Le phosphate, un accélérateur du vieillissement ?

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Klotho and calciprotein particles as therapeutic targets against accelerated ageing
Makoto Kuro-o Clin Sci (Lond) (2021) 135 (15): 1915–1927.

The klotho gene, named after a Greek goddess who spins the thread of life, was identified as a putative ‘ageing-suppressor’ gene. Klotho-deficient mice exhibit complex ageing-like phenotypes including hypogonadism, arteriosclerosis (vascular calcification), cardiac hypertrophy, osteopenia, sarcopenia, frailty, and premature death. Klotho protein functions as the obligate co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate intake.

Thus, Klotho-deficient mice suffer not only from accelerated ageing but also from phosphate retention due to impaired phosphate excretion. Importantly, restoration of the phosphate balance by placing Klotho-deficient mice on low phosphate diet rescued them from premature ageing, leading us to the notion that phosphate accelerates ageing.

Because the extracellular fluid is super-saturated in terms of phosphate and calcium ions, an increase in the phosphate concentration can trigger precipitation of calcium-phosphate. In the blood, calcium-phosphate precipitated upon increase in the blood phosphate concentration is adsorbed by serum protein fetuin-A to form colloidal nanoparticles called calciprotein particles (CPPs). In the urine, CPPs appear in the renal tubular fluid when FGF23 increases phosphate load excreted per nephron. CPPs can induce cell damage, ectopic calcification, and inflammatory responses. CPPs in the blood can induce arteriosclerosis and non-infectious chronic inflammation, whereas CPPs in the urine can induce renal tubular damage and interstitial inflammation/fibrosis.

Thus, we propose that CPPs behave like a pathogen that accelerates ageing and should be regarded as a novel therapeutic target against age-related disorders including chronic kidney disease.

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For example, soybeans are a major plant source of protein and listed as an ingredient rich in phosphate in the food composition table

In plants, phosphate exists mainly as phytate. In order for phosphate in phytate to be absorbed from the gastrointestinal tract, inorganic phosphate must be released from phytate by hydrolyzation of the inositol-phosphate linkages with phytase (Figure 5). Phytase is an enzyme produced by enteric bacteria that reside in the gut of ruminant animals [35]. Therefore, cows and sheep can hydrolyze phytate and utilize soybeans as a source of phosphate but monogastric animals such as pigs and chickens cannot.

The fact that pigs and chickens are unable to absorb phosphate from phytate raises two problems [36]. First, inorganic phosphate must be added to their feed to support their growth. Second, phytate excreted into feces can cause soil pollution with phosphorus. To solve these problems, phytase has been added to the feed containing soy flour for pigs and chickens. Because humans cannot utilize phytate as a source of phosphate either, replacement of animal-based protein with plant-based protein is considered as an effective way to reduce phosphate absorption without restricting protein intake

Second, it is of critical importance for dietary phosphate restriction to avoid food additives containing inorganic phosphate [5,32]. Unlike phosphate in foods, phosphate in food additives is inorganic and thus adsorbed nearly 100%

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Phosphate Additives in Food—a Health Risk
Eberhard Ritz, Dtsch Arztebl Int. 2012 Jan; 109(4): 49–55.

Background
Hyperphosphatemia has been identified in the past decade as a strong predictor of mortality in advanced chronic kidney disease (CKD). For example, a study of patients in stage CKD 5 (with an annual mortality of about 20%) revealed that 12% of all deaths in this group were attributable to an elevated serum phosphate concentration. Recently, a high-normal serum phosphate concentration has also been found to be an independent predictor of cardiovascular events and mortality in the general population. Therefore, phosphate additives in food are a matter of concern, and their potential impact on health may well have been underappreciated.

Methods
We reviewed pertinent literature retrieved by a selective search of the PubMed and EU databases (www.zusatzstoffe-online.de, www.codexalimentarius.de), with the search terms “phosphate additives” and “hyperphosphatemia.”

Results
There is no need to lower the content of natural phosphate, i.e. organic esters, in food, because this type of phosphate is incompletely absorbed; restricting its intake might even lead to protein malnutrition. On the other hand, inorganic phosphate in food additives is effectively absorbed and can measurably elevate the serum phosphate concentration in patients with advanced CKD. Foods with added phosphate tend to be eaten by persons at the lower end of the socioeconomic scale, who consume more processed and “fast” food. The main pathophysiological effect of phosphate is vascular damage, e.g. endothelial dysfunction and vascular calcification. Aside from the quality of phosphate in the diet (which also requires attention), the quantity of phosphate consumed by patients with advanced renal failure should not exceed 1000 mg per day, according to the guidelines.

