Klotho supplement: boost your longevity protein

In 1997, Japanese researchers accidentally discovered a gene that controls how fast you age.

They were experimenting with mice, inserting a genetic mutation at random locations in the genome. One mutation produced something unexpected: the mice developed a syndrome that looked exactly like accelerated human aging. Shortened lifespan. Skin atrophy. Osteoporosis. Atherosclerosis. Emphysema. These mice were falling apart, and fast.

The gene they had disrupted? They named it after Klotho, the Greek goddess who spins the thread of life.

Since then, klotho has become one of the most studied proteins in longevity science. Not because it's a magic pill, but because understanding it reveals exactly what's happening in your body as you age and, more importantly, what you can do about it. You can use WinAging's biological age calculator to get a sense of how your biological age compares to your chronological age, but klotho testing goes even deeper. It's one of the most direct windows into the aging process we have.

This guide covers everything: what klotho actually is, what the research says about lifespan extension, why there's no pill you can just swallow, and the evidence-based strategies that genuinely move your klotho levels.

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What is klotho?

Klotho is a protein encoded by the KL gene on chromosome 13. It's primarily produced by kidney tubule cells, with smaller amounts made in the choroid plexus of the brain and the parathyroid gland.

The protein exists in two main forms. Transmembrane klotho sits anchored in cell membranes, where it acts as a co-receptor for a hormone called FGF23 (fibroblast growth factor 23). This partnership regulates calcium and phosphate metabolism. Soluble klotho is different. Enzymes called secretases cleave the transmembrane version, releasing a fragment that enters the bloodstream and circulates as a hormone throughout the body. This soluble form is what most longevity researchers care about when they talk about klotho as an anti-aging molecule.

There's also beta-klotho, a related protein encoded by a different gene. Beta-klotho handles a separate set of metabolic tasks, mainly around liver function, bile acid synthesis, and fat metabolism. It's the target of some exciting drug trials (more on that later). But when people say "klotho supplement," they mean alpha-klotho, the original longevity protein.

Think of klotho as a systems coordinator. It doesn't do one specific thing. It regulates multiple pathways simultaneously: mineral metabolism, oxidative stress, inflammation, insulin signaling, synaptic plasticity in the brain. That's actually what makes it so interesting. A single protein influencing all these aging-related processes.

Why klotho levels matter as you age

Here's the problem. Klotho levels drop as you get older.

The decline is progressive and consistent across both sexes, though women tend to maintain somewhat higher levels than men at any given age. By the time you're in your late fifties or older, your klotho levels are meaningfully lower than they were in your thirties. This isn't subtle variation. It's a significant, measurable change.

And the consequences are real. A 2024 study established that serum alpha-klotho below around 700 pg/mL is associated with increased all-cause mortality risk. The cardiovascular risk threshold comes in around 548 pg/mL. People with klotho levels at or below 400 pg/mL show nearly three times the rate of high-grade white matter brain lesions compared to those with higher levels.

Low klotho doesn't just predict poor outcomes. It contributes to them. When klotho drops, several bad things happen simultaneously: phosphate metabolism goes haywire, oxidative stress increases, vascular calcification accelerates, brain synaptic plasticity declines, and the kidneys become more vulnerable to injury. These aren't independent problems. They're interconnected, and klotho is part of what holds the system together.

This is why klotho has become such a hot topic in longevity research. It's not just a marker of aging. It appears to be a driver of aging. And that distinction matters enormously for figuring out what to do about it.

The lifespan data: what the research actually shows

The mouse data is striking.

In 2005, a team led by Makoto Kurosu published a landmark paper in Science (PMID 16123266) showing that overexpressing klotho in transgenic mice extended their lifespan significantly. Male mice with the highest klotho expression lived around 936 days on average, compared to 715 days for controls. That's roughly a 31% lifespan extension. Females showed around a 19% extension.

The mechanism? Klotho suppresses insulin and IGF-1 signaling. This is the same pathway targeted by caloric restriction, rapamycin, and several other well-studied longevity interventions. It's evolutionarily conserved across species, from nematodes to mammals. When you dampen insulin/IGF-1 signaling at the right level, organisms live longer. Klotho does this naturally.

