The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder that affects multiple organs and systems and increases the risk of morbidity and mortality in patients with CKD, especially those receiving dialysis therapy. CKD-MBD is highly prevalent in CKD patients, and its treatment is gaining attention from healthcare providers who manage these patients. Additional important pathologies often observed in CKD patients are chronic inflammation and malnutrition/protein-energy wasting (PEW). These two pathologies coexist to form a vicious cycle that accelerates the progression of various other pathologies in CKD patients. This concept is integrated into the term "malnutrition-inflammation-atherosclerosis syndrome" or "malnutrition-inflammation complex syndrome (MICS)". Recent basic and clinical studies have shown that CKD-MBD directly induces inflammation as well as malnutrition/PEW. Indeed, higher circulating levels of inorganic phosphate, fibroblast growth factor 23, parathyroid hormone, and calciprotein particles, as markers for critical components and effectors of CKD-MBD, were shown to directly induce inflammatory responses, thereby leading to malnutrition/PEW, cardiovascular diseases, and clinically relevant complications. In this short review, we discuss the close interplay between CKD-MBD and MICS and emphasize the significance of simultaneous control of these two seemingly distinct pathologies in patients with CKD, especially those receiving dialysis therapy, for better management of the CKD/hemodialysis population. 

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Emerging cross-talks between chronic kidney disease–mineral and bone disorder (CKD–MBD) and malnutrition–inflammation complex syndrome (MICS) in patients receiving dialysis

Sarcopenia and impaired cardiorespiratory fitness are commonly observed in older individuals and patients with chronic kidney disease (CKD). Declines in skeletal muscle function and aerobic capacity can progress into impaired physical function and inability to perform activities of daily living. Physical function is highly associated with important clinical outcomes such as hospitalization, functional independence, quality of life, and mortality. While lifestyle modifications such as exercise and dietary interventions have been shown to prevent and reverse declines in physical function, the utility of these treatment strategies is limited by poor widespread adoption and adherence due to a wide variety of both perceived and actual barriers to exercise. Therefore, identifying novel treatment targets to manage physical function decline is critically important. Klotho, a remarkable protein with powerful anti-aging properties has recently been investigated for its role in musculoskeletal health and physical function. Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, endothelial function, oxidative stress, and inflammation. This is particularly important for older adults and patients with CKD, which are known states of Klotho deficiency. Emerging data support the existence of Klotho-related benefits to exercise and for potential Klotho-based therapeutic interventions for the treatment of sarcopenia and its progression to physical disability. However, significant gaps in our understanding of Klotho must first be overcome before we can consider its potential ergogenic benefits. These advances will be critical to establish the optimal approach to future Klotho-based interventional trials and to determine if Klotho can regulate physical dysfunction.

Klotho: An Emerging Factor With Ergogenic Potential

Purpose To compare the capacity of blood myostatin concentration and physical, cognitive, and affective function tests to predict frailty among long-term care (LTC) residents. Methods This cross-sectional analysis used baseline data from three randomized controlled trials involving 260 older adults in 14 LTC centers. Serum myostatin levels were analyzed by enzyme-linked immunosorbent assay. Frailty, physical fitness, cognitive and affective functions were assessed using validated tests and scales. Results The Timed Up and Go, gait speed, 6-minute walk, and Berg Balance Scale had excellent capabilities in identifying frail individuals in accordance with Fried’s Frailty Phenotype (FFP). The best tests for identifying frailty in accordance with the Clinical Frailty Scale (CFS) were Timed Up and Go and Berg Balance Scale. For the Tilburg Frailty Indicator (TFI), the best tests were Quality of Life in Alzheimer’s Disease (QoL-AD) and Goldberg Anxiety. Myostatin, along with physical, cognitive, and affective function tests, improved the capability of the hand grip, arm-curl, Montreal Cognitive Assessment, Goldberg Anxiety, Goldberg Depression, and QoL-AD to identify frailty according to FFP, while myostatin improved CFS-defined frailty identification by the hand grip, arm-curl, 6-minute walk test, Berg Balance Scale, 30-second chair-stand, gait speed, Montreal Cognitive Assessment, Goldberg Anxiety, and De Jong-Gierveld Loneliness Scale. Conclusion Among LTC residents, serum myostatin was associated with being frail according to FFP and CFS. However, this measure was less discriminating of frailty than physical fitness tests (for FFP and CFS) and affective function parameters (for TFI). However, evaluated concurrently with physical, cognitive, and affective parameters, myostatin improved the capabilities of these measures to predict CFS-defined frailty.

Improving the Identification of Frailty in Long-Term Care Residents: A Cross-Sectional Study

Abstract Objectives Klotho is found to be associated with better cognitive outcomes in selected small sample of aged population. We aimed to examine the association of serum klotho with cognitive function among older adults using a nationally representative sample of the U.S. Method A total of 2,173 older adults aged 60–79 years in the National Health and Nutrition Examination Survey from 2011 to 2014 were included. Klotho was measured and quantified in laboratory. Cognitive function was measured using the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning subtest [CERAD-WL] immediate and delayed memory, the Animal Fluency test [AFT], the Digit Symbol Substitution Test [DSST]). Test-specific and global cognition z-scores were calculated based on means and standard deviations. Multivariable linear regression models were applied to examine the association of quartiles of serum klotho with test-specific and global cognition z-scores. Subgroup analysis was conducted by sex. Results Serum klotho level in the lowest quartile was associated with lower z-score for DSST (beta (β)=-0.13, 95% confidence interval (CI): -0.25, -0.01). For subgroup analysis, serum klotho level in the lowest quartile was associated with lower z-scores for DSST (β=-0.16, 95% CI: -0.32, -0.003) and global cognition (β=-0.14, 95% CI: -0.28, -0.01) among women. No significant association was found among men. Conclusions Low serum klotho was associated with poorer cognitive function, particularly among women. Future studies are expected to examine the longitudinal associations between klotho levels and cognitive outcomes. 

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Serum Klotho and Cognitive Functioning in Older Adults Aged 60 and 79: The National Health and Nutrition Examination Survey 2011 to 2014

Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment. Future translational research should aim to validate klotho’s putative role as a biomarker that could identify the risk of aging-related adverse events in clinical practice.

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Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents.

Jon Garin-Balerdi

Papers

Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents.