Abstract
Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.
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Acknowledgements
This study could not have been performed without the support of Dr. Shoshanna Yakar, who provided the mouse strain used to derive these cohorts. The authors would also like to thank the staff of the Rodent Barrier Facility at the University of Oklahoma Health Sciences Center, especially Bonita Johnson, for superb animal care throughout this study, as well as Jessica Landoll, Eileen Parks, Alex Yeganeh, and Dr. Arlan Richardson for their scientific input. This work was supported by grants from the National Institute on Aging (R01-AG038747 to W.E.S, R01-AG047879 to A.C., F32AG048728 to N.M.A), the American Federation for Aging Research (AFAR Breakthroughs in Gerontology Award to W.E.S.), the Ellison Medical Research Foundation Senior Scholar Award (to W.E.S.), the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to Z.U.; P30 AG028718), the Oklahoma Center for the Advancement of Science and Technology (to A.C., Z.U., W.E.S.), the San Antonio Nathan Shock Center Pathology Core (P30 AG013319), the Oklahoma Nathan Shock Center of Excellence in the Biology of Aging (P30 AG050911), and the Donald W. Reynolds Foundation.
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Ashpole, N.M., Logan, S., Yabluchanskiy, A. et al. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. GeroScience 39, 129–145 (2017). https://doi.org/10.1007/s11357-017-9971-0
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DOI: https://doi.org/10.1007/s11357-017-9971-0