◉ Perspective

Immediately after my first meeting as the research director of a non-profit clinical research foundation, I received a piece of advice from our medical director that initially seemed insightful. He cautioned me that if a scientist or biotech representative claimed their drug could treat multiple diseases, they were either snake oil salesmen, charlatans or delusional. This was in 1990, and the idea that a single agent could address the underlying root cause of most human diseases - aging - was not even a remotely viable consideration.

I included this personal antidote because Klotho’s demonstrated effectiveness against a broad spectrum of age-related diseases suggests that it addressees a fundamental and root controlling mechanism of aging. In other words, Klotho's ability to prevent, ameliorate and/or treat this extensive inventory of diseases, affirms its designation as the "anti-aging protein". This isn't about a miracle cure-all or delusional science, but addressing one of agings core controlling processes.

◉ Summary

The Klotho protein appears to play a protective role in all age-related diseases, potentially through its anti-inflammatory, antioxidative, anti-fibrotic, and other protective effects. This suggests that enhancing Klotho function might be a promising strategy for treating these conditions and promoting healthy aging.

Elevating Klotho levels in humans opens a pioneering avenue in the field of anti-aging, holding promises of significant strides against formidable age-related diseases. Klotho, an influential protein and overseer of aging, wields control over the pathways shaping our biological aging process. It serves as an anchor, not only decelerating aging, but also actively defending against a host of age-related maladies. For instance, an increased concentration of Klotho has shown potential in combating Alzheimer's disease, mitigating cognitive decline, and offering a protective shield for our memory centers. Likewise, in the realm of cardiovascular health, higher Klotho levels may counteract heart diseases, decreasing the likelihood of heart failure and atherosclerosis. It has also shown promising effects on kidney diseases, osteoporosis and even certain types of cancer. Thus, amplifying Klotho levels is like tuning our body's internal defense mechanism to resist age-associated deterioration, thereby offering a captivating prospect in our quest for not just a lengthier, but a healthier and more vibrant lifespan.

A 2019 review comprehensively describes the current understanding of the FGF–Klotho endocrine system, including the accumulating evidence of its crucial role in the pathophysiology of common ageing-related disorders.

[2019] The Klotho proteins in health and disease

As the symbol [₪] in the title of this page indicates, this is also a reciprocal signaling process. Many diseases affect the systemic signaling milieu resulting in the down regulation of Klotho, increasing the likelihood of the host developing more diseases associated with aging. Chronic Kidney Disease (CKD) is an excellent example. Uremic toxins suppress the expression of Klotho by blocking the promoter region of Klotho via methylation, an epigenetic rate limiting, controlling mechanism. Thus an initial decline in Klotho can facilities kidney disease and kidney disease can further down regulate the expression of Klotho. Although not limited to these two diseases, CKD often leads to 1) cardiac disease processes and 2) neoplasms that would have been blocked by increased levels of Klotho.

[2012] Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation

Alzheimers Disease (AD) 

Studies indicate that Klotho has neuroprotective effects, potentially inhibiting the progression of Alzheimer's disease. The protein appears to work by reducing oxidative stress and inflammation in the brain, processes which are implicated in the pathogenesis of Alzheimer's disease. Furthermore, Klotho might play a role in modulating synaptic plasticity, cognitive function, and resilience to stress. Some findings also suggest Klotho could hinder the production or aggregation of beta-amyloid peptides, one of the main pathological markers of Alzheimer's disease.

Taken together, the study findings demonstrate that a greater amount of Klotho protein within the CSF is associated with reduced CSF amyloid and tau burden levels. These differences were independent of both KL-VS heterozygosity and APOE4 status, thus indicating that the KL-VS haplotype is not necessarily indicative of AD pathogenesis to the same extent as Klotho protein levels.

