Acid-Base Balance: Foods and Supplements

I previously wrote about the role lactic acid can play in disease.  This raised the question of whether foods and supplements can buffer metabolic acidity.  If so, which foods or supplements are most beneficial?  Does pH correlate to the effect on the acid-base balance of the body?

This is important because:

• Chronic acid load can deplete alkalinizing minerals, leading to e.g. calcium bone loss.
• Long Covid may be caused by metabolic acidosis: https://researchaidnetworks.org/hypothesis-summary/

After researching this, I concluded that a food's pH does not directly correlate with its impact on overall acid base balance.  Potential Renal Acid Load (PRAL) is determined by mineral and protein composition, not its inherent acidity.  

For example:

• Lemons taste acidic due to citric acid, but have a negative PRAL (alkaline-forming) because they're rich in potassium and other compounds that generate bicarbonate when metabolized
• Animal proteins may not taste acidic but have a high positive PRAL (acid-forming) due to sulfur-containing amino acids that get metabolized to sulfuric acid.

The key biochemical factors that determine a food's PRAL include:

1. Protein content (especially sulfur amino acids) - metabolized to produce acids
2. Mineral content: 
1. Potassium, calcium, magnesium - metabolized to produce bicarbonate (alkaline)
2. Phosphorus, chloride - contribute to acid load
3. Organic acid content - intermediates in the citric acid cycle (Krebs cycle), their oxidation generates bicarbonate. Each molecule of malate or citrate metabolized can generate multiple bicarbonate molecules.

Details

The pH of urine is influenced by the body's metabolic acid load and the kidney's ability to regulate hydrogen ion (H⁺) excretion.  The kidneys play a crucial role in maintaining acid-base balance by adjusting the amount of hydrogen ions eliminated or retained.  When the body experiences a metabolic acid load, the kidneys respond by increasing H⁺ excretion. This lowers urine pH, reflecting the increased acid load on the body.  However, positive cations can also stimulate renal acid-base regulation, leading to increased hydrogen ion excretion (and bicarbonate (HCO₃⁻) regeneration).  This results in a decrease in urine pH, even as the body experiences a reduced metabolic acid load.

Cations can also activate enzymes that convert metabolic acids to bicarbonate.  The more positively charged the cation, the more efficiently it can displace hydrogen ions.

Organic acid conjugation to cations enhances alkalinization.  For example, citrate enters the citric acid cycle directly and generates multiple bicarbonate (HCO₃⁻) upon oxidation.

Table of Common Supplements and Food Additives; their pH and effect on acid-base balance.  

This data shows how solution pH and PRAL effects don't always correlate. For example, while KCl has a neutral pH in solution, it has a slightly negative PRAL due to the potassium content. However, extreme pH (either acid or base) can correlate with PRAL effect.

Categories of Supplements

1. Neutral pH, Alkalizing Effect: 
1. Potassium citrate
2. Calcium lactate
3. Potassium gluconate
4. These demonstrate the pH vs. physiological effect paradox
2. Mineral-Organic Complexes: 
1. Magnesium citrate and malate show slightly acidic pH but strong alkalizing effects
2. Zinc citrate has less alkalizing effect despite similar pH
3. Simple Salts: 
1. KCl shows neutral pH with mild alkalizing effect
2. NaCl shows neutral pH and neutral physiological effect
4. Strong Acids/Bases: 
1. HCl, KOH, NaOH show correlation between pH and physiological effect
2. These are exceptions to the general trend of pH not predicting physiological impact

Alkalinizing Potential Ranking

The formula for PRAL (mEq/100g) is: PRAL = 0.49 × protein (g) + 0.037 × phosphorus (mg) - 0.021 × potassium (mg) - 0.026 × magnesium (mg) - 0.013 × calcium (mg).  

Negative PRAL indicates an alkalizing effect on the body.

Example:  mice

Mice diets were compared using Dietary Cation Anion Balance (DCAB), a similar metric to PRAL.  DCAB is calculated by adding the weighted amount of acidifying anions and alkalizing cations in the diet. 

It has been shown in many species that the dietary cation anion balance (DCAB) influences acid base homeostasis and urine pH.  With the DCAB, the resulting urinary pH can be predicted with species-specific equations. 

DCAB [mmol/kg DM] = 49.9 · Ca + 82.3 · Mg + 43.5 · Na + 25.6 · K − 59.0 · P − 62.4 · S − 28.2 · Cl; mineral content in g/kg DM.  (Negative DCAB indicates an acidifying effect on the body.)

The paper found that a negative DCAB results in metabolic acidosis, and "Fed long-term, this can contribute to the reduction of bone mineral density due to a PTH-mediated increase in renal calcium excretion. Metabolic acidosis also induces renal phosphorus excretion, resulting in hypophosphatemia."

Citation: https://www.mdpi.com/2076-2615/11/3/702 

Böswald, L.F.; Matzek, D.; Kienzle, E.; Popper, B. Influence of Strain and Diet on Urinary pH in Laboratory Mice. Animals 2021, 11, 702. https://doi.org/10.3390/ani11030702

Example:  human athletes

Alkaline water has demonstrated its effectiveness as an alkalizing agent in the treatment of metabolic acidosis in both animal and human research. Past studies have shown that daily intake of 2.5–4 L of alkaline water for 3~6 weeks has significant impacts on anaerobic performance and acid–base balance in athletes.  This study showed that alkaline water co-ingested with glutamine led to decreased stress markers in athletes.  Masterjohn hypothesizes that glutamine is converted to glutamate to buffer lactic acid in muscles, and that decreasing PRAL contributes to more available glutamine for other metabolic functions..  

