The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome
Abstract
:1. Introduction
2. Relevance of Ferroptosis to Rising Metabolic and Related Diseases
2.1. Core Features of Ferroptosis: Lipid Peroxidation and Iron Overload
2.2. Type 2 Diabetes
2.3. Nonalcoholic Fatty Liver Disease
2.4. Cardiovascular Disease
2.5. Neurodegenerative Disease
2.6. Therapeutic Approaches to Ferroptosis
3. Essentiality of C15:0, Evidence of Nutritional Deficiencies, and Relevance to Metabolic and Related Diseases
3.1. Evidence of Essentiality
- Dietary C15:0 intake is directly and reliably correlated to circulating C15:0 concentrations, demonstrating that C15:0 is primarily exogenous [49].
3.2. Evidence of Nutritional C15:0 Deficiencies
3.2.1. Normal C15:0 Concentrations in Humans
3.2.2. Associations between Lower C15:0 Concentrations and Increased Risk of Type 2 Diabetes, Cardiovascular Disease, and NAFLD
3.2.3. Importance of Normal C15:0 Concentrations to Support Healthy Pregnancies and Early Child Development
3.2.4. Drivers for Declining C15:0 Concentrations
4. Metabolic Diseases and Iron Overload in Dolphins: Insights on an Emerging C15:0 Nutritional Deficiency Syndrome
4.1. Physiologic Similarities between Dolphins and Humans
4.2. Fatty Liver Disease, Iron Overload, and Metabolic Syndrome in Dolphins: Dysmetabolic Iron Overload Syndrome
4.3. Dysmetabolic Iron Overload Syndrome in Humans
4.4. Lower Dietary and Circulating C15:0 Are Associated with DIOS in Dolphins
4.5. An Unexpected Clue: Increased Dietary C15:0 Alleviates Anemia in Dolphins
4.6. C15:0 Attenuation of Anemia, DIOS, NASH, and Metabolic Syndrome in a Relevant Model
5. Proposed Nutritional-C15:0-Deficiency-Driven Cellular Fragility Syndrome
5.1. Proposed Nutritional C15:0 Deficiency Definition
- C15:0 deficiency, defined as ≤0.2% of total circulating fatty acids, results in Cellular Fragility Syndrome, which includes higher risks of developing DIOS, ferroptosis, anemia, advanced NAFLD and NASH, cardiovascular disease, and type 2 diabetes. In addition to low C15:0 concentrations and indices associated with liver and cardiometabolic diseases, people with Cellular Fragility Syndrome are expected to have (1) hyperferritinemia, (2) elevated lipid peroxidation levels, (3) red blood cells with elevated osmotic fragility, and (4) elevated red blood cell distribution width (RDW) [3,4,5,6,47,140,142].
5.2. Proposed Pathophysiology of Nutritional C15:0 Deficiencies (Cellular Fragility Syndrome)
- First, red blood cell membranes containing C15:0 ≤ 0.2% total fatty acids become fragile and susceptible to lipid peroxidation. In addition to C15:0 measurements, tests to detect this stage may include osmotic fragility tests, RDW, and systemic lipid peroxidation.
- Second, fragile red blood cells are engulfed by macrophages, including liver Kupffer cells, which over time results in regenerative anemia and DIOS. Tests that may detect this stage include low hemoglobin, high reticulocytes, high RDW, and hyperferritinemia.
- Third, combined elevated lipid peroxidation with iron overload results in ferroptosis in the liver and the subsequent advancement of NAFLD and NASH, including increased inflammation, cell damage, and fibrosis in the liver. Tests that may detect this stage include elevated liver enzymes and increased inflammatory markers (elevated globulins, IL-6, TNFα, and MCP-1).
- Fourth, impaired liver function and ferroptosis results in insulin resistance, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Tests to detect this stage include non-specific markers of these diseases, including elevated insulin, glucose, cholesterol, and triglycerides.
- Finally, spillover iron and systemically fragile cell membranes result in systemic iron overload and ferroptosis, which pairs with fragile cells to further impair tissues, resulting in accelerated aging, including accelerated cardiovascular disease.
6. Demonstrated In Vivo Efficacies of Oral C15:0 Supplementation to Reverse Cellular Fragility Syndrome
6.1. C15:0 Supplementation Stabilizes Red Blood Cells, Attenuates Anemia, and Lowers Lipid Peroxidation
6.2. C15:0 Supplementation Decreases Erythrophagocytosis by Liver Kupffer Cells, Resulting in Attenuated DIOS, NAFLD, and NASH
6.3. C15:0 Supplementation Lowered Indices of Insulin Resistance, Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease
7. Conclusions
8. Patents
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Fish Species | C15:0 Content (% Total Fatty Acids) |
---|---|
Mullet | 1.18% |
Catfish | 0.94% |
Striped red mullet | 0.92% |
Sea bass | 0.82% |
Eel | 0.73% |
Red porgy | 0.63% |
Golden grouper | 0.62% |
Sardine | 0.60% |
Carp | 0.53% |
Sole | 0.50% |
Sea bream | 0.42% |
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Venn-Watson, S. The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome. Metabolites 2024, 14, 355. https://doi.org/10.3390/metabo14070355
Venn-Watson S. The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome. Metabolites. 2024; 14(7):355. https://doi.org/10.3390/metabo14070355
Chicago/Turabian StyleVenn-Watson, Stephanie. 2024. "The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome" Metabolites 14, no. 7: 355. https://doi.org/10.3390/metabo14070355