The primate data is even more relevant to humans.

In 2023, a team from UC San Francisco published a study in Nature Aging (PMID 37400721) that got the longevity world buzzing. They gave aged rhesus macaques (15 to 28 years old) a single subcutaneous injection of recombinant klotho protein, at a dose of 10 micrograms per kilogram. The results were remarkable. Memory performance on spatial delayed tasks improved significantly, with benefits measurable both 4 hours after injection and still present 2 weeks later.

Two things made this study especially interesting. First, the dose-response was unusual: lower doses worked better than higher doses. At 20 or 30 mcg/kg, the benefits disappeared. This isn't how most compounds behave, and it suggests klotho works through a highly regulated, context-sensitive mechanism rather than a simple "more is better" relationship.

Second, a single injection produced effects lasting two weeks. This hints at downstream changes in synaptic plasticity rather than just a transient hormonal effect.

For humans, this is encouraging but preliminary. No Phase 2 efficacy trials of injectable klotho in people have been completed yet. But Phase 1 safety studies are in development following the primate results. The research trajectory is optimistic.

Can you actually take a klotho supplement?

Here's the honest answer: not in any direct sense.

Klotho is a large protein, approximately 130 kilodaltons in molecular weight. If you swallowed it, your digestive system would break it down into amino acids before any of it reached your bloodstream. Oral bioavailability is essentially zero. This is why the primate study used subcutaneous injection.

You'll find products online marketed as "klotho supplements." These aren't klotho. They're collections of nutrients that the manufacturers claim might support your body's own klotho production. The concept isn't fraudulent (some of those nutrients have legitimate evidence for influencing klotho levels) but the framing is misleading. You're not supplementing klotho. You're trying to influence the conditions that determine how much klotho your body produces.

Some researchers have explored klotho peptide fragments, but there's no validated consumer peptide product derived from klotho with solid human data.

The actual klotho protein used in research contexts is recombinant human alpha-klotho produced in a laboratory, administered by injection. It's not commercially available. Several biotech companies are working on therapeutic versions, and clinical development is accelerating, but this isn't something you can order online.

So what can you actually do? Quite a bit, as it turns out.

How to boost klotho naturally

Exercise: the most powerful lever

If there's one thing backed by the most consistent evidence for raising klotho, it's regular physical activity.

Multiple studies show that both aerobic exercise and resistance training increase circulating soluble klotho levels. A 12-week aerobic intervention in aging mice stimulated klotho production and reduced age-related kidney fibrosis. Human studies show similar patterns. A meta-analysis of different exercise protocols concluded that training generally raises circulating soluble klotho, though the magnitude varies by type and intensity.

One important nuance: for pre-frail older adults specifically, strength training (not explosive power training) appears to be particularly effective at raising soluble alpha-klotho. If you're older or less fit, prioritizing steady resistance training over jumping and speed work may give you better klotho results.

The mechanism makes sense. Exercise activates AMPK (an energy-sensing enzyme), reduces systemic inflammation, and improves insulin sensitivity. All three of these factors support klotho gene expression. Exercise also appears to protect klotho expression in the hippocampus following brain injuries, suggesting the brain benefits from exercise-induced klotho are direct, not just downstream effects of cardiovascular health.

Practically: consistent aerobic exercise 3-5 times per week at moderate intensity, combined with resistance training 2-3 times per week, is the evidence-based approach. Not extreme. Not occasional. Consistent.

Vitamin D: the co-regulator

Klotho and vitamin D are deeply intertwined. They regulate each other.

Klotho modulates vitamin D metabolism through the FGF23 signaling pathway. In the other direction, vitamin D receptor (VDR) activation can upregulate klotho gene transcription. Research in chronic kidney disease models showed that vitamin D receptor agonists increase klotho expression while reducing vascular calcification. A 2024 study demonstrated that vitamin D supplementation prevents kidney injury through ferroptosis inhibition linked to klotho pathways.

The practical implication: vitamin D deficiency likely impairs your klotho status, and many people are deficient. Optimizing serum 25-hydroxyvitamin D to the 40-60 ng/mL range is one of the best-supported interventions for supporting the klotho system. You get vitamin D through sun exposure and supplements. Most people in northern latitudes need supplemental vitamin D, especially in winter. Vitamin D, K2, and vitamin A work together in a co-factor relationship that's worth understanding if you're optimizing your levels.

Check your stack combinations with the supplement interaction checker before adding anything new.

Magnesium: the underrated connection

Magnesium's relationship with klotho is one of the most consistent findings in the nutritional literature, and it's dramatically underappreciated.

Analysis of NHANES data (a large national nutrition survey of US adults, 2007-2016) found that magnesium depletion correlates with lower serum klotho levels in middle-aged and older adults. Animal studies have shown that low-magnesium diets worsen phosphate-induced kidney injury and suppress renal alpha-klotho expression. Conversely, adequate magnesium helps prevent vascular calcification in klotho-deficient states.

The mechanistic connection runs through the FGF23/klotho axis. Magnesium and phosphate compete, and adequate magnesium protects the kidney-klotho system that phosphate overload disrupts.

Most adults don't get enough magnesium. The dietary sources are leafy greens, nuts, seeds, legumes, and whole grains. Supplemental magnesium (glycinate, malate, or citrate forms are well-absorbed) is a low-risk, high-value addition to any longevity stack.

Resveratrol: direct gene expression effects

Resveratrol has some of the most direct mechanistic evidence for raising klotho among supplements.

It upregulates klotho gene expression via a signaling pathway involving activating transcription factor 3 (ATF3) and the c-Jun complex. Multiple studies confirm this: in hypertensive patients, resveratrol supplementation elevated serum klotho alongside sirtuin 3 and antioxidant enzymes; in aged mice, it enhanced kidney and brain repair while upregulating klotho gene expression; in kidney models, SIRT1-mediated klotho expression provided protection against age-related glomerulosclerosis.

The SIRT1 connection is notable. Resveratrol activates SIRT1, and SIRT1 in turn upregulates klotho. This creates a compound effect: you're getting direct klotho gene activation and pathway-level support simultaneously. The question of whether to take resveratrol or NMN as your primary longevity compound is one we've addressed before, and for the klotho connection specifically, resveratrol vs NMN is worth reading if you're building out your stack.

Berberine: cardiac and kidney protection via klotho

Berberine has emerged as one of the more interesting klotho-supporting compounds in recent years.

A 2022 study demonstrated that berberine protects against cardiac senescence specifically via the Klotho/SIRT1 signaling pathway. A 2025 study showed renoprotective effects in acute kidney injury mediated by klotho activation alongside the AMPK/mTOR autophagy pathway. A 2026 review listed berberine alongside quercetin and resveratrol as compounds that protect against ovarian aging through alpha-klotho mechanisms.

Berberine is already one of the most evidence-backed compounds for metabolic health. Adding klotho pathway activation to its mechanism of action makes it even more compelling. If you're not already familiar with berberine, start with our comprehensive berberine guide. The berberine synergy stack article explains how to combine it effectively with other compounds. And if you're comparing berberine with other metabolic compounds, the berberine complex overview breaks down the different forms.

Spermidine: mitochondrial protection in klotho deficiency

The relationship between spermidine and klotho is bidirectional and fascinating.

Klotho-deficient mice show disrupted spermidine biosynthesis in salivary glands. And spermidine supplementation, when given to klotho-deficient aging cells, increased mitochondrial number and suppressed excessive mitophagy. The picture that emerges: klotho helps maintain healthy spermidine metabolism, and spermidine helps compensate for some of the mitochondrial dysfunction that comes with klotho decline.

This makes spermidine a particularly logical addition to a klotho-focused longevity protocol. The compound already has strong autophagy-induction data on its own. Spermidine-rich foods are the most accessible source (wheat germ is by far the richest food source), but supplements are available for higher doses. For more on optimal dosing, how much spermidine per day covers the research on dosage ranges. The benefits appear somewhat different for men and women, so spermidine benefits for men and spermidine benefits for women are both worth reading depending on your context.

