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23 June 2024

The Cellular Stability Hypothesis: Evidence of Ferroptosis and Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome

1
Seraphina Therapeutics Inc., San Diego, CA 92106, USA
2
Epitracker Inc., San Diego, CA 92106, USA
Metabolites2024, 14(7), 355;https://doi.org/10.3390/metabo14070355
This article belongs to the Special Issue Impact of Macronutrients on Metabolism
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Abstract

Ferroptosis is a newly discovered form of cell death caused by the peroxidation of fragile fatty acids in cell membranes, which combines with iron to increase reactive oxygen species and disable mitochondria. Ferroptosis has been linked to aging-related conditions, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Pentadecanoic acid (C15:0), an odd-chain saturated fat, is an essential fatty acid with the primary roles of stabilizing cell membranes and repairing mitochondrial function. By doing so, C15:0 reverses the underpinnings of ferroptosis. Under the proposed “Cellular Stability Hypothesis”, evidence is provided to show that cell membranes optimally need >0.4% to 0.64% C15:0 to support long-term health and longevity. A pathophysiology of a newly identified nutritional C15:0 deficiency syndrome (“Cellular Fragility Syndrome”) is provided that demonstrates how C15:0 deficiencies (≤0.2% total circulating fatty acids) can increase susceptibilities to ferroptosis, dysmetabolic iron overload syndrome, type 2 diabetes, cardiovascular disease, and NAFLD. Further, evidence is provided that C15:0 supplementation can reverse the described C15:0 deficiency syndrome, including the key components of ferroptosis. Given the declining dietary intake of C15:0, especially among younger generations, there is a need for extensive studies to understand the potential breadth of Cellular Fragility Syndrome across populations.

1. Introduction

Based on A.J. Hulbert’s Cell Membrane Pacemaker Theory of Aging, mammalian longevity is determined by the stability of fatty acids in cell membranes, which protect against lipid peroxidation and slow the onset of diseases that eventually lead to mortality [1]. In support of this theory, Hulbert showed that cell membranes containing fatty acids with higher saturation had greater cellular stability. In turn, this stability resulted in lowered circulating lipid peroxidation and was associated with longer mammalian species’ lifespans. There is evidence that this association between cell membrane stability and lifespan is not limited to variations between species but also within species, including humans.
Just over a decade ago, a new form of cell death, called ferroptosis, was discovered [2]. Prior to this discovery, there were only three recognized types of cell death: apoptosis, necrosis, and autophagy. Ferroptosis involves the lipid peroxidation of fragile polyunsaturated fatty acids in cell membranes, which combines with abnormal intracellular iron to induce mass production of reactive oxygen species, resulting in disabled mitochondria and cell death. Ferroptosis has been linked to many aging-related diseases in humans, including type 2 diabetes, cardiovascular disease, NAFLD, and neurodegenerative diseases [3,4,5,6]. Despite over 10,000 published peer-reviewed papers on ferroptosis since its discovery in 2012, it is not clear how or why ferroptosis emerged.
This review introduces the “Cellular Stability Hypothesis”, which proposes that C15:0, an odd-chain saturated fatty acid newly discovered as essential, is integral to stabilizing and strengthening cell membranes. Further, when red blood cell membrane C15:0 concentrations are near or below 0.2% of total fatty acids, the result is ferroptosis. Herein, evidence of the pathophysiology of ferroptosis is provided, which starts with nutritional C15:0 deficiencies and culminates in accelerated metabolic, liver, and cardiovascular disease. This proposed nutritional C15:0 deficiency syndrome (termed “Cellular Fragility Syndrome”) is a form of accelerated cellular aging that may explain why aggressive forms of aging-associated diseases are increasing among younger people. Importantly, this deficiency is fixable.

