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

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

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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.

Original languageEnglish
Pages (from-to)185-208
Number of pages24
Issue number2
StatePublished - 15 Apr 2019
Externally publishedYes


  • Aging
  • Brain
  • Cognitive and sensorimotor decline
  • Cognitive function
  • Healthspan
  • IGF-1
  • Intransasal


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