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 approximately 129 weeks, equivalent to approximately 80 years in humans.
“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
The Results section reports lifespans for B6 (C57BL/6J) mice, so the source supports identifying this strain and discussing its lifespan. It gives mean lifespans of 810 ± 32 days for females and 866 ± 28 days for males, but does not give the claimed median of approximately 129 weeks. The human-age equivalence is attached to a different citation and is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany mouse strains survive longer than 600 days in standard SPF housing.
“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]
The Discussion reports strains with mean lifespans longer than 600 days, supporting the lifespan portion of the claim. Materials and Methods describes housing in ventilated cages with HEPA-filtered air, but does not identify the housing as standard specific-pathogen-free (SPF) housing. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDoxycycline-treated control mice showed no significant difference in median survival compared with historical published BL6/J mice, suggesting that doxycycline alone had no adverse or advantageous effects.
“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
The Results compare survival between B6 and B6.C3H-Igf1 mice, and the Materials and Methods describe mouse husbandry, but neither addresses doxycycline treatment. Searches for doxycycline and for treated controls compared with historical B6/J mice found no passage supporting the claimed effect on median survival. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Назарова, Г. Г., Proskurnyak, L. P., & Yuzhik, E. I. (2021) · Biology Bulletin · doi:10.1134/s1062359021090168 · Cited by 2 · see citing works
- 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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