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). Agerelated 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

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BackgroundThe complement system can act as part of the innate immune system as well as the adaptive immune system. Complement activation in the brain has been shown to play a role in neurogenesis, synaptic pruning and plasticity. It has also been specifically involved in microglial function, since our group has previously shown that when the complement component 3a receptor 1 (C3aR1) is disrupted in mice, phagocytosis by primary microglia cells is impaired as compared to WT microglia. Therefore, it is hypothesized that complement might have neuroprotective effects early in life but neurotoxic effects later in life or within a disease context, such as during Alzheimer’s disease (AD) impeding to effectively clear hallmarks of the disease.MethodWe performed bulk RNA sequencing (RNAseq) analysis from cortex tissue of 8mo old male and female wild‐type, C3aR1 knock‐out (KO), 5xFAD and 5xFAD‐C3aR1 KO mice. We also performed Barnes Maze on these mice to assess spatial learning and memory, as well as biochemical assays to measure several AD markers.ResultData obtained from RNAseq analysis has shown a sexually‐dimorphic trend in various differentially‐expressed genes (DEGs). For instance, when comparing 5xFAD‐C3aR1 KO with 5xFAD mice, male mice show downregulated DEGs in axon guidance and calcium signaling pathways according to KEGG pathway terms, but this is not seen in females. Similarly, barnes maze has shown sexually‐dimorphic differences, with 5xFAD‐C3aR1 KO male mice showing improve memory and learning when compared to 5xFAD mice, and no differences are seen in female mice.ConclusionInterestingly, other studies in humans have shown increased complement proteins in the cerebrospinal fluid of men, compared to women, showing the importance of studying the complement system in both males and females. Assessing these sexually‐dimorphic differences in this AD mouse model is also important, given that generally not only female mice present more aggressive phenotypes of AD, but also AD in humans is more prevalent in women.