Abstract
Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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Acknowledgements
This work was supported by R00 AG037574, the American Federation for Aging Research (AFAR), and Einstein Startup Funds to D.M.H. This work was also supported by the Einstein Nathan Shock Center (P30 AG038072) and the Einstein-Sinai Diabetes Research Center (P30 DK020541). We would also like to acknowledge support from the NCI supported Einstein Cancer Center (P30 CA013330). This work was also supported by R01 AG055395 and R01 NS100782 to Z.U. and R01 AG 038747 and R01 NS 056218 to W.E.S. Mitochondrial assays were performed with assistance from the UAB Diabetes Research Center BARB Core (P30 DK079626). Einstein Analytical Imaging Core were supported by NIH SIG awards (no. 1S10OD019961-01; 1S10OD023591-01). We would also like to acknowledge Vera DesMarais and Hillary Guzik for expert advice/assistance in microscopy and software analysis. Finally, we would like to thank Drs. Pinchas Cohen and Junxiang Wan in the USC Aging Biomarker Core for technical advice and assistance with IGF-1 assays.
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GEFQ, MHC, CAB, ZU, MG, WES, and DMH designed the experiments. GEFQ, KM, ZH, AN, MHC, KP, DRM, ST, TK, and AY performed the experiments. GEFQ, ZH, MHC, CAB, KP, DRM, ZU, and DMH analyzed and interpreted the data. GEFQ, ZU, and DMH wrote the manuscript and SG, WES, ST, TK, AY, and MHC revised the paper.
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Farias Quipildor, G.E., Mao, K., Hu, Z. et al. Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. GeroScience 41, 185–208 (2019). https://doi.org/10.1007/s11357-019-00065-3
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DOI: https://doi.org/10.1007/s11357-019-00065-3