Alzheimer’s disease ( β -amyloid and Tau protein pathologies), hippocampal neuronal loss (Klotho promotes regeneration), cognitive deficits, frailty

[2010] Development of Klotho Enhances as Novel Therapeutics for Alzheimer’s

[2012] Small-molecule Klotho enhancers as novel treatment of neurodegeneration

[2020] Alignment of Alzheimer's disease amyloid β‑peptide and klotho

[2022] Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden

[2023] Neuroprotective Role of Klotho on Dementia

International Alzheimer's and Related Dementias Research Portfolio: Development of Klotho Enhancers as Novel Therapeutics for AD

Anemia

Klotho, a type of protein that is typically associated with aging, has shown some influence on the development and progression of anemia, particularly in individuals with chronic kidney disease (CKD). CKD often leads to a decrease in the production of erythropoietin (EPO), a hormone that stimulates the production of red blood cells, causing anemia. Klotho appears to play a role in enhancing the production of EPO, thereby indirectly contributing to the alleviation of anemia symptoms. Moreover, decreased Klotho levels in CKD patients are also associated with resistance to treatment with EPO-stimulating agents. Therefore, the Klotho protein could represent a potentially crucial link in our understanding of anemia, particularly in populations with compromised kidney function. Future research may even find ways to utilize this protein for anemia treatment strategies.

It was indicated that the risk of anemia was reduced when Klotho <9.746/100 pg/mL. When Klotho is greater than 9.746/100 pg/mL, there may not be a relationship with the risk of anemia development. A recent study by Changhong Du et al. found that renal soluble Klotho can act directly on hematopoietic stem cells and that Klotho is involved in the regulation of bone marrow hematopoiesis by inhibiting SLC20A1mediated inorganic phosphate uptake by hematopoietic stem cells [27]. It is evident that the interaction between the kidney and bone marrow hematopoietic stem cells goes beyond the role that can be explained by erythropoietin.

[2023] Association between anemia and serum Klotho in middle-aged and older adults

Arteriosclerosis, Cardiovascular, Male sexual dysfunctions

Klotho, when delivered as a humoral factor, can protect the vasculature. Klotho gene delivery by adenoviral vector increased endothelium-dependent nitric oxide synthesis and prevented adverse vascular remodeling in an arteriosclerotic, obese rat model. Recently, soluble Klotho has been shown to regulate vascular tonus, and a nitric oxide (NO) stimulatory ability was confirmed in vitro. NO is produced in the vascular endothelium (the inner lining of blood vessels). Endothelial dysfunction, often resulting from conditions like hypertension, diabetes, and hypercholesterolemia, is a common cause of reduced NO production and is a major contributing factor to erectile dysfunction.

[2015] The vascular secret of Klotho

Arthritis

Studies have suggested that the expression of Klotho is downregulated in arthritic conditions such as rheumatoid arthritis and osteoarthritis, which are inflammatory diseases characterized by joint degradation. Klotho is believed to exert anti-inflammatory and anti-oxidative stress effects that may mitigate the pathogenesis of these diseases. In animal models of arthritis, increasing Klotho levels has been associated with reduced cartilage degradation, suppressed inflammatory responses, and alleviated pain behaviors. Therefore, enhancing Klotho expression or activity could potentially serve as a novel therapeutic approach for arthritis.

[2023] Association between anemia and serum Klotho in middle-aged and older adults

[2021] Association Between the Anti-Aging Gene Klotho and Selected Rheumatologic Autoimmune Diseases

Autoimmune Diseases

The role of Klotho in autoimmune diseases is still under investigation. However, given Klotho's anti-inflammatory and immunomodulatory properties, it is plausible that Klotho might have a protective role in these diseases. Indeed, some studies suggest that Klotho could potentially modulate autoimmune responses and reduce the severity of autoimmune diseases.

