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J Gerontol A Biol Sci Med Sci. 2015 Jul;70(7):817-26. doi: 10.1093/gerona/glu114. Epub 2014 Jul 28.

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1.

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The Jackson Laboratory, Bar Harbor, Maine. Geriatric Research Division, Internal Medicine, School of Medicine, Southern Illinois University, Springfield.
The Jackson Laboratory, Bar Harbor, Maine.
The Jackson Laboratory, Bar Harbor, Maine. Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.


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.


Female sexual maturation; Genetics; Life span; Mouse; Pcsk2.

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