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

While the section above provides evidence that lower circulating C15:0 levels are associated with a higher risk of type 2 diabetes, cardiovascular disease, and NAFLD, a pathophysiologic mechanism is needed to justify the proposal of C15:0 nutritional deficiencies. This section reviews learnings from long-lived, large-brained dolphins, which have revealed two central tenets of a proposed C15:0 nutritional deficiency syndrome: increased cellular fragility and iron overload.
Bottlenose dolphins are mammals that once lived on land but re-entered the ocean an estimated 50 million years ago [111]. As deer-like artiodactyls, the land-based predecessor to dolphins was likely primarily a plant eater that evolved to eating fish at sea. We previously proposed that dolphins developed an observed insulin-resistant state to support all-meat diets that require liver production of glucose to meet high demands by their large brains [112]. This hypothesis parallels the same proposed “carnivore connection” in humans, where insulin resistance was an advantageous condition during the Ice Ages, as humans moved from a mixed plant-and-meat diet to pure-meat diets [113].
Further evidence of special parallels between dolphins and humans includes shared rapid glucose GLUT-1 transport in red blood cells as adults; high encephalization quotients (brain-to-body mass ratios); and remarkable synteny of chromosome 1, which has been conserved among only humans, dolphins, great apes, and two-toed sloths [114,115,116]. Thus, dolphins and humans have co-evolved similar mechanisms and metabolism, likely to support glucose demands for large brains and long lives. This may also explain why aging dolphins and humans share similar chronic conditions [117].
The U.S. Navy has cared for a sustained population of approximately 100 bottlenose dolphins, currently living in San Diego Bay, for over 60 years. While dolphins in the wild live an average of 20 years, U.S. Navy dolphins routinely live into their 40s and even 50s [118]. These older dolphins have provided invaluable insight into chronic diseases of aging, including insulin resistance, metabolic syndrome, nonalcoholic fatty liver disease, dysmetabolic iron overload syndrome, and anemia. These insights are provided below.

4.2. Fatty Liver Disease, Iron Overload, and Metabolic Syndrome in Dolphins: Dysmetabolic Iron Overload Syndrome

Bottlenose dolphins are naturally susceptible to fatty liver disease that mimics NAFLD in humans, including the presence of steatosis, iron deposition within Kupffer cells (liver macrophages or reticuloendothelial cells), and inflammation [7]. Dolphins with fatty liver disease have phasic increases in liver enzymes (ALT, AST, and/or GGT), and compared to healthy controls, individuals with elevated liver enzymes have higher iron, serum globulins, bilirubin, cholesterol, triglycerides, glucose levels, and erythrocyte sedimentation rate and lower platelet counts [119]. This presentation, especially preferential iron deposition within Kupffer cells, is consistent with iron overload related to aggressive NAFLD in people [120].
In addition to high serum iron (>300 µg/dl) and visualized iron deposition in liver Kupffer cells (hemochromatosis), dolphins with iron overload have hyperferritinemia and moderately elevated transferrin saturation that increase with age [121]. Similar to humans with liver iron overload, the use of routine phlebotomy treatments to reduce body iron stores temporarily lowers serum ferritin, iron, total iron binding capacity, and liver enzyme levels [122]. Ferritin, a measurement of iron storage in the body, is also higher in people with NALFD compared to healthy controls [123].
Naturally occurring metabolic syndrome in dolphins also parallels that in humans. In addition to fatty liver disease and liver iron overload, dolphins with metabolic syndrome have elevated insulin (13 ± 13 µIU/mL), glucose (108 ± 12 mg/dl), triglycerides (128 ± 45 mg/dl), and total cholesterol (217 ± 51 mg/dl) [124]. Those with the highest insulin (>14 µIU/mL) have higher glucose, iron, and GGT compared to healthy controls. While dolphins with metabolic syndrome do not have a higher body mass index (BMI) compared to healthy controls, those with the highest insulin (i.e., greatest insulin resistance) do have a higher BMI compared to controls. These studies show that dolphins have a consistent phenotype of fatty liver disease that includes macrophage-preferential liver iron overload and metabolic syndrome. This presentation in dolphins is remarkably consistent with dysmetabolic iron overload syndrome in humans [125].

