We previously reported that mouse strains with lower circulating insulin-like growth factor 1 (IGF1) level at 6 mo have significantly extended longevity. Here we report that strains with lower IGF1 have significantly delayed age of female sexual maturation, measured by vaginal patency (VP). Among strains with normal lifespans (mean lifespan >600 d), delayed age of VP associated with greater longevity (P = 0.015), suggesting a genetically regulated tradeoff at least partly mediated by IGF1. Supporting this hypothesis, C57BL/6J females had 9% lower IGF1, 6% delayed age of VP, and 24% extended lifespan compared with C57BL/6J.C3H/HeJ-Igf1, which carries a C3H/HeJ allele on chromosome (Chr) 10 that increases IGF1. To identify genetic loci/genes that regulate female sexual maturation, including loci that mediate lifespan tradeoffs, we performed haplotype association mapping for age of VP and identified significant loci on Chrs 4 (Vpq1) and 16 (Vpq2 and 3). At each locus, wildderived strains share a unique haplotype that associates with delayed VP. Substitution of Chr 16 of C57BL/6J with Chr 16 from a wild-derived strain significantly reduced IGF1 and delayed VP. Strains with a wild-derived allele at Vpq3 have significantly extended longevity compared with strains with other alleles. Bioinformatic analysis identified Nrip1 at Vpq3 as a candidate gene. Nrip1−/− females have significantly reduced IGF1 and delayed age of VP compared with Nrip1 +/+ females. We conclude that IGF1 may coregulate female sexual maturation and longevity; wild-derived strains carry specific alleles that delay sexual maturation; and Nrip1 is involved in regulating sexual maturation and may affect longevity by regulating IGF1 level.aging | reproduction | hormone E pidemiology studies have suggested that sexual maturation is genetically regulated (1, 2). According to evolutionary theory, natural selection plays an important role in selecting alleles that regulate female sexual maturation (3-5). The evolutionary theory of aging predicts that the timing of female sexual maturation is linked to the rate of aging by pleiotropic genes that mediate a tradeoff between sexual maturation and aging (6, 7). This theory is supported by a field population study of mammalian species ranging from mouse to elephant that identified a positive correlation between age of reproduction and lifespan (8). In rodent, caloric restriction delays female maturity and slows aging (9). Also, reduced female reproduction and extended longevity were found in most models that carry mutations in genes of the growth hormone/insulin-like growth factor 1 (IGF1) pathway (10). These studies suggest that the set of genes that regulate sexual maturation includes a subset of pleiotropic genes that mediate a lifehistory tradeoff between development and aging.Previous studies have suggested that considerable genetic variance of female reproductive development exists within Mus musculus. However, before our study, the age of sexual maturation of inbred strains had not been systematically measu...

Background Mast cells are a critical component of allergic responses in humans, and animal models that allow the in vivo investigation of their contribution to allergy and evaluation of new human-specific therapeutics are urgently needed. Objective We have developed a new humanized mouse model that supports human mast cell engraftment and human IgE-dependent allergic responses. Methods This model is based on the NOD-scid IL2rgnull SCF/GM-CSF/IL3 (NSG-SGM3) strain of mice engrafted with human thymus, liver and hematopoietic stem cells (termed BLT). Results Large numbers of human mast cells develop in NSG-SGM3 BLT mice and populate the immune system, peritoneal cavity, and peripheral tissues. The human mast cells in NSG-SGM3 BLT mice are phenotypically similar to primary human mast cells and express CD117, tryptase, and FcεRI. These mast cells undergo degranulation in an IgE-dependent and independent manner, and can be readily cultured in vitro for additional studies. Intradermal priming of engrafted NSG-SGM3 mice with a chimeric IgE containing human constant regions resulted in development of a robust passive cutaneous anaphylaxis (PCA) response. Moreover, we describe the first report of a human mast cell antigen-dependent passive systemic anaphylaxis (PSA) response in primed mice. Conclusions NSG-SGM3 BLT mice provide a readily available source of human mast cells for investigation of mast cell biology and a pre-clinical model of PCA and PSA that can be used to investigate the pathogenesis of human allergic responses and to test new therapeutics prior to their advancement to the clinic.

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