Conclusion
Prospective controlled trials are currently unavailable. In view of the high prevalence of CKD and the potential harm caused by phosphate additives to food, the public should be informed that added phosphate is damaging to health. Furthermore, calls for labeling the content of added phosphate in food are appropriate.





Typical foods with large amounts of added phosphate are processed meat, ham, sausages, canned fish, baked goods, cola drinks, and other soft drinks. Dietary counseling is all the more difficult because the phosphate content in food—and, in particular, the added phospate content—is not marked on the package.

serum phosphate concentration is controlled by two newly discovered factors called fibroblast growth factor 23 (FGF23) and klotho

an elevated concentration of FGF23 leads to increased renal excretion of phosphate and diminishes the activation of vitamin D to calcitriol.

As mentioned above, organic phosphate esters are found mainly in protein-rich foods such as dairy products, fish, meat, sausages, and eggs. They are slowly hydrolyzed in the gastrointestinal tract and then slowly resorbed from the intestine. About 40% to 60% of the organic phosphate esters consumed in the diet are resorbed (e1, e8).

The phosphates found in grains, nuts, and legumes are mainly in the form of phytic acid (hexaphospho-inositol), which cannot be split in the human intestine because of the lack of the enzyme phytase (19). The bioavailability of vegetable phosphate esters is usually less than 50% (8, 20) and thus much lower than that of the phosphate esters in protein-rich foods. It follows that the phosphate content of food cannot be automatically equated with the phosphate load.

The phosphate content of industrially processed food is much higher than that of natural food, because polyphosphates are commonly used as an additive in industrial food production (Table). In the European Union, sodium phosphate (E 339), potassium phosphate (E 340), calcium phosphate (E 341), and salts of orthophosphoric acid diphosphate (E 450), triphosphate (E 451), and polyphosphate (E 452) can legally be added to food as preservatives, acidifying agents, acidity buffers, and emulsifying agents. Phosphate salts are also added to many foods as stabilizers or taste intensifiers.

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Chronic High Phosphate Intake in Mice Affects Macronutrient Utilization and Body Composition
Marko Ugrica Molecular Nutrition & Food Research 22 February 2022

In the last decades, dietary phosphate intake has increased due to a higher consumption of ultraprocessed food. This higher intake has an impact on body composition and health state. Recently, this study finds that a high chronic phosphate diet leads to no major renal alterations, but negatively affects parameters of bone health probably due to the chronic acid load. Here the effect of high phosphate consumption on parameters of energy metabolism is assessed.

Methods and Results
Healthy mature adult mice are fed for 1 year or 4 months with either a standard (0.6 % w/w) or a high phosphate (1.2 % w/w) diet. Males and females of two different genetic backgrounds are investigated. Mice feed the high phosphate diet show an attenuated body-weight gain, lower respiratory exchange ratio, decreased body fat mass, and increased lean-to-fat mass ratio. Moreover, the high phosphate diet leads to fasting hypoglycemia with no differences in the glucose response to an oral glucose tolerance test. Triglycerides and cholesterol in blood are similar independently of dietary phosphate content. However, 1-methylhistidine is lower in animals feed a chronic high phosphate intake.

Conclusions
High phosphate diet attenuates body weight gain, but induces hypoglycemia and may alter muscle homeostasis.

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Traduction de l'étude

L'apport chronique élevé en phosphate chez les souris affecte l'utilisation des macronutriments et la composition corporelle
Marko Ugrica Nutrition moléculaire et recherche alimentaire 22 février 2022

Au cours des dernières décennies, l'apport alimentaire en phosphate a augmenté en raison d'une consommation accrue d'aliments ultra-transformés. Cet apport plus élevé a un impact sur la composition corporelle et l'état de santé. Récemment, cette étude a révélé qu'un régime chronique riche en phosphate n'entraîne aucune altération rénale majeure, mais affecte négativement les paramètres de la santé osseuse, probablement en raison de la charge acide chronique. Ici, l'effet d'une consommation élevée de phosphate sur les paramètres du métabolisme énergétique est évalué.