4.3. Dysmetabolic Iron Overload Syndrome in Humans

Up until 25 years ago, iron overload (also called hemochromatosis) in humans was primarily considered a hereditary disease caused by HFE gene mutations that increased gut absorption of dietary iron [126]. Between 1998 and 2000, however, a new, non-hereditary form of iron overload was recognized and referred to as “dysmetabolic-associated liver iron overload syndrome”, “dysmetabolic hepatosiderosis”, or “dysmetabolic iron overload syndrome” (DIOS) [127,128,129]. In 2003, 15% of patients with iron overload had DIOS [130]. Key differentiators between DIOS versus hereditary hemochromatosis include iron deposition in mesenchymal cells (Kupffer cells or other macrophages), presence of metabolic syndrome, and hyperferritinemia with normal transferrin saturation [131,132]. Of the 23 people with DIOS in the 2003 study, 50% had NAFLD or NASH, and 12% had advanced, bridging fibrosis or cirrhosis.
By 2011, DIOS was characterized as “a frequent finding in the general population” and present in approximately 33% of people with NAFLD and metabolic syndrome [133]. Further, DIOS has been identified as a causal factor for more severe NASH, cardiovascular disease, insulin resistance, hyperglycemia, type 2 diabetes, and cancer [133,134,135]. As such, treatments targeting DIOS have the potential to attenuate all these related conditions. People with DIOS not only have higher liver iron levels but also have overall higher mobilized iron and overall body iron stores [136]. Further, DIOS is characterized as a condition involving poor export of iron out of cells, resulting in more cells with intracellular iron [137]. This lays the groundwork for DIOS as the potential epicenter of ferroptosis throughout the body [3].
Interestingly, obesity and NAFLD are associated with both DIOS and iron deficiency, which on the surface appear to be opposite conditions [138]. As shared by Malesza et al., however, both DIOS and iron deficiency involve higher circulating hepcidin and lower ferroportin, suggesting they are different manifestations of a similar problem [136]. This is why the treatment of iron deficiency anemia with iron supplementation can be problematic and why alternative options are actively being sought to address iron imbalance conditions.
Given that the underlying causes of both DIOS and ferroptosis have remained a mystery and that both conditions involve abnormal intracellular iron deposition which emerged during a similar timeframe, it is logical to believe that DIOS and ferroptosis have shared etiologies. Returning to the dolphin studies, a key risk factor for DIOS was discovered: lower dietary and circulating concentrations of odd-chain saturated fatty acids, including C15:0.

4.4. Lower Dietary and Circulating C15:0 Are Associated with DIOS in Dolphins

Unlike humans, who have complicated diets, dolphins primarily eat fish. As such, many proposed risk factors for poor health in the human diet (sugar, artificial trans-fatty acids, and ultra-processed foods) can be immediately eliminated as contributors to DIOS, NAFLD, and metabolic syndrome in dolphins. To evaluate potential dietary risk and protective factors for these conditions in dolphins, an initial study used a standard fatty acid panel to measure total fatty acids in dolphins’ archived serum, as well as fish in their diets. This study found that dolphins with higher serum concentrations of OCFAs (C15:0 and C17:0) had lower, healthier insulin levels (2–5 µIU/mL) compared to dolphins with lower C15:0 and C17:0 (insulin = 11 ± 12 µIU/mL) [139]. When different dietary fish types were tested for fatty acids, there was a surprising variation in OCFAs; for example, C17:0 content ranged from no detectable C17:0 in capelin to 164 mg per 100 g in mullet. Thus, there was the opportunity to provide dolphins with more fish containing higher amounts of OCFAs to effectively raise their OCFA levels.

