Klotho, longevity biology, and oral health

Klotho is a large protein encoded on chromosome 13q12, primarily produced in the kidneys and brain, and functions as a circulating hormonelike regulator of phosphate–vitamin D metabolism, oxidative-stress defenses, inflammatory pathways, and cellular repair. As medicine accelerates into its peptide era, klotho’s broad influence on metabolic balance, tissue integrity, and longevity has made it a prime target for therapeutic peptide development designed to harness its antiaging and tissue-protective effects. Could dentistry gain a powerful new ally as these klotho-based therapeutics advance?

How klotho was identified

Originally identified through a mutation that caused striking premature-aging features in mice, it’s now understood as a central regulator of healthy aging across renal, cardiovascular, metabolic, neurologic, and—more recently—oral and maxillofacial tissues.¹ A review in 2025 showed that reduced klotho activity contributes to periodontal tissue loss, impaired bone turnover, salivary gland dysfunction, and degenerative changes in mucosa and dentin.¹

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The original work by Kuro-O et al. showed that disrupting the KL gene produces a dramatic premature-aging syndrome—vascular calcification, bone loss, skin thinning, infertility, cognitive decline, and shortened lifespan (figure 1).² In contrast, increasing klotho expression in mice extends lifespan by roughly 30%, establishing klotho as a direct modulator of biological aging.³ Klotho levels decrease steadily with age and drop further in chronic diseases such as chronic kidney disease and diabetes. Low klotho heightens oxidative stress, weakens autophagy, and destabilizes major repair pathways, leading to accelerated tissue breakdown.⁴

An active driver of aging biology

A common human genetic variant, the KL-VS haplotype, increases klotho secretion and is associated with better cognitive performance and greater odds of healthy longevity.^5,6 These genetic patterns reinforce klotho’s role as an active driver of aging biology rather than a passive biomarker. Klotho functions as an endocrine integrator, shaping oxidative balance, immune tone, metabolic efficiency, and cellular repair. Deficiency produces elevated reactive oxygen species, mitochondrial dysfunction, increased NF-κB–
mediated inflammation (inflammaging), impaired autophagy, and proteostasis. These shifts create a biochemical environment highly susceptible to tissue breakdown across organ systems—including the oral cavity.

A measurable biomarker of oral biological aging?

Large-scale human studies now link low circulating klotho to poorer oral health. In NHANES data (n = 6,187), lower α-klotho independently predicted higher odds of moderate-to-severe periodontitis, tooth loss, and worse self-rated oral health, and a separate clinical cohort showed a stepwise decline in serum klotho with increasing disease severity.^7,8 Is this support that klotho is a measurable biomarker of oral biological aging?

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Patients with periodontitis exhibit reduced klotho expression in gingival tissues and periodontal ligament cells.¹ Experimental work demonstrates that exogenous (outside of cell) klotho can counter several pathogenic processes: it lowers oxidative stress, restores mitochondrial membrane potential, and reduces apoptosis in periodontal ligament stem cells (PDLSCs), while also enhancing PDLSC osteogenesis and improving bone-regenerative capacity.^9,10

In vivo studies show that klotho is needed in the early bone-forming cells that build the jaw’s alveolar bone. Without klotho in these precursor cells, mandibular bone does not form normally, and osteoclast activity becomes excessive.¹¹ Klotho helps preserve periodontal architecture by supporting stem-cell function, maintaining balanced bone turnover, and limiting inflammatory tissue injury.

Klotho-deficient mice develop striking dental defects, including disorganized odontoblast layers, irregular predentin (unmineralized organic matrix that odontoblasts lay down before it matures into dentin), poorly defined dentin–predentin borders, and disrupted expression of key mineralization proteins.^12,1 Klotho is needed for healthy dentinogenesis and mineralization, and reduced levels may leave root surfaces more vulnerable, weaken reparative dentin responses, and contribute to the structural changes characteristic of aging dentin.

Experimental studies show that klotho deficiency reduces saliva flow, promotes oral dryness, and speeds tooth-surface deterioration.¹³ Restoring soluble klotho improves salivary gland function through two key pathways. Activating KLF4, a transcription factor that supports epithelial integrity, and helps maintain healthy saliva-producing cells.¹³ At the same time, klotho stabilizes AMPK/mTOR, the cellular energy–sensing system that keeps metabolic stress in check.¹⁴ Together, these effects strengthen antioxidant defenses, protect glandular tissue, and support more normal saliva output. Because klotho levels naturally fall with age, this decline may contribute to xerostomia and its downstream risks, including caries, mucosal irritation, and oral dysbiosis.

Periodontitis elevates systemic cytokines such as IL-12. IL-12 has been shown to suppress klotho expression in pancreatic β-cells and worsen metabolic dysfunction.¹⁵ Reduced klotho then feeds back into higher inflammatory tone, greater oxidative stress, and increased periodontal susceptibility. This bidirectional loop—oral inflammation driving klotho suppression, and reduced klotho amplifying oral pathology—represents a central mechanism in the oral-systemic cascade.

Implications for oral health

Across longevity genetics, systemic disease models, cell-based studies, and human epidemiology, klotho appears as a central regulator of biological aging with direct implications for oral health. Low klotho disrupts periodontal repair, destabilizes alveolar bone, weakens dentin structure, and reduces salivary gland function, and clinical data show that low circulating klotho independently predicts periodontitis and tooth loss. Taken together, it indicates that klotho is not only a systemic aging molecule but an active regulator of oral and maxillofacial tissue biology—positioning it as both a biomarker of oral frailty and a promising therapeutic target for periodontal regeneration, xerostomia management, and craniofacial tissue repair. This highlights two important points: separating oral health from medical care is an obsolete framework, and providers must have a strong scientific foundation to keep pace with rapidly advancing knowledge. 

Editor's note: This article appeared in the March 2026 print edition of RDH magazine. Dental hygienists in North America are eligible for a complimentary print subscription. Sign up here.

References

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