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Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains
Open accessAbstract
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, wild-derived 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.
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“WT C57BL6/J mice have a median lifespan of ∼129 weeks (Yuan et al., 2012), equivalent to ∼80 years in humans (Ackert-Bicknell et al., 2015)”
From Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (2024) · cites this paper as Yuan et al., 2012
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“as many mouse strains survive longer than 600 days in standard SPF housing [351].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [351]
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“we found no significant differences in median survival, suggesting that doxycycline alone had no adverse nor advantageous effects (Fig. 1b)”
From Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (2024) · cites this paper as Yuan et al., 2012
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Metadata
- Authors
- Yuan, R., Meng, Q., Nautiyal, J., Flurkey, K., Tsaih, S.-W., Krier, R., Parker, M. G., Harrison, D. E., & Paigen, B.
- Affiliations
- Jackson Laboratory (US)
- Imperial College London (GB)
- Medical College of Wisconsin (US)
- The Jackson Laboratory, Bar Harbor, ME 04609;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-05-07
- Volume
- 109
- Issue
- 21
- Pages
- 8224-8229
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3361401
- OpenAlex
- W2077067158
- Cited by
- 121
- References
- 50
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 10 · 2023: 18 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 8 · 2013: 7 · 2012: 1
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute on Aging (R21AG034349, AG034349, P30AG025707, AG-038070, AG025707, R01AG038560, AG038560, P30AG038070)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- insulin-like growth factor I, female sexual maturation, lifespan, inbred mouse strains, NRIP1, C57BL/6J mice, C3H/HeJ
- MeSH terms
- Nuclear Receptor Interacting Protein 1, Aging, Animals, Body Weight, Female, Haplotypes, Insulin-Like Growth Factor I, Longevity, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Nuclear Proteins, Sexual Maturation, Species Specificity, Genomics, Adaptor Proteins, Signal Transducing, Mice
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