NMN and NAD+ precursors: pathway-level support

The connection between NMN/NAD+ and klotho is real but less direct than resveratrol or berberine.

A comprehensive aging signaling review placed NMN and klotho in the same longevity framework: both are anti-aging molecules that decline with age, and both influence SIRT1 pathways. Since SIRT1 activation upregulates klotho transcription, anything that boosts NAD+ (which feeds SIRT1 activity) can indirectly support klotho levels.

There aren't direct studies showing NMN supplementation raises serum klotho in humans, so the evidence here is more mechanistic than clinical. But given the shared pathways, supporting NAD+ production makes sense as part of a klotho-supportive protocol. NAD+ vs NMN explains the different supplementation options, and NMN before and after gives a realistic picture of what to expect from real-world use.

Not sure which compounds to stack together? WinAging's AI protocol builder designs a personalized longevity stack based on your age, goals, and current supplements. It's built on the same kind of research this article covers.

What tanks your klotho levels

Knowing what raises klotho matters. Knowing what destroys it matters just as much.

A high-phosphate diet is one of the clearest klotho suppressors. Even one week of elevated dietary phosphate intake suppressed klotho markers in animal studies. Phosphate is high in processed foods, sodas (phosphoric acid), fast food, and many packaged snacks. Reducing these isn't just good for your metabolic health. It's directly protective of your klotho levels.

Smoking reduces klotho levels measurably. Light smoking (fewer than 5 pack-years) is associated with roughly a 10% drop in klotho levels. Moderate smoking shows around a 6% decline. Heavy long-term smokers show somewhat attenuated decline numbers, possibly due to survivor bias in the data. Either way, smoking is directly harmful to klotho status and accelerates the lung inflammation and cellular senescence that klotho normally helps buffer.

Chronic inflammation suppresses klotho gene expression. Inflammatory cytokines act on the kidney tubule cells that produce klotho, reducing output. This is one reason why obesity, metabolic syndrome, chronic poor sleep, and high-sugar diets all correlate with lower klotho. Reducing systemic inflammation, through diet, exercise, sleep, and stress management, is protective.

Chronic kidney disease both causes and is worsened by klotho decline. The kidneys are the primary production site for klotho. As kidney function declines, so does klotho output. And lower klotho then accelerates vascular damage, worsening kidney function further. It's a vicious cycle that's one of the main reasons CKD carries such high cardiovascular risk.

Aging itself is the primary driver of klotho decline. Everything else on this list accelerates a process that was already happening. The interventions above don't reverse the fundamental biology of aging, but they can meaningfully slow the rate of klotho decline and maintain higher levels than you'd have without them.

Klotho and the diseases you're trying to avoid

Alzheimer's and cognitive decline

This is where klotho research has generated some of the most excitement.

People who carry a specific genetic variant called KL-VS (heterozygous) show attenuated age-related tau burden, reduced neuroinflammation, and better cognitive outcomes on multiple biomarkers including pTau181, total tau, neurofilament light, and others. KL-VS appears especially protective in APOE4 carriers, the genetic group at highest risk for late-onset Alzheimer's.

Klotho protects neurons from amyloid-beta and glutamate toxicity and increases synaptic plasticity. Lower klotho in older adults is associated with a nearly 3-fold higher rate of high-grade white matter brain lesions. And the primate study showing two-week cognitive improvements from a single klotho injection is directly relevant here.

Kidney disease

Klotho is inseparable from kidney health. The kidneys make most of the body's klotho, and low klotho directly worsens kidney function. This bidirectional relationship means kidney disease accelerates aging, and aging accelerates kidney disease. Interventions that support klotho, particularly magnesium adequacy, reducing dietary phosphate, avoiding NSAIDs chronically, and maintaining cardiovascular fitness, are directly protective of kidney health too.

Cardiovascular disease

Low klotho correlates with vascular calcification, arterial stiffness, and cardiovascular mortality. The 548 pg/mL threshold identified in the 2024 study as predicting cardiovascular mortality risk is a concrete number researchers can use to risk-stratify patients. Exercise, vitamin D optimization, and reducing phosphate load all support the FGF23/klotho axis that keeps vascular calcification in check.

