Klotho is a protein your body produces naturally that plays a central role in aging, kidney health, brain function, and mineral balance. First discovered in 1997 when researchers found that mice lacking the klotho gene aged rapidly and died young, it has since become one of the most studied proteins in aging science. In healthy adults, soluble klotho circulates in the blood at levels ranging from about 286 to 1,639 pg/mL, with an average around 698 pg/mL. Those levels decline with age and with certain diseases, particularly kidney disease.
The Three Forms of Klotho
Klotho exists in three primary forms, each with different jobs. The first is the full-length transmembrane form, which sits on the surface of cells, particularly in the kidneys. This version partners with receptors on those cells to help regulate minerals like calcium and phosphate in your blood.
The second, and arguably most important for overall health, is the soluble form. Enzymes clip the transmembrane version off the cell surface, releasing it into the bloodstream, urine, and cerebrospinal fluid. This circulating klotho travels throughout the body acting as a hormone, influencing everything from heart health to brain function. A third, much rarer form is produced through a different process of gene reading and appears to contribute to tumor suppression and heart protection.
Alpha-Klotho and Beta-Klotho
There are also two distinct family members: alpha-klotho and beta-klotho. When people say “klotho” without a qualifier, they almost always mean alpha-klotho, which is the version tied to aging, kidneys, and cognition. Alpha-klotho works as a co-receptor for a hormone called FGF23, helping the kidneys excrete excess phosphate and regulate vitamin D levels.
Beta-klotho serves a completely different set of hormones: FGF19 and FGF21. These hormones regulate bile acid synthesis, fat metabolism, blood sugar control, and energy expenditure. FGF19 controls how much bile acid your liver produces and influences fat storage, while FGF21 improves insulin sensitivity and promotes weight loss. Both hormones need beta-klotho to dock onto their receptors and send signals properly. Without beta-klotho, these metabolic hormones can’t do their jobs.
How Klotho Regulates Minerals
One of klotho’s best-understood roles is helping the kidneys manage phosphate. High phosphate levels accelerate aging in blood vessels and soft tissues, so the body works hard to keep them in check. Here’s the chain of events: when phosphate rises, bones release FGF23. That hormone travels to the kidneys, where it binds to receptors that alpha-klotho has primed. This triggers the kidneys to flush more phosphate into the urine by pulling phosphate transporters off the surface of kidney cells.
At the same time, FGF23 signaling suppresses the kidney’s production of active vitamin D, which in turn reduces how much phosphate (and calcium) the gut absorbs from food. Soluble klotho also contributes independently by directly promoting the removal of phosphate transporters from kidney cells, even without FGF23. The net result is a tightly controlled system that keeps blood phosphate at safe levels.
Klotho and Kidney Disease
Klotho is most heavily produced in the kidney’s tubular cells, which makes it both a protector and a casualty of kidney disease. In the early stages of chronic kidney disease (CKD), klotho expression in the kidneys starts to drop. As kidney function worsens through progressive CKD stages, circulating klotho levels fall in parallel.
This decline matters. Animal studies show that restoring klotho can slow CKD progression through several mechanisms: reducing oxidative stress, dialing down inflammation, activating the cell’s cleanup process (autophagy), and limiting damage to mitochondria. In human data from the National Health and Nutrition Examination Survey, blood klotho levels below 700 pg/mL in CKD patients were associated with a gradually increasing risk of death from any cause, including cardiovascular death. Patients in the lowest quarter of klotho levels had a 34% higher risk of dying compared to those in the highest quarter, even after accounting for age, lifestyle, and disease severity. Because soluble klotho comes from the cleavage of the membrane-bound form in the kidneys, falling blood levels may serve as an early signal of kidney aging before other markers change.
Effects on Brain and Cognition
Klotho has a striking relationship with brain health. Mice genetically engineered to produce extra klotho show enhanced learning and memory, driven by stronger connections between neurons in the hippocampus and frontal cortex. The protein works in part by boosting the function of a specific receptor (NMDA receptor) critical for forming new memories and strengthening synaptic connections. When klotho is elevated in mouse models of Alzheimer’s disease, it reverses synaptic damage and cognitive decline.
On the flip side, mice that lack klotho develop poor myelination (the insulation around nerve fibers), abnormal synapses, and memory problems. In human studies, plasma klotho levels have been positively correlated with attention, working memory, verbal memory, and executive function. Executive function, the set of mental skills you use for planning, problem-solving, and self-control, showed the strongest link to klotho levels. These cognitive-enhancing effects appear to involve both antioxidant protection and optimization of neural signaling in the brain’s memory and decision-making centers.
The KL-VS Genetic Variant
Not everyone produces klotho equally. A common genetic variant called KL-VS, which involves two amino acid changes in the klotho protein, influences how well the protein is made and how it functions. Carrying one copy of this variant has been linked in some studies to better cognitive performance and longer life. Carrying two copies, however, tells a different story. Research across three independent populations (Bohemian Czech, Baltimore Caucasian, and Baltimore African-American) found that people homozygous for KL-VS were significantly underrepresented among elderly individuals, with a combined odds ratio of 2.59 for reduced survival. In other words, having two copies of this variant appears to decrease life expectancy, suggesting that klotho function contributes meaningfully to how quickly people develop age-related conditions.
Exercise as a Klotho Booster
The most reliable way to raise your circulating klotho levels without medication is regular exercise. A meta-analysis of 12 controlled trials involving 621 participants found that chronic exercise training of at least 12 weeks significantly increased soluble klotho, with a large effect size. This held true regardless of whether participants were healthy or had existing health conditions.
About 150 minutes per week appears to be the sweet spot for triggering klotho increases. The mechanism likely involves exercise’s ability to create a brief burst of oxidative stress, which ramps up the body’s antioxidant defenses and reduces chronic inflammation, both of which favor klotho production. Exercise also activates a molecular pathway in muscle and other tissues that directly promotes klotho expression. Interestingly, the meta-analysis found that combined aerobic plus resistance training was the one exception that didn’t show a clear klotho boost, though pure aerobic or pure resistance training did. Training duration and total weekly volume seem to matter more than intensity alone.
Skeletal muscle itself secretes klotho during exercise, placing it in the growing category of “exerkines,” beneficial molecules released by working muscles that influence distant organs. This means the benefits of exercise on klotho aren’t limited to what the kidneys produce.
Where Klotho Therapy Stands
Given klotho’s broad protective effects, researchers are exploring whether it can be delivered as a treatment. As of 2025, one early-phase clinical trial is recruiting 30 healthy adult volunteers to test a combination klotho and follistatin gene therapy delivered via injection, with results expected by mid-2026. No klotho-based drugs or supplements are currently available, and there are no established cut-points for using klotho blood levels as a clinical tool for biological age. The protein’s potential as both a biomarker and a therapeutic target remains one of the more active areas in aging research.