Klotho, Aging, and the Failing Kidney Buchanan, Sarah; Combet, Emilie; Stenvinkel, Peter ...
Frontiers in endocrinology (Lausanne),
08/2020, Letnik:
11
Journal Article
Recenzirano
Odprti dostop
Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor ...(FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.
Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle ...wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.
The observation that unhealthy diets (those that are low in whole grains, fruits and vegetables, and high in sugar, salt, saturated fat and ultra-processed foods) are a major risk factor for poor ...health outcomes has boosted interest in the concept of 'food as medicine'. This concept is especially relevant to metabolic diseases, such as chronic kidney disease (CKD), in which dietary approaches are already used to ameliorate metabolic and nutritional complications. Increased awareness that toxic uraemic metabolites originate not only from intermediary metabolism but also from gut microbial metabolism, which is directly influenced by diet, has fuelled interest in the potential of 'food as medicine' approaches in CKD beyond the current strategies of protein, sodium and phosphate restriction. Bioactive nutrients can alter the composition and metabolism of the microbiota, act as modulators of transcription factors involved in inflammation and oxidative stress, mitigate mitochondrial dysfunction, act as senolytics and impact the epigenome by altering one-carbon metabolism. As gut dysbiosis, inflammation, oxidative stress, mitochondrial dysfunction, premature ageing and epigenetic changes are common features of CKD, these findings suggest that tailored, healthy diets that include bioactive nutrients as part of the foodome could potentially be used to prevent and treat CKD and its complications.
Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic ...kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology ECH-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.
Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing.
Phosphorylation, ...acetylation, and ubiquitination cover >90% of all the reported PTMs. Several of the main PTMs are involved in normal “healthy” ageing and in different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, and bone diseases, as well as cancer and chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also from long-living animal species, imply that PTMs are critical regulators of the ageing process. Mechanistically, PTMs target epigenetic and non-epigenetic pathways during ageing. In particular, epigenetic histone modification has critical implications for the ageing process and can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates to reduce the burden of ageing-related diseases. Several phosphorylation and acetylation inhibitors have already been FDA-approved for the treatment of other diseases and offer a unique potential to investigate both beneficial effects and possible side-effects. As an example, the most well-studied senolytic compounds dasatinib and quercetin, which have already been tested in Phase 1 pilot studies, also act as kinase inhibitors, targeting cellular senescence and increasing lifespan. Future studies need to carefully determine the best PTM-based candidates for the treatment of the “diseasome of ageing”.
•Post-translational modifications (PTMs) link oxidative stress and ageing.•Data from progeroid syndromes and long-living animals implicate PTMs in the ageing process.•PTMs are highly relevant for the epigenetic regulation of ageing and related diseases.•Phosphorylation and acetylation inhibitors are therapeutic targets in ageing.
A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood ...experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (
n
= 7769) with
n
= 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.
Abstract
Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by cardiovascular disease, persistent uraemic inflammation, osteoporosis muscle wasting and frailty. The ...accelerated early vascular ageing (EVA) process mediated by medial vascular calcification (VC) is a hallmark of senescence as well as a strong predictor of cardiovascular morbidity and mortality in the CKD population. Current clinical therapeutic strategies and novel treatments for VC have not yet been proven to prevent or reverse VC progression in patients with CKD. Knowledge of the fundamental mechanism underlying EVA is urgently needed to identify and develop novel and efficient therapeutic targets for VC and EVA. An accumulating body of evidence indicates that deoxyribonucleic acid (DNA) damage–induced cellular senescence and ‘inflammaging’ may largely contribute to such pathological conditions characterized by accelerated EVA. Growing evidence shows that nuclear factor erythroid 2–related factor 2 (NRF2) signalling and vitamin K play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammaging, whereby NRF2 activation and vitamin K supplementation may provide a novel treatment target for EVA. In this review we discuss the link between senescence and EVA in the context of CKD, with a focus on the role of NRF2 and vitamin K in DNA damage signalling, senescence and inflammaging.
Among several theories to explain the complicated process of human ageing, the mitochondrial oxidative stress hypothesis has received recent attention. Considering that lifespan and ageing rates vary ...considerably across taxa, a better understanding of factors that lead to negligible or extremely rapid senescence in mammals may generate novel approaches to target human ageing. Several species, such as naked mole rats, ocean quahog, rockfish and Greenland shark, have been identified that exhibit negligible senescence and superior resistance to age-related diseases. Considering that the available literature suggests that their outstanding stress resistance is linked to maintenance of protein homeostasis and robust mitochondrial functions, treatments that target protein modification and upregulation of matrix antioxidants may have implications for extending human health span.
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