title: Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging.
abstract: Cognitive decline is a major biomedical challenge as the global population ages. Elevated levels of the longevity factor klotho suppress aging, enhance cognition, and promote synaptic plasticity and neural resilience against aging and Alzheimer's disease (AD)-related pathogenic proteins. Here, we examined the relationship between human genetic variants of KLOTHO and systemic klotho levels - and assessed neuroanatomic correlates of serum klotho in a cohort of healthy older adults. Serum klotho levels were increased with KL-VS heterozygosity, as anticipated. We report, for the first time, that serum klotho levels were paradoxically decreased with KL-VS homozygosity. Further, we found that higher serum klotho levels were associated with measures of greater intrinsic connectivity in key functional networks of the brain vulnerable to aging and AD such as the fronto-parietal and default mode networks. Our findings suggest that elevated klotho promotes a resilient brain, possibly through increased network connectivity of critical brain regions.
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA. jennifer.yokoyama@ucsf.edu.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Gabe
authors.initials: G
authors.lastname: Marx
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Neurology and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California, Los Angeles, CA, 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA. dena.dubal@ucsf.edu.
authors.forename: Dena B
authors.initials: DB
authors.lastname: Dubal
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D063132:Connectome / Q000379:methods; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005966:Glucuronidase / Q000097:blood* / Q000235:genetics*; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D009415:Nerve Net / Q000033:anatomy & histology* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013702:Temporal Lobe / Q000033:anatomy & histology* / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Aging; Cognition; Connectivity; Frontal cortex; Genetic variation; Imaging; Klotho; Longevity; Resilience