[2017] Autoimmune disease and mitochondrial dysfunction in chronic diseases

 Bacterial Infections

Nuclear factor erythroid 2–related factor 2 (NRF2), a pivotal regulator of cellular defenses against oxidative stress, plays a significant role in the body's response to bacterial infections. During such infections, the immune system produces reactive oxygen species (ROS) to combat invading pathogens, but this can inadvertently cause cellular damage. NRF2 mitigates this by governing the antioxidant response, shielding the body against ROS-induced harm. Furthermore, NRF2 is instrumental in maintaining the integrity of epithelial barriers like skin, gut, and lung linings, thus preventing bacterial invasion. There's also potential that NRF2 activation could boost antibiotic effectiveness by minimizing oxidative stress and inflammation, thereby facilitating tissue healing and improving infection outcomes. However, as of my last update in September 2021, detailed understanding of NRF2's role in bacterial infections still requires further research.

[2020] Analysis of Immune Responses in Acinetobacter baumannii-Infected Klotho Knockout Mice- A Mouse Model of Acinetobacter baumannii Infection in Aged Hosts

Chronic Kidney Disease (CKD)

Chronic kidney disease/fibrosis, hyperphosphatemia, ischemic injury, nephrectomy, toxic injury (adriamycin streptozotocin), diabetic nephropathy, calciprotein deposition (aging)

Klotho is a key protein in the field of kidney health. It acts as a co-receptor for fibroblast growth factor 23 (FGF23), a hormone that is instrumental in phosphate homeostasis. Dysfunction or deficiency in either FGF23 or Klotho has been observed to result in abnormal phosphate metabolism, which in turn can lead to chronic kidney disease (CKD). CKD patients have been consistently reported to exhibit lower serum Klotho levels. Furthermore, the Klotho gene itself is predominantly expressed in the kidneys, further emphasizing its connection to kidney health. It is believed that the protective effects of Klotho against CKD stem from its actions on multiple pathways, including its antioxidative effects, suppression of inflammation, and inhibition of Wnt/β-catenin signaling. These actions could potentially slow the progression of CKD by mitigating the damage done to renal tissue, thereby preserving renal function.

[2016] The Role of Klotho Protein in Chronic Kidney Disease: Studies in Animals and Humans

[2018] The role of klotho in chronic kidney disease

[2020] Klotho, Aging, and the Failing Kidney

[2023] Upstream and downstream regulators of Klotho expression in chronic kidney disease

Cancer

Research suggests that Klotho has anti-cancer properties, playing a role in inhibiting cellular proliferation and promoting apoptosis in various types of cancer, including breast, pancreatic, lung, and colorectal cancer. The primary anti-cancer mechanism of Klotho is believed to be its ability to inhibit the insulin/IGF1 and Wnt/β-catenin signaling pathways, both of which are frequently dysregulated in many types of cancer. By inhibiting these pathways, Klotho can prevent uncontrolled cell growth and induce apoptosis, thereby limiting tumor growth and progression. In addition, the anti-inflammatory and antioxidant effects of Klotho might also contribute to its anti-cancer properties by preventing chronic inflammation and oxidative stress, which are known to promote tumorigenesis.

Klotho has been found to act as a tumor suppressor in several types of cancer, including breast cancer, lung cancer, and liver cancer, among others. Its anti-tumor effects may be related to its ability to inhibit the Insulin-like growth factor (IGF-1) and Fibroblast growth factor (FGF) signaling pathways, both of which are often upregulated in cancer and promote cell proliferation and survival. Additionally, Klotho has anti-inflammatory and anti-oxidative stress properties, which may help prevent the DNA damage that can lead to cancer. However, the relationship between Klotho and cancer is complex, with some studies suggesting that high levels of Klotho may promote cancer progression in certain contexts. More research is needed to fully understand the role of Klotho in cancer and its potential as a therapeutic target.