Citation: https://www.mdpi.com/2072-6643/16/3/454

Lu, T.-L.; He, C.-S.; Suzuki, K.; Lu, C.-C.; Wang, C.-Y.; Fang, S.-H. Concurrent Ingestion of Alkaline Water and L-Glutamine Enhanced Salivary α-Amylase Activity and Testosterone Concentration in Boxing Athletes. Nutrients 2024, 16, 454. https://doi.org/10.3390/nu16030454

Thanks to Claude Sonnet for back-and-forth conversation, and for creating the table and figure above.  

Clues toward the Cause of Long COVID

I previously shared some of the amazing data from the paper "Muscle abnormalities worsen after post-exertional malaise in long COVID" by Appelman et al. 

The paper will undoubtable become a classic in the field of Long COVID, providing a fascinating series of clues that the researchers followed past several dead-ends to their interesting implications. 

First, and most importantly, the researchers confirmed beyond a shadow of doubt that Post-Exertional Malaise (PEM) is a real disease, with myriad muscle and metabolic abnormalities in the Long COVID patients following intense exercise.  Metabolomics provided additional key findings, including the first clue: a possible blockage of glycolysis in Long COVID (see diagrams in previous post).  

A Clue: Glycolysis Blockage

In the glycolysis pathway, the phosphoenolpyruvate (PEP) levels of Long COVID patients were increased, while pyruvate levels were decreased, indicating a disruption or imbalance in enzyme activities within the pathway.   This could be due to a decreased activity of the enzyme pyruvate kinase (PK), which converts PEP to pyruvate in the final step of glycolysis.  Reduced PK activity would result in a buildup of PEP.  With less PEP being converted to pyruvate, the downstream levels of pyruvate would be lower.  

There are several interconnected regulatory pathways that can reduce the activity of pyruvate kinase (PK), the two most relevant being Oxidative Stress and Hypoxia.  Increased levels of reactive oxygen species (ROS) or oxidative stress can lead to the oxidation and inactivation of PK.  Under hypoxic conditions (low oxygen levels), the transcription factor HIF-1 (Hypoxia-Inducible Factor 1) can be activated, which can lead to the downregulation of PK expression and activity.  This is part of the cellular adaptation to hypoxia, where glycolysis is regulated to favor the production of metabolic intermediates for other pathways.

Hypoxia?

In the context of Long Covid and post-exertional malaise (PEM), hypoxia from microclots has been suggested to increase lactic acid production. However, in this study the metabolomics showed decreased* lactic acid, because glycolysis was shut down at PEP by loss of PK activity, not at pyruvate by loss of pyruvate dehydrogenase (PDH).  

The researchers looked for but did not find decreased muscle oxygen perfusion or any differences in microvasculature.  The researchers noted decreased oxygen utilization, but this could be due to anything that disrupts metabolism and does not indicate hypoxia as a specific issue.  

They noted amyloid plaques in the extracellular matrix; the plaques were not blocking the microcapillaries and it is unclear what role they play in the pathophysiology of Long COVID: are they a cause of PEM, or a consequence?  

Their observation that Long COVID patients' muscle force was not dependent on The Citric Acid (TCA) cycle enzyme succinate dehydrogenase (SDH) can also be explained by impaired metabolism upstream of TCA Cycle, i.e. in glycolysis.

Oxidative Stress

Therefore, it seems likely that the regulatory pathway most likely to contribute to reduced pyruvate kinase (PK) expression and activity is the oxidative stress pathway.  

Long Covid patients have been reported to exhibit higher levels of oxidative stress markers, such as lipid peroxidation products and decreased antioxidant levels, compared to healthy individuals or those who have recovered from acute COVID-19 infection.  Physical exertion and exercise can lead to an acute increase in reactive oxygen species (ROS) production, potentially exacerbating oxidative stress in individuals with Long Covid and triggering PEM symptoms.

Some studies have suggested that Long Covid patients may experience mitochondrial dysfunction, which can further contribute to increased ROS generation and oxidative stress.

Next Steps

The paper concluded with these results, but the logical next step would be to use metabolomics to assess free radical concentrations.  One theory is that COVID spike proteins form "pores", or holes in the mitochondrial membranes, disrupting the mitochondria and releasing free radicals into the cell.  

The researchers did look at COVID nucleocapsid protein, but found it in both the control and Long COVID groups in equal concentrations, suggesting that remnant viral protein doesn't explain the pathophysiology of Long COVID.  But maybe remnant virus affects the Long COVID patients differently?  

The researchers noted immune cell infiltration into muscle tissue, which could be in response to a signal from excess free radicals, or could be due to some other reason like persistent COVID infection/expression.  

Lactate?

This study seems to indicate the lactate is not an important variable for the pathophysiology of Long COVID.  However, the details about how lactate was measured limit these conclusions. The researchers measured lactate from three different sources:  metabolomic blood (venous) and muscle lactate measured before and after PEM, and capillary (i.e. finger prick) lactate measured during exercise.  Venous lactate measured one week after PEM induction showed a slightly increased level in Long COVID patients, but none of the other metabolomic lactate measurements showed any difference.  The capillary lactate also showed a slightly elevated blood lactate level before exercise in the Long COVID patients, but the difference was not significantly different.  

However, the baseline measurements were not taken in a fasted condition, and because eating normally raises resting lactate it cannot be determined from this study if fasted lactate might show other differences that are important to Long COVID.

Post Exertional Malaise in Long Covid

 Severe exercise-induced myopathy has been found in long COVID post-exertional malaise (PEM).  

Just look at these long COVID patients (in red) pushing close to 20 mmol/L lactate on the exercise bike!  That is serious dedication for a group of patients who know what the consequences will be.

After the exercise test, blood metabolomics show elevated glycolysis, but decreased pyruvate and TCA cycle metabolites.

Muscle biopsy metabolomics show decreased purine synthesis and TCA cycle.

Key:

Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3