Cancer

Klotho functions as a tumor suppressor by inhibiting the insulin/IGF-1 and FGF signaling pathways, both of which drive cancer cell proliferation. Aberrant (reduced) klotho expression has been found across multiple cancer types including colorectal cancer, lung cancer, and high-grade glioma. While klotho-targeted cancer therapy isn't clinical yet, maintaining higher klotho levels through lifestyle may offer some protection through this mechanism.

Drugs and clinical trials on the horizon

Two areas of pharmaceutical development are worth watching.

MK-3655 is a monoclonal antibody developed by Merck that selectively activates the FGFR1c/beta-klotho co-receptor (the FGF21 signaling pathway). It's completed Phase 2b trials for pre-cirrhotic MASH (metabolic-associated steatohepatitis). This targets beta-klotho rather than alpha-klotho, so it's aimed at metabolic and liver disease rather than the broader aging phenotype, but it represents validation of the klotho family as a drug target.

Recombinant human alpha-klotho for injection is the more direct longevity therapeutic. Following the 2023 primate study, academic medical centers are developing Phase 1 safety studies in humans. If the safety profile is acceptable, Phase 2 efficacy trials for cognitive protection could follow. This is still years from any consumer availability, but the scientific rationale is strong.

In the meantime, the lifestyle interventions in this article are what's available and evidence-backed right now.

How to test your klotho levels

Serum alpha-klotho can be measured with ELISA immunoassays, and reference ranges have been established in several studies. The 2022 Espuch-Oliver study defined age- and sex-specific reference values for healthy adults aged 18-85. A 2025 study by Schweizer et al. expanded these reference intervals further.

Practically: serum klotho testing isn't on standard blood panels. You won't get it from your annual physical. But specialty and functional medicine labs do offer it, and some longevity-focused clinics include it in comprehensive biomarker panels. If you're serious about tracking your biological aging, it's one of the more informative markers you can check.

For context on your results: all-cause mortality risk increases below approximately 700 pg/mL, with the cardiovascular mortality threshold around 548 pg/mL. These aren't absolute cutoffs but risk gradients. Higher is better.

You can pair klotho testing with other biological age markers using WinAging's biological age calculator for a more complete picture. Combining subjective self-assessment data with objective biomarkers gives you better signal than either alone.

Building a klotho-supportive protocol

You don't need to do everything at once. Here's a practical framework:

Foundation (non-negotiable): Consistent exercise (aerobic + resistance), 4-5 sessions per week. This is the most powerful klotho lever you have. Nothing replaces it.

Reduce processed food and soda intake. Phosphate suppression of klotho is real and dose-dependent. Even modest reductions help.

Optimize vitamin D. Get your 25-OH vitamin D tested. Target 40-60 ng/mL. Most people need 2,000-5,000 IU of D3 daily, ideally taken with vitamin K2 to ensure proper calcium metabolism.

Supplement tier 1 (strong evidence): Magnesium glycinate or malate: 300-400mg daily. Cheap, safe, underused.

Resveratrol: 250-500mg daily with a fat-containing meal. Direct klotho gene expression effects through the SIRT1 pathway.

Supplement tier 2 (good supporting evidence): Berberine: 500mg 2-3x daily with meals. Berberine and inositol together is a common stack that adds metabolic benefits. Pairs well with the above.

Spermidine: 1-2mg daily from wheat germ or supplement. Start low, as higher doses can cause digestive discomfort initially.

NMN or NR: 250-500mg daily. Indirect klotho support via NAD+/SIRT1 pathway. Good supporting data for cellular energy and DNA repair. Glycine for anti-aging is another amino acid worth considering in this tier.

Track your progress: If you test baseline klotho and retest after 6 months of consistent protocol, you'll have real data on what's working. Combine that with the biological age calculator for a broader picture.

Use the supplement interaction checker to confirm your stack combinations are safe before starting.

Frequently asked questions

What is klotho and why does it matter for aging?