[2017] Effects of Klotho on fibrosis and cancer- A renal focus on mechanisms and therapeutic strategies

[2020] Klotho and the Treatment of Human Malignancies

[2022] Association of serum Klotho levels with cancer and cancer mortality- Evidence from National Health and Nutrition Examination Survey

Cardiovascular Disease, Arteriosclerosis

The Klotho protein, originally discovered for its roles in aging and longevity, has been shown to have significant implications in cardiovascular disease. Klotho deficiency has been associated with various forms of cardiovascular disease, including hypertension, atherosclerosis, and heart failure. Conversely, higher levels of Klotho appear to have protective effects against these conditions. This is likely due to several mechanisms: Klotho is known to inhibit vascular calcification, a major risk factor for cardiovascular disease; it exerts anti-inflammatory and anti-oxidative stress effects, which can mitigate vascular damage; and it modulates several signaling pathways that are critical for cardiovascular health, such as the insulin-like growth factor (IGF-1) and fibroblast growth factor (FGF) pathways. Therefore, enhancing Klotho expression or function could potentially serve as a novel therapeutic strategy for cardiovascular disease. However, further research is needed to fully understand this complex relationship and to translate these findings into effective treatments.

[2022] Associations Between Serum Soluble α-Klotho and the Prevalence of Specific Cardiovascular Disease

[2022] Klotho protein and atherosclerotic cardiovascular diseases- prolonging the thread of life

[2023] Role of Klotho and AGE/RAGE-Wnt/ β -Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes

Cognitive Impairment/Performance

Research has shown that increased levels of Klotho can prevent cognitive decline and even enhance cognitive abilities in some cases. The mechanisms underlying these effects are still under investigation, but it is believed that Klotho may influence synaptic plasticity, the ability of the connections between neurons to change in strength, which is a key process in learning and memory. Furthermore, Klotho may reduce oxidative stress and inflammation in the brain, thereby preserving the health and function of neurons.

[2021] Longevity factor klotho enhances cognition in aged nonhuman primates

[2023] Blood-to-brain communication in aging and rejuvenation

[2023] Klotho controls the brain-immune svstem interface in the choroid plexus

[2023] Longevity factor klotho enhances cognition in aged nonhuman primates

[2023] Neuroprotective Role of Klotho on Dementia

[2023] The relationship between serum klotho and coanitive performance in a nationallv representative sample of US adults

[2023] Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice

[2023] Platelet factors attenuate inflammation and rescue cognition in ageing

[2023] Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice

Chronic Respiratory Disease 

Pulmonary fibrosis, a disease characterized by the progressive scarring of lung tissue, Klotho may exert anti-fibrotic effects. Animal studies have suggested that Klotho deficiency might exacerbate fibrotic processes, whereas its restoration or overexpression could potentially attenuate fibrosis. Klotho might achieve these effects by modulating key fibrotic pathways and mitigating oxidative stress, which is a major contributor to the pathogenesis of pulmonary fibrosis.

Similarly, in chronic obstructive pulmonary disease (COPD), a condition marked by chronic inflammation and progressive airflow limitation, Klotho could be therapeutically beneficial. Reduced levels of Klotho have been observed in COPD patients and in animal models of the disease. These findings suggest that Klotho deficiency may be implicated in the disease's pathogenesis, potentially through its effects on oxidative stress and inflammation. Enhancing Klotho expression or function might thus mitigate the chronic inflammation, oxidative stress, and tissue damage characteristic of COPD.

Dementia

[2023] Neuroprotective Role of Klotho on Dementia

Depression 

While the relationship between Klotho and depression is not as extensively studied as some other conditions, some evidence suggests a potential link. In particular, lower levels of Klotho have been found in individuals with depression, suggesting that Klotho deficiency might contribute to depressive symptoms. Moreover, animal studies suggest that Klotho may have neuroprotective effects that could be beneficial for mental health. However, more research is needed to fully understand the role of Klotho in depression and its potential as a therapeutic target.

Dermatological diseases

Diabetes Mellitus

The protein Klotho may play a protective role in diabetes mellitus due to its multifaceted effects, which include an enhancement of insulin signaling and resistance against diabetic nephropathy, a common diabetes complication. Primarily, Klotho boosts insulin sensitivity, a function frequently impaired in diabetes, and this aspect contributes to the regulation of glucose and lipid homeostasis. Klotho also exhibits renoprotective effects, safeguarding against kidney damage often seen in diabetic patients. Beyond this, Klotho may help combat pancreatic β-cell apoptosis, a feature present in both type 1 and type 2 diabetes, and potentially promote the regeneration of these β cells. Additionally, Klotho's anti-inflammatory and antioxidative properties could serve to mitigate the chronic inflammation and oxidative stress typically associated with diabetes, further exemplifying its protective role in this condition.

