3. Sarcopenia, Phosphate Toxicity, and PD
Sarcopenia, low muscle mass, and muscle function increase disability, frailty, morbidity, and mortality and lowers quality of life in the elderly population
[18]. Core muscle loss was associated with reduced brain gray matter volume in patients with PD
[19]. A recent systematic review and meta-analysis found that “the pooled prevalence of sarcopenia was 29% in PD, which was higher than the healthy older control group”
[20]. The researchers suggested that sarcopenia and PD may share a common pathway of neuroinflammation. Coincidentally, a higher prevalence of sarcopenia was found in diabetic compared to non-diabetic individuals in a meta-analysis of an Asian population
[21], yet again implying common pathways shared with PD.
Of relevance, increasing dietary Pi fed to lab animals in a model of chronic kidney disease showed a dose-dependent increase in levels of tumor necrosis factor-alpha, a biomarker of systemic inflammation, as well as decreased animal body weight, a biomarker of malnutrition, and increased vascular calcification with reduced lifespan
[22]. These findings are consistent with sarcopenia as well as inflammation in PD
[23], providing additional support for phosphate toxicity in PD etiology. Moreover, concentrated levels of Pi added to cultured muscle cells directly produced cell autophagy
[24], and future studies should investigate muscle cell autophagy associated with phosphate-induced mitochondrial damage.
4. Cancer, Phosphate Toxicity, and PD
Tumorigenesis is associated with phosphate toxicity
[25], briefly summarized here. As excessive amounts of dysregulated Pi are sequestered into precancerous cells through overexpressed sodium phosphate cotransporters, cell signaling pathways stimulate tumor growth. For example, the phosphoinositide 3 kinase (PI3K) pathway phosphorylates Akt (protein kinase B), leading to activation of mTOR (mammalian target of rapamycin), which upregulates protein synthesis in tumor growth. Phosphorus is a rate-limiting factor in biological growth, and reducing phosphorus transport into a tumor by half is predicted to reduce a tumor’s size by 75%
[26].
Positive associations have been found between PD and cancers of the breast, brain, and melanoma, and cancer incidence may occur either before or after PD incidence, which is consistent with a common causative pathway in both of these “pathologically convergent diseases”
[27]. Nevertheless, “the lower risks of lung, bladder, and colorectal cancer, all smoking-related cancers, in PD patients are generally undisputed”. Feasibly, lower risks of smoking-related cancers could be explained by the fact that “smokers reported reduced compliance with the DRI [dietary reference intake] for iron, phosphorus, vitamin C, riboflavin, and folate compared to nonsmokers”
[28]. With a DRI of 700 mg phosphorus per day for U.S. adults, “the average daily phosphorus intake from foods is 1189 mg for women and 1596 mg for men”
[29], implying that smokers’ phosphorus intake is approximately twice as low as the average intake. Moreover, lower phosphorus intake could explain “a causally protective effect of current smoking on the risk of PD”
[30].
5. High Dietary Phosphate and PD
Globally, “the presence of any known causal PD mutation is rare, occurring in less than 2% of the PD population”, inferring that environmental factors such as diet are likely to play a significant role in PD etiology
[31]. Relevant to the potential contribution of phosphate toxicity to PD pathophysiology, “high phosphorus intake is associated with increased mortality in a healthy US population”
[32]. Importantly, “dairy products, fish, and other types of meat are a major source of phosphate in the human diet”, and “preservatives and additive salts commonly used in processed foods contain large amounts of phosphate”
[33].
A prospective study of the EPIC-Greece cohort found that “incident PD exhibited strong positive association with consumption of milk, but not cheese or yoghurt”, and an “inverse association was found between polyunsaturated fat intake and incident PD”
[34]. Milk consumption, but not fermented milk, was also weakly associated with increased risk of PD in a recent Swedish study
[35]. Associations between various food items and PD could be mediated by an inverse relationship between the phosphorus and fat content in foods—phosphorus in food is naturally found in combination with protein
[36], not with fat. Full-fat dairy products provide more calories and have lower phosphorus caloric densities (lower phosphorus levels per kcal), which helps meet caloric dietary needs with overall less phosphate, compared to low-fat or non-fat dairy products that provide fewer calories and have higher phosphorus caloric densities, which may drive up overall phosphorus intake to meet calorie requirements. Accordingly, a Harvard analysis of data from the Nurses’ Health Study and the Health Professionals’ Follow-Up Study found that three or more servings of low-fat dairy was associated with a higher risk of PD diagnosis, but no association was found with consumption of full-fat dairy
[37].
Low phosphorus in a high-fat ketogenic diet (KD) could also explain neuroprotection of the KD, although “the literature does not yet support a neuroprotective effect of the KD in PD”
[38]. Nevertheless, current data suggest benefits in non-motor symptoms of PD patients using a ketogenic diet
[39]. Additionally, whole-food plant-based diets such as the Mediterranean diet, with reduced Pi intake from animal food products and highly processed foods, have been associated with delayed onset of PD
[40]. A recent analysis of dietary patterns in the Rotterdam Study reported reduced associated risks of PD in the Netherlands general population that “corroborate previous findings of a possible protective effect of the Mediterranean diet”
[41]. This type of plant-based diet often contains an abundance of whole fruit, which has low phosphorus caloric density.
Table 1 shows the phosphorus caloric density of various food items based on data from the U.S. Department of Agriculture (USDA) National Nutrient Database for Standard Reference, Legacy 2018
[42]. Note that whole fruit, although high in sugar, is also high in fiber with a low glycemic index
[43], and whole fruit is associated with decreased risk of diabetes
[44][45]. Future studies should investigate potential PD benefits specifically associated with lower phosphate intake in whole-food plant-based diets.
Table 1. Phosphorus caloric density of selected food items.
Based on data from USDA National Nutrient Database for Standard Reference, Legacy (2018).
Restriction of dietary phosphate, 800–1000 mg/day, is currently used in managing phosphate serum levels in patients with chronic kidney disease
[46], and similar strategies should be investigated to prevent and delay progression of PD. Dietary counseling from renal dietitians and other trained healthcare providers “can lead to better control of phosphorus intake”
[36]. Importantly, in vivo regression of ectopic calcification is associated with the phosphoprotein osteopontin (OPN)
[47], and vascular calcification reversal in rats fed low-phosphate diets was suggested to be linked to OPN
[48]. Phosphorylation regulates the inhibitory effect of OPN on vascular calcification
[49], providing a potential compensatory response to calcification associated with elevated phosphate levels
[50]. This evidence implies that some degree of regression of mitochondrial calcification in PD may be possible by placing patients with PD on restricted-phosphate diets.