Variation in longevity gene KLOTHO is associated with greater cortical volumes

OBJECTIVE: Identifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype “KL-VS” in longevity gene KLOTHO (KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies. METHODS: We performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL-VS and gray matter volume using voxel-based morphometry. RESULTS: We found that KL-VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex (rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL-VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition. INTERPRETATION: These results suggest that variation in KL is associated with bigger brain volume and better function.