[2019] Klotho protein supplementation reduces blood pressure and renal hypertrophy in b/db mice, a model of type 2 diabetes

[2020] Klotho ameliorates diabetic nephropathy by activating Nrf2 signaling pathway in podocyt

[2021] Antiinflammatory Actions of Klotho- Implications for Therapy of Diabetic Nephropathy

[2021] Beta-klotho in type 2 diabetes mellitus- From pathophysiology to therapeutic strategies

[2021] Klotho and SIRT1 changes from pre-diabetes to diabetes and pre-hypertension to hyertension

[2023] Flavonoids improve type 2 diabetes mellitus and its complications- a review

[2023] Targeting epigenetics in diabetic cardiomyopathy- Therapeutic potential of flatonoids

DNA DAMAGE

GI

Hair / Dermatology

Hearing Loss

[2002] Expression of Klotho protein in the inner ear

Hypertension and Heart Failure/ Salt

Klotho has a profound impact on the cardiovascular system, exerting protective effects against various pathological conditions such as hypertension, atherosclerosis, and cardiac hypertrophy. One of the primary protective mechanisms of Klotho in the cardiovascular system is its ability to inhibit vascular calcification, a critical pathological process that is common in many cardiovascular diseases. This inhibition is achieved through its action on FGF23 signaling and the suppression of phosphate-induced vascular smooth muscle cell calcification. Furthermore, Klotho's antioxidant effects have been shown to suppress vascular inflammation and endothelial dysfunction, both crucial factors in the development of atherosclerosis. Studies also suggest that Klotho can prevent cardiac hypertrophy and remodeling, which are key contributors to heart failure, by inhibiting the insulin-like growth factor 1 (IGF1) and Wnt/β-catenin signaling pathways.

Arterial/aortic calcification, Atheroslerosis, Cardiomyopathy, Cardiac hypertrophy, Hypertension, Myocardial ischemic injury/infarct

[2021] Klotho and SIRT1 changes from pre‑diabetes to diabetes and pre‑hypertension to hypertension.pdf alias

[2021] Role of Klotho in the Development of Essential Hypertension

[2021] The role and molecular mechanism of Klotho in salt-sensitive hypertensive renal injury

[2023] Novel mechanisms of salt-sensitive hypertension

IBD

Inflammaging

Inflammaging is a term that refers to the chronic, low-grade inflammation that is often associated with aging and is a risk factor for many age-related diseases. Klotho might play a protective role against inflammaging due to its anti-inflammatory properties. Specifically, Klotho has been shown to inhibit the NF-κB signaling pathway, a key regulator of inflammation. By inhibiting this pathway, Klotho can potentially suppress chronic inflammation and mitigate the damage it causes.

[2020] Towards Age-Related Anti-Inflammatory Therapy- Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocyt

[2021] Antinflammatory Actions of Klotho- Implications for Therapy of Diabetic Nephropa

[2022] Klotho Levels and Their Relationship with Inflammation and Survival among Alcoholic Patients

[20221 Soluble klotho as an effective biomarker to characterize inflammatory states.

Kidney Stones

[2023] Klotho inhibits the formation of calcium oxalate stones by regulating the Keap1-Nrf2-ARE signaling pathway | SpringerLink

Metabolic Syndrome

Multiple Sclerosis

NASH Liver Disease

Neurodegenerative Diseases  and Alzheimer’s Disease: Cognitive Impairment, Dementia

Research has shown that Klotho has significant neuroprotective effects, which could have major implications for neurodegenerative diseases like Alzheimer's. Animal models with elevated levels of Klotho have shown improved cognition and increased synaptic plasticity, which is crucial for learning and memory. Furthermore, the Klotho protein appears to ameliorate neurodegenerative changes and reduce the toxicity of β-amyloid, a protein that forms plaques in the brains of Alzheimer's patients. This suggests that enhancing Klotho function could be a potential therapeutic strategy for neurodegenerative diseases.

Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant global health concern. These disorders might be linked to the protein Klotho, levels of which are often diminished in AD patients' brains. This deficiency could contribute to neurodegeneration, a theory that animal studies support, showing enhanced cognitive function and synaptic plasticity with Klotho overexpression. The neuroprotective properties of Klotho might stem from its influence on various pathways, including Wnt/β-catenin, insulin/IGF1, and Nrf2 signaling. Klotho's inhibition of Wnt/β-catenin signaling, for instance, may shield against synaptic toxicity induced by amyloid-beta, a protein prevalent in AD patients' brains. Furthermore, Klotho enhances neuronal survival and resilience to oxidative stress via Nrf2 signaling activation. Additionally, Klotho appears to alleviate the neurodegenerative changes and toxicity associated with β-amyloid, a protein that forms plaques in the brains of Alzheimer's patients. This, coupled with Klotho's propensity to promote hippocampal neuronal regeneration, could significantly reduce the cognitive deficits and frailty associated with AD.

Obesity

Klotho, a hormone with various roles including aging and insulin signaling, appears to influence obesity through several pathways. First, it plays a regulatory role in metabolism, as suggested by studies showing metabolic abnormalities, such as insulin resistance and glucose intolerance, in Klotho-deficient mice. These metabolic disturbances are often associated with obesity. Second, Klotho potentially helps in maintaining insulin sensitivity, crucial for glucose utilization and energy production in cells, disruptions in which are typically seen in obesity. Third, Klotho demonstrates anti-inflammatory properties, potentially countering the chronic low-grade inflammation commonly linked with obesity and the subsequent development of insulin resistance. Lastly, preliminary evidence points to a role for Klotho in energy expenditure, a key aspect of weight regulation that can impact obesity. However, our understanding of Klotho's role in obesity is still developing and is primarily based on animal studies. Although the Klotho-obesity connection is intriguing, comprehensive strategies for managing obesity still focus primarily on lifestyle modifications like diet and physical activity.

Oral & Paradontal

Osteoporosis

Klotho plays a critical role in bone health due to its involvement in phosphate and vitamin D metabolism.Animal studies suggest that Klotho deficiency can lead to decreased bone mineral density and increased bone fragility, which are key characteristics of osteoporosis. On the other hand, overexpression of Klotho has been shown to protect against bone loss. The role of Klotho in bone health is primarily mediated through its interaction with FGF23. Together, Klotho and FGF23 regulate phosphate and vitamin D metabolism, thereby maintaining bone mineralization. Additionally, Klotho may also indirectly influence bone health through its antioxidative effects, as oxidative stress is known to contribute to osteoporosis.

Oxadative Stress

Parkinson's Disease

Periodontitis

The Klotho protein, recognized for its anti-aging properties, may also have potential implications for periodontal health, although this field of study is still developing. Klotho demonstrates anti-inflammatory effects that could mitigate the chronic inflammation characteristic of periodontitis, a serious gum infection. Additionally, Klotho's anti-oxidative properties could counteract the oxidative stress that contributes to periodontitis by neutralizing harmful free radicals and protecting periodontal tissues. Klotho's role in regulating calcium and phosphate metabolism, essential for healthy bone mineral density, could influence the status of alveolar bone, which supports the tooth sockets and can deteriorate in severe periodontitis. It's essential to note that our understanding of Klotho's involvement in periodontitis is nascent and primarily based on preclinical studies. Further research is required to confirm these findings in humans and examine potential Klotho-based therapeutic strategies for periodontitis. As of my last training data in September 2021, no Klotho-specific treatments for periodontitis had been established.

