FGF21

July 28, 2019

P53

January 4, 2020

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro-o et al.^[9] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,^[10]^[11] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.^[12]

The binding of certain fibroblast growth factors(FGF’s) viz., FGF19, FGF21, and FGF23, to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.^[13]^[14]

Klotho-deficient mice manifest a syndromeresembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endotheliumdependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.^[8] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.^[15]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.^[16]Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.^[16] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).^[17]^[18]^[19]^[20]

Recently it has been found that the decreased Klotho expression may be due to DNA hypermethylation, which may have been induced by the overexpression of DNMT3a.^[21] Klotho may be a reliable gene for early detection of methylation changes in oral tissues, and can be used as a target for therapeutic modification in oral cancer during the early stages.

Suppression of Aging in Mice by the Hormone Klotho

A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.

Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.

Biological Role of Anti-aging Protein Klotho

Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for FGF23, which is involved in aging and the development of chronic diseases via regulation of P_i and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho.

Effect of cordyceps sinensis extract on Klotho expression (in ACB)

CONCLUSION: Cordyceps Sinensis can increase the expression of Klotho down-regulated by Ang II, decrease P53 and P21 expression and caspase-3 activity, and reduce Ang II induced NRK-52E cell apoptosis, which may be part of its mechanism of the protective effects on hypertensive renal damage.

High-intensity physical exercise increases Klotho

The recently discovered klotho proteins have roles in a diverse range of metabolic processes with the oldest protein, α-klotho, implicated in various cellular pathways in energy, glucose, and phosphate metabolism. Circulating soluble klotho (sKl), derived from membrane α-klotho cleavage, not only has effects on ion channels and insulin signaling pathways, but is inversely associated with mortality. Effects of physical exercise on sKl have not been well studied. The effect of a single high-intensity standardized exercise on sKl and serum phosphate (sPi) levels in healthy adults was investigated. In conclusion, a single high-intensity exercise session is associated with a transient increase in sKl, a delayed reduction in blood glucose, and a nonsignificant decrease in sPi levels in healthy adults. The evaluation of long-term effects of cardiovascular fitness programs on sKl and sPi in healthy individuals and disease cohorts are required to identify potential lifestyle modifications to help improve chronic disease management and long-term outcomes.

Acetyl‐11‐keto‐β‐boswellic acid from Boswellia Serrata (frankincense) increases Klotho (in ACB)

Acetyl 11‐keto‐β‐boswellic acid (AKBA), a pentacyclic triterpenoid compound (Figure 1A), is one of the most potent active principles within the multi‐component mixture of Boswellia serrata resin.

Klotho is a multifunctional protein that is well known for its anti‐ageing property. Deficiency of Klotho in mice often leads to short lifespan, cognitive dysfunction, osteoporosis, vascular calcification, etc.22 While overexpression of Klotho could extend lifespan23 and alleviate renal disease.24, 25 It was reported that full Klotho knockout mice (Klotho^−/−) have a more striking phenotype and serious pathological changes than heterozygous Klotho mice (Klotho^+/−).4 Compared to the wild‐type mice, constitutive overexpression of Klotho in mice could lead to less expression of fibrosis‐related proteins, such as α‐SMA and collagen I.25 As expected, the results in our study showed that the levels of Klotho were significantly decreased in obstructed kidneys and hypoxia‐induced HK‐2 cells. AKBA administration up‐regulated the expression of Klotho in a dose‐dependent manner. And the renal protective effect of AKBA was reversed with the transfection of siRNA‐Klotho. FEATURED IN ACB

Anti-aging Gene Klotho Deficiency Causes Hypertension and Vascular Dysfunction via Upregulation of mTOR

Klotho is a recently discovered anti-aging gene. Genetic mutation of klotho expedites the aging process and shortens the lifespan while overexpression of klotho slows down the aging process and extends the lifespan by 20%. Interestingly, blood pressure (BP) was elevated significantly and vasodilatory responses to acetylcholine and sodium nitroprusside were impaired in klotho heterozygeous (+/-) mice, suggesting that klotho deficiency causes hypertension and vascular dysfunction. It is noted that klotho deficiency is associated with upregulation of mTOR expression and NADPH oxidase activity and downregulation of Mn-SOD expression in aortas and kidneys. Inhibition of mTOR by rapamycin abolished the upregulation of NADPH oxidase activity and O₂^– production and the downregulation of Mn-SOD expression and decreased BP to the control levels. Inhibition of mTOR also abolished vascular endothelial dysfunction and macrophage infiltration in kidneys in klotho (+/-) mice. The upregulation of NADPH oxidase activity and downregulation of Mn-SOD may be involved in klotho deficiency-induced hypertension which can be decreased significantly by apocynin (NADPH oxidase inhibitor) or Tempol (O₂^–scavenger). These results demonstrate, for the first time, that klotho is essential in the maintenance of normal blood pressure. Klotho deficiency-induced hypertension and vascular dysfunction are mediated by upregulation of mTOR. This study also reveals a previously unidentified role of mTOR in the regulation of NADPH oxidase and MnSOD.

