Klotho, Kidneys and Micronutrient Signaling, a Promising Paradigm for Healthy Aging.

Abstract

Klotho, a transmembrane protein with pleiotropic anti-aging properties, is increasingly recognized as a central regulator of longevity and metabolic resilience. Primarily expressed in the kidneys and brain, Klotho governs phosphate and calcium homeostasis, modulates redox signaling, and influences key metabolic pathways, including PI3K/AKT and IGF-1. Declining Klotho expression is associated with both biological and chronological aging and has been mechanistically implicated in the pathogenesis of chronic kidney disease (CKD), cardiovascular disease (CVD), neurodegeneration, and metabolic dysfunction. Klotho expression is modifiable through diet, in preclinical and observational offering a promising avenue for delaying cellular aging and preserving physiological function. Micronutrients such as magnesium, vitamin D, folate, and vitamin B12, as well as phytochemicals including sulforaphane and curcumin, have been shown to modulate Klotho expression through redox-sensitive and transcriptional mechanisms. Macronutrient balance-particularly carbohydrate quality and saturated fat intake-also plays a critical role in maintaining Klotho activity via insulin sensitivity, mitochondrial integrity, and inflammatory signaling. Inflammatory dietary profiles, quantified through tools such as the Dietary Inflammatory Index (DII), have been inversely associated with serum α-Klotho concentrations and biological age acceleration. This review critically synthesizes current knowledge on nutrient-specific and dietary pattern-level influences on Klotho, with emphasis on antioxidant, anti-inflammatory, and epigenetically active compounds. In parallel, the Klotho-FGF23 axis is examined regarding dietary calcium and phosphate regulation, highlighting the distinct effects of whole food-derived versus supplemental calcium on mineral metabolism and vascular health. Klotho emerges as a potential modifiable determinant and current limitations as a potential biomarker within precision nutrition strategies aimed at extending health-span and attenuating age-related disease risk. Key concepts discussed include dietary factors in klotho modulation and chronic disease Prevention, as well as opportunities and limitations of soluble klotho as a multifaceted biomarker of human health and longevity.