Scaropenia / Muscle Loss / Frailty

Sarcopenia, characterized by the age-related loss of muscle mass and function, might be influenced by Klotho levels. Some studies have demonstrated a potential link between Klotho and muscle function. In animal models, Klotho deficiency has been associated with reduced muscle strength and endurance, while Klotho overexpression appears to exert protective effects. However, further research is required to confirm these findings and elucidate the mechanisms behind Klotho's potential role in sarcopenia.

Sarcopenia is a syndrome characterized by the progressive and generalized loss of skeletal muscle mass and strength, largely driven by oxidative stress and inflammation, both of which damage aging muscle tissues. The transcription factor, NRF2, is pivotal in countering this oxidative stress. When activated, NRF2 binds to the DNA's antioxidant response elements, instigating the production of antioxidant and cytoprotective proteins that neutralize harmful reactive oxygen species (ROS), reduce inflammation, and stave off cellular damage. Therefore, in the case of sarcopenia, decreased NRF2 activity could exacerbate oxidative stress and muscle degeneration. Conversely, amplifying NRF2 activity could boost the body's antioxidant defenses, protecting muscle tissues from oxidative damage, potentially decelerating the progression of sarcopenia.

[2018] Age-related declines in a-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration.pdf alias

[2020] The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle functionn

[2021] Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home ts

[2021] Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles.pdf

[2022] Klotho- An Emerging Factor Wogenic Potential

[2023] Association between Serum Klotho and Physical Frailty in Middle-Aged and Older Adults- Finding From the National Health Assessment

Sleep

High quality sleep is a correlate of health and longevity. There is a direct link between Klotho levels and quality of sleep. Higher levels correlate with better sleep quality.

A direct relationship was observed between the subjective sleep quality (inverse of PSQI scores) and the S-Klotho plasma levels in sedentary middle-aged adults. Improving sleep quantity and quality could be considered an anti-aging therapeutic approach for the prevention, slowing, and even reversal of the physiological decline and degenerative pathologies that are certainly related to the aging process.

[2020] Is sleep associated with the S-Klotho anti-aging protein in sedentary middle-aged adults? The FIT-AGEING study

[2021] Association Between the Anti-Aging Protein Klotho and Sleep Duration in General Population

[2021] Klotho and Sleep Duration in General Population

Stem Cell Regulation

The composition and origin of extrinsic cues required for hematopoietic stem cell (HSC) maintenance are incompletely understood. Here we identify renal Klotho and inorganic phosphate (Pi) as extrinsic factors that antagonistically regulate HSC maintenance in the bone marrow (BM). Disruption of the Klotho-Pi axis by renal Klotho deficiency or Pi excess causes Pi overload in the BM niche and Pi retention in HSCs, leading to alteration of HSC maintenance.

[2022] Renal Klotho and inorganic phosphate are extrinsic factors that antagonistically regulate hematopoietic stem cell maintenance

Strokes and Heart Attacks

Klotho's role in cardiovascular health suggests that it might also be involved in the pathophysiology of strokes and heart attacks. Klotho deficiency is associated with increased vascular calcification and arterial stiffness, which are risk factors for these conditions. Furthermore, Klotho's antioxidative and anti-inflammatory effects could potentially help protect against the damage caused by strokes and heart attacks. However, more research is needed to fully understand Klotho's role in these conditions.

Vascular

Thus, the augmentation of Klotho function emerges as a potential therapeutic approach for neurodegenerative diseases like Alzheimer's.

insulin/IGF1, and Nrf2 signaling. For example, Klotho's inhibition of Wnt/β-catenin signaling may protect against synaptic toxicity caused by amyloid-beta, a protein that accumulates in the brains of AD patients. Moreover, Klotho can enhance neuronal survival and resist oxidative stress by activating Nrf2 signaling.

[2015] Mammalian target of Rapamycin signaling inhibition ameliorates vascular calcification via Klotho up-regulation

[2015] The vascular secret of Klotho

[2023] The Research Progress of Vascular Aging Related Diseases