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