Longevity factor klotho and chronic psychological stress

Chronic psychological stress is associated with accelerated aging and premature morbidity and mortality; however, the biology linking chronic psychological stress and its maladaptive effects remains largely unknown. Klotho is a pleiotropic hormone that regulates the aging process and promotes better brain and body health. Whether klotho is linked to psychosocial stress or its negative impact in humans has not been investigated. To address this gap, we recruited 178 healthy women who were either chronically high-stress maternal caregivers for a child with autism spectrum disorder (n= 90) or low-stress control mothers of a typically developing child (n= 88). We found that women under high chronic stress displayed significantly lower levels of the longevity hormone klotho compared with low-stress controls (t (176)= 2.92, P= 0.004; d= 0.44), and the decrease among those under high stress was age-dependent. In addition, high-stress caregivers who reported more depressive symptoms displayed even lower klotho levels compared with low-stress participants. These findings provide the first evidence that klotho levels are sensitive to psychosocial stressors and raise the possibility that klotho may serve as a novel biological link connecting stress, depression and risk for accelerated disease development. Furthermore, these findings have important implications for understanding the plasticity of the aging process and may represent a therapeutic target for mitigating the deleterious effects of chronic psychological stress on health and well-being.

EGCG (in ACB & matcha green tea) increases Klotho

(−)-Epigallocatechin-3-O-gallate (EGCG) has long been known as a potent inducer of keratinocyte differentiation. Although its molecular mechanisms have been extensively studied, its actions on human skin remain to be elucidated. In this study, we demonstrated that methylated EGCG and EGCG increase the expression of klotho, and that klotho functions as a downstream target of EGCG and methylated EGCG in keratinocyte differentiation. We demonstrated that methylated EGCG3 and EGCG induce morphological changes in normal human epidermal keratinocytes (NHEKs) that are related to up-regulation of klotho expression. We also demonstrated that a klotho-induced keratinocyte differentiation marker in NHEKs is inhibited by H-89, a protein kinase (PKA) inhibitor. These results suggest that methylated EGCG and EGCG may function as inducers of keratinocyte differentiation via transcriptional regulation of the klotho protein.

Klotho recovery by genistein (in ACB)

Renal fibrosis is a common histomorphological feature of renal aging and chronic kidney diseases of all etiologies, and its initiation and progression are substantially influenced by aberrant epigenetic modifications of fibrosis-susceptible genes, yet without effective therapy. “Epigenetic diets” exhibit tissue-protective and epigenetic-modulating properties; however, their anti-renal fibrosis functions and the underlying mechanisms are less understood. In this study, we show that genistein, a phytoestrogenic isoflavone enriched in dietary soy products, exhibits impressive anti-renal fibrosis activities by recovering epigenetic loss of Klotho, a kidney-enriched anti-aging and fibrosis-suppressing protein. Mouse fibrotic kidneys induced by UUO (unilateral ureteral occlusion) displayed severer Klotho suppression and adverse expression of renal fibrosis-associated proteins, but genistein administration markedly recovered the Klotho loss and attenuated renal fibrosis and the protein expression abnormalities. The examination of possible causes of the Klotho recovery revealed that genistein simultaneously inhibited histone 3 deacetylation of Klotho promoter and normalized the promoter DNA hypermethylation by suppressing elevated DNA methyltransferase DNMT1 and DNMT3a. More importantly, genistein’s anti-renal fibrosis effects on the renal fibrotic lesions and the abnormal expressions of fibrosis-associated proteins were abrogated when Klotho is knockdown by RNA interferences in UUO mice. Thus, our results identify Klotho restoration via epigenetic histone acetylation and DNA demethylation as a critical mechanism of genistein’s anti-fibrosis function and shed new lights on the potentials of epigenetic diets in preventing or treating aging or renal fibrosis-associated kidney diseases. FEATURED IN ACB

Key messages

Genistein prevents renal fibrosis and the associated Klotho suppression in UUO mice.
Genistein upregulates Klotho in part by reversing the promoter histone 3 hypoacetylation.
Genistein also preserves Klotho via relieving Klotho promoter hypermethylation.
Genistein demethylates Klotho promoter by inhibiting aberrant DNMT1/3a expression.
Genistein restoration of Klotho is essential for its anti-renal fibrosis function.

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FGF21

P53

FGF21

P53

Effect of cordyceps sinensis extract on Klotho expression (in ACB)

Anti-aging Gene Klotho Deficiency Causes Hypertension and Vascular Dysfunction via Upregulation of mTOR

Longevity factor klotho and chronic psychological stress

Klotho recovery by genistein (in ACB)

Key messages

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