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Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Citation
Quipildor, G. E. F., et al. “Central Igf-1 Protects Against Features Of Cognitive And Sensorimotor Decline With Aging In Male Mice.”. Geroscience, pp. 185-208.
Center Albert Einstein College of Medicine University of Alabama at Birmingham
Multicenter
Multicenter
Author Gabriela E Farias Quipildor, Kai Mao, Zunju Hu, Ardijana Novaj, Min-Hui Cui, Maria Gulinello, Craig A Branch, Sriram Gubbi, Khushbu Patel, Douglas R Moellering, Stefano Tarantini, Tamas Kiss, Andriy Yabluchanskiy, Zoltan Ungvari, William E Sonntag, Derek M Huffman
Keywords aging, brain, Cognitive and sensorimotor decline, Cognitive function, Healthspan, IGF-1, Intransasal
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.

Year of Publication
2019
Journal
GeroScience
Volume
41
Issue
2
Number of Pages
185-208
Date Published
12/2019
ISSN Number
2509-2723
DOI
10.1007/s11357-019-00065-3
Alternate Journal
Geroscience
PMID
31076997
PMCID
PMC6544744
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