Longevity factor klotho enhances cognition in aged nonhuman primates

Abstract

Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.

Development of an α-Klotho Recognizing High-Affinity Peptide Probe from In-Solution Enrichment

“…α-Klotho (hereinafter abbreviated as Klotho) is a transmembrane protein related to aging. , Klotho acts as a coreceptor for fibroblast growth factor 23 (FGF23) by binding to fibroblast growth factor receptors (FGFR) 1c, 2c, and 4, to primarily regulate phosphate homeostasis in the kidney. − When the extracellular domain of Klotho is cleaved by the ADAM family proteases, it is secreted into circulation as soluble Klotho . Klotho levels significantly decrease in various age-related dysfunctions, including diabetes, cancers, Alzheimer’s disease, and chronic kidney disease (CKD). − In support of potential clinical relevance, it was shown that a single administration of low-dose secreted Klotho (10 μg/kg) was able to enhance memory in aging rhesus macaques . In addition, Klotho is thought to have an antifibrotic effect in CKD. , Given its role as a biomarker and a potential hormone, it is crucial to develop reagents capable of accurately detecting Klotho with high affinity and selectivity.…”

“… 6 − 9 In support of potential clinical relevance, it was shown that a single administration of low-dose secreted Klotho (10 μg/kg) was able to enhance memory in aging rhesus macaques. 10 In addition, Klotho is thought to have an antifibrotic effect in CKD. 8 , 11 Given its role as a biomarker and a potential hormone, it is crucial to develop reagents capable of accurately detecting Klotho with high affinity and selectivity.…”

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer’s disease-linked brain microRNAs and tRNA fragments

“…Klotho-deficient mice show premature aging symptoms, including cognitive decline 3 , whereas Klotho excess extends lifespan and improves cognitive functions 4,5 . Injected Klotho enhances cognition in aged rhesus macaques 6 , while Klotho overexpression improves amyloid-β clearance and cognition in one AD mouse model 7 , and LTP and behavior in another AD model 5 . Moreover, human AD patients show lower Klotho levels in the cerebrospinal fluid (CSF) than age-matched controls 8 , contrasting a human variant that elevates the levels of the functional Klotho protein and which associates with both longevity 9 and lower AD risk 10 .…”

Functional and Extracellular Production and Antitumor Activity of Mouse Alpha Klotho in Model Microalga Chlamydomonas reinhardtii

“…[2] Beyond its transmembrane domain, the fibronectin type III-like extracellular domain of KL contains two tandem repeats; α-Klotho and β-Klotho, responsible for binding to fibroblast growth factor receptors (FGPRs). Secreted α-KL (sKL) circulates as a hormone after being liberated from cellular transmembrane domain and regulates various physiological processes such as wingless-related integration site (Wnt), insulin, [3] and fibroblastic growth factor (FGF) signaling, [4] mineral and cognitive homeostasis, [5] and N-methyl-D-aspartate receptor (NMDAR) function, [6] and the aging process. [7,8] α-KL is the most extensively studied isoform and is primarily expressed in brain and kidney distal tubule cells, where it controls phosphate (Pi) absorption and 1,25-dihydroxyvitamin D3 activity.…”