Klotho is a protein primarily produced by the kidneys that acts as a circulating hormone influencing multiple aging-related processes: phosphate metabolism, oxidative stress, inflammation, insulin signaling, and brain synaptic plasticity. Klotho levels decline progressively with age, and lower levels are associated with higher rates of cardiovascular disease, cognitive decline, and all-cause mortality.

Can you take klotho as a supplement?

No direct klotho supplement is available to consumers. Klotho is a large protein (~130 kDa) with essentially zero oral bioavailability. Products marketed as "klotho supplements" are actually nutrients that may support your body's own klotho production. Injectable recombinant klotho is used in research but is not commercially available. Phase 1 human trials are being developed following the 2023 primate study.

Which supplements have the best evidence for raising klotho?

Resveratrol has the most direct mechanistic evidence (upregulates klotho gene expression via the ATF3/c-Jun/SIRT1 pathway). Magnesium has strong population correlation data. Berberine has emerging evidence through cardiac and kidney protection via the Klotho/SIRT1 axis. Vitamin D has strong mechanistic data through the VDR/FGF23/klotho co-regulation system.

How do you test klotho levels?

Serum alpha-klotho is measured via ELISA immunoassay. It's available through functional medicine labs and some longevity clinics but isn't on standard blood panels. Reference intervals vary by age and sex. Values below 700 pg/mL are associated with increased all-cause mortality risk, with 548 pg/mL as an identified cardiovascular mortality threshold.

Does exercise increase klotho?

Yes. Multiple studies confirm that both aerobic and resistance training raise circulating soluble klotho. For pre-frail older adults, strength training (not explosive power work) appears most effective. Moderate-intensity aerobic exercise 3-5x per week, combined with resistance training 2-3x per week, is the evidence-based recommendation.

What lowers klotho levels?

High phosphate intake (processed foods, sodas), smoking, chronic inflammation, chronic kidney disease, diabetes, obesity, and aging itself all reduce klotho levels. Avoiding these factors where possible protects your klotho status.

How does klotho relate to Alzheimer's disease?

People with the KL-VS genetic variant show attenuated tau accumulation, reduced neuroinflammation, and better cognitive biomarker profiles, with particular benefit for APOE4 carriers. Klotho protects neurons from amyloid-beta and glutamate toxicity and supports synaptic plasticity. Low klotho levels are associated with significantly higher rates of white matter brain lesions.

Is klotho the same as the "longevity gene"?

Klotho is often called a longevity gene because its overexpression extended mouse lifespan by 19-31% in the landmark 2005 Science study, and because klotho-deficient mice develop accelerated aging. But it's more accurate to call it a longevity protein or anti-aging molecule, one of several important regulators of the aging process. Other longevity-related mechanisms (sirtuins, mTOR, NAD+) work in parallel and overlap with the klotho pathway.

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Related guides

• Resveratrol vs NMN: which longevity compound wins?
• Best berberine supplement: the complete guide
• Spermidine-rich foods: the autophagy longevity diet
• Vitamin A, K2, and D3: the fat-soluble stack
• Biological age calculator

Sources

• Kurosu H et al. (2005). Suppression of Aging in Mice by the Hormone Klotho. Science, 309(5742), 1829-1833. PMID: 16123266
• Castner SA et al. (2023). Longevity factor klotho enhances cognition in aged nonhuman primates. Nature Aging, 3(9), 1026-1040. PMID: 37400721
• Liu W et al. (2024). Serum alpha-klotho and mortality risk. Aging (Albany NY). PubMed indexed 2024.

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Klotho is one of the clearest examples of why longevity science has moved beyond simple supplement recommendations. It's a systems protein. It touches kidney function, brain health, vascular integrity, and cancer suppression simultaneously. You can't just take it. But you can absolutely influence how much of it your body produces.

The levers are exercise, vitamin D optimization, magnesium adequacy, and targeted supplements with direct klotho pathway evidence. None of this is experimental. All of it is accessible today.

Start with the basics, track what you can, and build a stack that actually matches your goals. WinAging's AI protocol builder creates a personalized longevity protocol based on your age, health data, and specific objectives. And if you want to know where you stand right now, the biological age calculator is a good starting point.