Méthodes et résultats
Des souris adultes matures en bonne santé sont nourries pendant 1 an ou 4 mois avec un régime standard (0,6 % p/p) ou un régime riche en phosphate (1,2 % p/p). Des mâles et des femelles de deux fonds génétiques différents sont étudiés. Les souris nourries avec le régime riche en phosphate présentent un gain de poids corporel atténué, un taux d'échange respiratoire inférieur, une diminution de la masse grasse corporelle et une augmentation du rapport masse maigre sur graisse. De plus, le régime riche en phosphate conduit à une hypoglycémie à jeun sans différence dans la réponse glycémique à un test de tolérance au glucose par voie orale. Les triglycérides et le cholestérol dans le sang sont similaires indépendamment de la teneur en phosphate alimentaire. Cependant, la 1-méthylhistidine est plus faible chez les animaux nourris avec un apport chronique élevé en phosphate.

conclusion
Un régime riche en phosphate atténue la prise de poids corporel, mais induit une hypoglycémie et peut altérer l'homéostasie musculaire.

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Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice
Elena Alcalde-Estévez Journal of Cachexia, Sarcopenia and Muscle 28 February 2023

Background
Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging.

Methods
Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test.

Results
Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P = 0.004). NMRI revealed a significant reduction in T2 relaxation time (P = 0.014) and increased magnetization transfer (P = 0.045) and mean diffusivity (P = 0.045) in low-P diet-treated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P = 0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P = 0.004 and P = 0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P = 0.032) and reducing transition time in the static rod by 55% (P = 0.012). Similar results were found when diet was supplemented with Velphoro®.

Conclusions
The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.

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Traduction de l'étude

La restriction alimentaire en phosphate prévient l'apparition de signes de sarcopénie chez les souris âgées
Elena Alcalde-Estévez Journal of Cachexia, Sarcopenia and Muscle 28 février 2023

Arrière-plan
La sarcopénie est définie par la perte progressive et généralisée de la masse musculaire et de la fonction associée au vieillissement. Nous avons précédemment proposé que l'hyperphosphatémie liée au vieillissement soit liée à l'apparition de signes de sarcopénie. Parce qu'il n'existe pas de traitements efficaces pour prévenir la sarcopénie, à l'exception des exercices de résistance, nous proposons ici d'analyser si la restriction alimentaire en phosphate pourrait être une stratégie utile pour améliorer la fonction et la structure musculaire dans un modèle animal de vieillissement.

Méthodes
Des souris C57BL6 mâles âgées de cinq mois (jeunes), de 24 mois (âgées) et de 28 mois (gériatriques) ont été utilisées. Des souris âgées et gériatriques ont été divisées en deux groupes, l'un nourri avec un régime standard (0,6 % de phosphate) et l'autre avec un régime pauvre en phosphate (faible teneur en P) (0,2 % de phosphate) pendant 3 ou 7 mois, respectivement. Un chélateur de phosphate, Velphoro®, a également été supplémenté dans un groupe de souris âgées, mélangé à un régime broyé standard pendant 3 mois. La masse musculaire a été mesurée par le poids des muscles gastrocnémiens et tibiaux, et la qualité par imagerie par résonance magnétique nucléaire (NMRI) et des tests de coloration histologique. La force musculaire a été mesurée par test de préhension et les propriétés contractiles du muscle tibial par stimulation électrique du nerf péronier commun. Les paramètres de marche ont été analysés lors de la locomotion spontanée des souris avec empreinte. L'orientation et la coordination motrice ont été évaluées à l'aide d'un test de tige statique.

Résultats
Les souris âgées nourries avec un régime pauvre en P ont montré une concentration réduite de phosphate sérique (16,46 ± 0,77 mg/dL jeunes ; 21,24 ± 0,95 mg/dL vieux ; 17,46 ± 0,82 mg/dL régime pauvre en P). Les souris âgées nourries avec un régime pauvre en phosphore affichaient 44 % de masse en plus dans les muscles gastrocnémiens par rapport aux souris âgées (P = 0,004). L'IRMN a révélé une réduction significative du temps de relaxation T2 (P = 0,014) et une augmentation du transfert d'aimantation (P = 0,045) et de la diffusivité moyenne (P = 0,045) chez les souris traitées avec un régime à faible teneur en P par rapport à leur cétané. Le régime hypophosphatémique a augmenté la taille des fibres et réduit la zone fibreuse de 52 % dans le muscle gastrocnémien par rapport aux souris âgées (P = 0,002). La force de contraction et la force tétanique ont été significativement augmentées chez les souris âgées nourries avec le régime hypophosphatémique (P = 0,004 et P = 0,014, respectivement). Les performances physiques ont également été améliorées, augmentant la vitesse de marche de 30 % (P = 0,032) et réduisant le temps de transition dans la tige statique de 55 % (P = 0,012). Des résultats similaires ont été trouvés lorsque le régime était complété par Velphoro®.

conclusion
La restriction alimentaire en phosphate chez les souris âgées améliore la quantité et la qualité musculaire, la force musculaire et les performances physiques. Des résultats similaires ont été trouvés en utilisant le liant de phosphate Velphoro®, soutenant le rôle du phosphate dans l'altération de la structure et de la fonction musculaire qui se produit au cours du vieillissement.

