20, 21, 43, 44];In humans, the same endocrine syndromes are associated with protection from some of the age-related diseases [44, 145], and from insulin resistance [146];In endocrinologically normal humans, genetic polymorphisms in genes related to the somatotropic axis and its downstream target FOXO3, and variation in the level of IGF-1 are associated with differences in the “risk” of achieving exceptional longevity [119, 121–123];Adult body size, a GH/IGF-1 dependent trait, is associated with extended longevity in laboratory rodents (including both normal and genetically altered animals) [44, 105–108], in various domestic animals (carnivores and ungulates) [114–117], and also, albeit less consistently, in the human [118, 119]. …”

“…Adult body size, a GH/IGF-1 dependent trait, is associated with extended longevity in laboratory rodents (including both normal and genetically altered animals) [44, 105–108], in various domestic animals (carnivores and ungulates) [114–117], and also, albeit less consistently, in the human [118, 119]. …”

Mitochondrial maintenance failure in aging and role of sexual dimorphism

“…This prediction is supported by the fact that the onset of senescence often correlates with the sexual and reproductive maturation of the animal [18, 115, 119, 120]. ROS signaling [121] can promote mammalian cell differentiation [122, 123], sexual differentiation in yeasts [124, 125] and reproduction in humans [126, 127].…”