Klotho is a protein that has attracted significant attention in longevity research due to its association with anti-aging pathways and extended lifespan in animal models. Circulating levels naturally decline as humans age, and lower levels are consistently linked to a higher risk of developing age-related diseases. This has led to the emergence of various supplements marketed to influence its production or activity. This article explores the science behind the Klotho protein and examines the evidence supporting the efficacy of commercial supplements designed to boost its levels.
The Biological Role of Klotho
The Klotho protein is primarily produced in the kidneys, but is also synthesized in the brain’s choroid plexus and the parathyroid glands. It exists in two main forms: a membrane-bound version and a soluble version (s-Klotho), which is shed into the blood and cerebrospinal fluid. The soluble form acts as a circulating hormone, allowing it to exert effects on distant organs and tissues.
The membrane-bound Klotho protein functions as an obligatory co-receptor for Fibroblast Growth Factor 23 (FGF23), a hormone originating in the bone. This complex regulates the body’s mineral homeostasis, particularly the balance of phosphate and calcium. Klotho signals the kidneys to increase phosphate excretion and suppress active vitamin D production, preventing mineral overload and tissue damage.
Independent of FGF23, soluble Klotho exerts pleiotropic protective effects across multiple systems. It acts by inhibiting cellular signaling pathways implicated in aging, such as the Insulin/Insulin-like Growth Factor 1 (IGF-1) pathway. Soluble Klotho also suppresses chronic, low-grade inflammation by blocking the NF-κB pathway and dampens fibrosis by interfering with the Transforming Growth Factor-beta (TGF-β) pathway.
Understanding Klotho Supplement Formulations
Klotho is a large protein (approximately 130 kilodaltons), which presents a barrier to direct oral supplementation. When consumed, large protein molecules are broken down into smaller amino acids and peptides by digestive enzymes before absorption. Therefore, consuming the intact Klotho protein will not result in it circulating to perform its hormonal function.
Due to this challenge, most products marketed as “Klotho supplements” are categorized as “Klotho boosters” or “enhancers.” These products contain small molecules, precursors, or herbal extracts intended to stimulate the body’s natural production of Klotho. Common ingredients include curcumin, resveratrol, and certain ginseng extracts, which have shown the ability to upregulate Klotho gene expression in preclinical models.
Researchers have identified specific small-molecule compounds that can activate the Klotho promoter, leading to increased Klotho production in cell lines. While these compounds represent a promising avenue for future drug development, they are distinct from the over-the-counter supplements. The goal of booster formulations is to encourage the body’s own cells to synthesize more soluble Klotho.
Scientific Status and Efficacy of Klotho Boosters
The most compelling data supporting Klotho’s therapeutic potential comes from studies involving recombinant protein administration or gene therapy in laboratory animals. In these models, increasing Klotho expression has resulted in significant extension of lifespan and improvements in cognitive function in aged mice and non-human primates. These experimental interventions demonstrate the biological effect that increased Klotho levels can have on age-related decline.
However, the efficacy of commercially available oral Klotho booster supplements is not supported by rigorous scientific evidence. There is a scarcity of large-scale, randomized, placebo-controlled human clinical trials investigating whether these nutraceutical compounds effectively raise circulating Klotho levels. The evidence for ingredients like curcumin or resveratrol affecting human Klotho levels is largely indirect, extrapolated from cell culture or animal studies.
Some clinical studies have observed an increase in Klotho levels in human patients, but these involved prescription pharmaceuticals like angiotensin-converting enzyme inhibitors (e.g., Losartan) or certain statins. These studies often focused on subjects with pre-existing conditions, such as diabetes or chronic kidney disease, and their findings do not translate to the efficacy of over-the-counter supplements.
Natural Methods to Upregulate Klotho
While the evidence for oral Klotho supplements is limited, established research indicates that specific lifestyle choices can naturally support the body’s endogenous Klotho production. Physical activity is the most reliable and consistently documented method to increase circulating Klotho levels. Regular aerobic exercise has been shown to significantly elevate s-Klotho concentrations.
Dietary interventions also modulate Klotho expression. Caloric restriction and intermittent fasting have been linked to higher Klotho levels, reflecting a response to nutritional stress that promotes cellular maintenance pathways. Diets rich in specific micronutrients and antioxidants are associated with better Klotho status.
Consuming foods containing polyphenols, such as those found in turmeric or grapes, can support the pathways that regulate Klotho production. Maintaining a healthy gut microbiome through the intake of probiotics and fiber-rich foods can also indirectly influence Klotho expression.