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Dietary phosphate disturbs of gut microbiome in mice
Naoko Oda Journal of Clinical Biochemistry and Nutrition 2023/07/15

Disorder of phosphate metabolism is a common pathological condition in chronic kidney disease patients. Excessive intake of dietary phosphate deteriorates chronic kidney disease and various complications including cardiovascular and infectious diseases. Recent reports have demonstrated that gut microbiome disturbance is associated with both the etiology and progression of chronic kidney disease. However, the relationship between dietary phosphate and gut microbiome remains unknown. Here, we examined the effects of excessive intake of phosphate on gut microbiome. Five-week-old male C57BL/6J mice were fed either control diet or high phosphate diet for eight weeks. Analysis of the gut microbiota was carried out using MiSeq next generation sequencer, and short-chain fatty acids were determined with GC-MS. In analysis of gut microbiota, significantly increased in Erysipelotrichaceae and decreased in Ruminococcaceae were observed in high phosphate diet group. Furthermore, high phosphate diet induced reduction of microbial diversity and decreased mRNA levels of colonic tight junction markers.

These results suggest that the excessive intake of dietary phosphate disturbs gut microbiota and affects intestinal barrier function.

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Traduction de l'étude

Le phosphate alimentaire perturbe le microbiome intestinal chez la souris
Naoko Oda Journal de biochimie clinique et de nutrition 2023/07/15

Le trouble du métabolisme du phosphate est une condition pathologique courante chez les patients atteints d'insuffisance rénale chronique. Une consommation excessive de phosphate alimentaire détériore les maladies rénales chroniques et diverses complications, notamment les maladies cardiovasculaires et infectieuses. Des rapports récents ont démontré que la perturbation du microbiome intestinal est associée à la fois à l'étiologie et à la progression de l'insuffisance rénale chronique. Cependant, la relation entre le phosphate alimentaire et le microbiome intestinal reste inconnue. Ici, nous avons examiné les effets d'une consommation excessive de phosphate sur le microbiome intestinal. Des souris mâles C57BL/6J âgées de cinq semaines ont été nourries soit avec un régime témoin, soit avec un régime riche en phosphate pendant huit semaines. L'analyse du microbiote intestinal a été réalisée à l'aide du séquenceur de nouvelle génération MiSeq et les acides gras à chaîne courte ont été déterminés par GC-MS. Dans l'analyse du microbiote intestinal, une augmentation significative chez les Erysipelotrichaceae et une diminution chez les Ruminococcaceae ont été observées dans le groupe à régime riche en phosphate. De plus, un régime riche en phosphate a induit une réduction de la diversité microbienne et une diminution des niveaux d'ARNm des marqueurs de jonctions serrées du côlon.

Ces résultats suggèrent que la consommation excessive de phosphate alimentaire perturbe le microbiote intestinal et affecte la fonction de barrière intestinale.

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Industrial Use of Phosphate Food Additives: A Mechanism Linking Ultra-Processed Food Intake to Cardiorenal Disease Risk?
by Mona S. Calvo Nutrients 2023, 15(16), 3510;

The consumption of ultra-processed food (UPF) keeps rising, and at the same time, an increasing number of epidemiological studies are linking high rates of consumption of UPF with serious health outcomes, such as cardiovascular disease, in the general population. Many potential mechanisms, either in isolation or in combination, can explain the negative effects of UPF. In this review, we have addressed the potential role of inorganic phosphate additives, commonly added to a wide variety of foods, as factors contributing to the negative effects of UPF on cardiorenal disease.

Inorganic phosphates are rapidly and efficiently absorbed, and elevated serum phosphate can lead to negative cardiorenal effects, either directly through tissue/vessel calcification or indirectly through the release of mineral-regulating hormones, parathyroid hormone, and fibroblast growth factor-23. An association between serum phosphate and cardiovascular and bone disease among patients with chronic kidney disease is well-accepted by nephrologists. Epidemiological studies have demonstrated an association between serum phosphate and dietary phosphate intake and mortality, even in the general American population. The magnitude of the role of inorganic phosphate additives in these associations remains to be determined, and the initial step should be to determine precise estimates of population exposure to inorganic phosphate additives in the food supply.