4.5. An Unexpected Clue: Increased Dietary C15:0 Alleviates Anemia in Dolphins

As a next step, six dolphins were provided a modified diet containing fish with higher amounts of C15:0 and C17:0. Specifically, the dolphins’ dietary C15:0 intake increased from 1 g to 5 g per day. This modified fish diet resulted in significant linear declines in ferritin over 18 weeks from a mean of 373 ng/mL at Week 0 to 243 ng/mL at Week 18 [139]. Additionally, triglycerides, glucose, and insulin levels normalized among dolphins with abnormal values at the beginning of the study. This study, while limited, suggested that lower circulating OCFAs may not only be associated with a higher risk of DIOS, metabolic syndrome, and NAFLD in dolphins but that increasing dietary OCFA intake may help attenuate these conditions.
Following this pilot study, a larger modified diet study was conducted with 20 dolphins on the modified diet and 10 dolphins on the baseline control diet. The modified fish diet increased daily dietary C15:0 intake from 1.3 g to 4.5 g per day, which resulted in mean serum C15:0 concentration increases from 7 to 28 µg/mL (from 0.27% to 1.2% of total fatty acids) and mean erythrocyte membrane C15:0 concentrations from 1.5 to 5.8 µg/mL (from 0.17% to 0.58% of total fatty acids) by the first month [140]. In addition to dolphins on the modified diet having lower insulin and lower cholesterol by Week 6 compared to control dolphins, the case dolphins also had the unexpected benefit of alleviated anemia.
Among 20 dolphins in the modified diet group, 10 had chronic anemia (hemoglobin < 12.5 g/dl) at the beginning of the study. Of these, anemia resolved in all dolphins by Month 3, which was sustained throughout the 6-month study. Resolved anemia included not only raised hemoglobin but raised hematocrit, total red blood cells, and nucleated (new) red blood cells, as well as lowered red blood cell distribution width (RDW, from 15% ± 2% to 13% ± 1% by Month 6) [140]. Further, using stepwise regression, increased erythrocyte C15:0 cell membrane concentrations from 1.5 to 5.8 µg/mL independently predicted the observed alleviated anemia. This study supported the following: (1) that at baseline, some dolphins had a regenerative anemia with premature red blood cell loss, leading to higher anisocytosis (i.e., RDW), which (2) was alleviated by increasing C15:0 concentrations in red blood cell membranes to 5.8 µg/mL (0.58% total fatty acids). Given this clue of C15:0’s near-term positive effect on anemia and red blood cell indices among dolphins with DIOS, NAFLD, and metabolic syndrome, an appropriate model was sought to test the efficacy of pure C15:0 supplementation on this disease phenotype.

4.6. C15:0 Attenuation of Anemia, DIOS, NASH, and Metabolic Syndrome in a Relevant Model

The pathophysiology of fragile red blood cells and anemia leading to iron overload, in association with DIOS, NAFLD, and metabolic syndrome, had been previously elucidated in a Japanese rabbit model that closely mimics these conditions in dolphins and humans [141]. When provided a high-cholesterol, high-fat diet, this model develops insulin resistance, metabolic syndrome, and NASH with bridging fibrosis, as well as anemia due to fragile and oxidized red blood cells, which are engulfed by Kupffer cells, resulting in DIOS and advanced NASH.
In this model, a group treated with daily oral C15:0 (>98.5% free fatty acid C15:0) for 11 weeks had lower total cholesterol, triglycerides, globulins, platelets, and bilirubin; less liver fibrosis (lower risk of advancing to bridging fibrosis) and liver iron deposition; lower nucleated red blood cells, RDW, and reticulocytes; and higher hemoglobin, hematocrit, and red blood cells compared to the non-treated disease group [47]. In summary, C15:0 effectively attenuated key components of this disease phenotype, including fragile red blood cells, DIOS, dyslipidemia, and NASH.
Beyond treating the full suite of our proposed underlying pathophysiology of what causes ferroptosis, C15:0 also attenuates the individual components of ferroptosis. This includes lowering lipid peroxidation, lowering reactive oxygen species, and repairing mitochondria. In a mouse model of NASH, C15:0-treated individuals had significantly lower liver lipid peroxidation compared to the non-treated disease group [50]. Regarding mitochondrial function, our own studies showed that C15:0 repairs mitochondrial function, including a significant reduction in mitochondrial reactive oxygen species; effective C15:0 concentrations were between 10 and 50 µM, with optimal efficacy at 20 µM (5 µg/mL) [47]. This optimal concentration of 20 µM (5 µg/mL) matches that of a robust cell-based activity assessment of C15:0. This emerging critical concentration was also seen in our previously reported dolphin studies, in which the higher-C15:0-content diet resulted in raised erythrocyte membrane C15:0 concentrations from 1.5 to 5.8 µg/mL (from 0.17% to 0.58% of total fatty acids); in turn, crossing over the 0.2% and 5 µg/mL thresholds resulted in stabilized red blood cells and alleviated anemia [140].
This section demonstrates that, beyond just associations between lower circulating C15:0 and a higher risk of multiple chronic diseases, the dolphin model presents the pathophysiology behind how low C15:0 levels in red blood cell membranes (<0.2% of fatty acids) cause ferroptosis and outfall conditions, which start at the liver. Further, this section showed that increasing dietary C15:0 directly increases red blood cell membrane C15:0 levels and that C15:0 directly ameliorated the suite of the proposed pathophysiology behind ferroptosis. This included the ability to use C15:0 to restore red blood cell stability, lower liver iron overload and lipid peroxidation, repair mitochondria and lower reactive oxygen species, and attenuate liver fibrosis and hyperlipidemia.

