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 ADsuch 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.

Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.

“…As an anti‐aging protein, β‐Klotho could retard the aging process through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy, and regulation of many signalling pathways (including insulin‐like growth factor and Wnt) . Furthermore, β‐Klotho plays an important role in the progression of aging‐related diseases such as vascular diseases and neurodegeneration . It is well known that aging is always accompanied by muscle atrophy and weakness.…”

“…8 Furthermore, β-Klotho plays an important role in the progression of aging-related diseases such as vascular diseases and neurodegeneration. 9,10 It is well known that aging is always accompanied by muscle atrophy and weakness. Thus, we speculate that extremely elevated FGF21 level may cause a relative deficiency in the levels of β-Klotho, which would weaken the anti-aging effect, thus leading to muscle mass loss; in other words, muscle atrophy may be attributed to the imbalance in FGF21-β-Klotho signalling caused by relative up-regulation of FGF21.…”

Longevity factor klotho and resistance to cognitive deficits in a transgenic mouse model and in individuals with Parkinson’s disease

“…Transgenic overexpression of klotho extends lifespan 7,8 and enhances cognition 8-10 in young mice and those that model AD, in part by increasing synaptic plasticity through NMDA receptordependent mechanisms [8][9][10] . In humans, a single allele genetic variant of KLOTHO, KL-VS, leads to increased serum levels of klotho 8, 18,19 . Carrying one allele of KL-VS associates with longer life 18 , better cognitive function in aging 8,20 , less cognitive decline in aging 21 , and protection against APOE 4-driven risk for Alzheimer's disease 22,23 .…”

Stemming the Alzheimer tsunami: introduction to the special issue on reserve and resilience in Alzheimer’s disease

“…While certain genetic variants, such as APOE4 , are now known to increase the risk of AD (Lambert et al, 2013), the study of genes that provide resilience against AD is just emerging. Two papers in this Special Issue investigated concepts related to such “genetic resilience.” The first one, by Yokoyama et al (2016) focused on the longevity promoter KLOTHO ( KL-VS ) and its systemic levels, building off prior studies that showed that KL-VS heterozygosity was associated with better cognition and resilience against AD pathologies (Dubal et al, 2015). The authors reported that klotho levels are increased with KL-VS heterozygosity but paradoxically decreased with KL-VS homozygosity.…”