5. Proposed Nutritional-C15:0-Deficiency-Driven Cellular Fragility Syndrome

5.1. Proposed Nutritional C15:0 Deficiency Definition

Given the studies above, paired with robust epidemiological studies and well-defined mechanisms of action around C15:0, the following categories are proposed:
  • C15:0 concentrations > 0.2% of total fatty acids are required in cell membranes to ensure cellular stability. Under this concentration, cell membranes can become fragile and are susceptible to lipid peroxidation and premature death [47,50,140,142].
  • Optimally, circulating C15:0 concentrations should be >0.4% to 0.64%, which studies show support long-term red blood cell stability, cardiovascular health, and longevity [58,66,140].
  • 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)

Given the dolphin modified diet and controlled intervention studies, paired with human epidemiological studies and known C15:0 mechanisms of action, the proposed pathophysiology of a nutritional C15:0 deficiency (Cellular Fragility Syndrome) is summarized in Figure 2. The stages are as follows:
Figure 2. Proposed C15:0 deficiency syndrome (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

If the proposed Cellular Fragility Syndrome is caused by nutritional C15:0 deficiencies, there should not only be evidence that low C15:0 levels cause this syndrome but that it can be reversed with C15:0 supplementation. As described in Figure 3 and below, controlled studies have shown that C15:0 supplementation reverses key components of Cellular Fragility Syndrome.
Figure 3. Demonstrated in vivo efficacies of C15:0 dietary supplementation, including reversal of Cellular Fragility Syndrome.

6.1. C15:0 Supplementation Stabilizes Red Blood Cells, Attenuates Anemia, and Lowers Lipid Peroxidation

Anemia was attenuated within 1 to 3 months in a model of anemia, DIOS, and NASH supplemented with C15:0, with effects including raised hemoglobin and lowered reticulocytes and RDW [9]. This study shows that C15:0 supplementation directly stabilizes red blood cells and reduces the need for the rapid production of new cells. These same results (alleviated anemia with raised hemoglobin and lowered reticulocytes and RDW within 1 to 3 months) occurred among dolphins provided a modified diet higher in C15:0, in which red blood cell membrane C15:0 concentrations were raised from 0.17% to 0.58% total fatty acids [140]. Further, C15:0 supplementation has been shown to lower lipid peroxidation in a mouse model of NAFLD and NASH [50]. These intervention studies are consistent with human studies showing that people with mild anemia have both higher red blood cell membrane C15:0 levels and lower systemic lipid peroxidation compared to people with severe anemia [142].

6.2. C15:0 Supplementation Decreases Erythrophagocytosis by Liver Kupffer Cells, Resulting in Attenuated DIOS, NAFLD, and NASH

Liver iron deposition and fibrosis were attenuated within 3 months in a model of anemia, DIOS, and NASH supplemented with C15:0 [47]. This study showed that C15:0 supplementation all but stopped iron deposition in the liver, while also preventing liver fibrosis from advancing from Stage II to Stage III (bridging) fibrosis. Further, a separate mouse model of NAFLD and NASH showed that C15:0 supplementation lowered ALT, AST, liver lipid peroxidation, and liver TNFα and IL-6 [50]. These intervention studies are consistent with human studies showing that people with higher C15:0 concentrations have a lower risk of having NAFLD or severe NASH [73,74].

6.3. C15:0 Supplementation Lowered Indices of Insulin Resistance, Metabolic Syndrome, Type 2 Diabetes, and Cardiovascular Disease

C15:0 supplementation lowered cholesterol and triglycerides in two models of metabolic syndrome, type 2 diabetes, and NAFLD [47]. In the type 2 diabetes model, C15:0 supplementation also lowered glucose, IL-6, and MCP-1. These intervention studies are consistent with human studies showing that people with higher C15:0 concentrations have a lower risk of having metabolic syndrome, type 2 diabetes, and cardiovascular disease [43,44,45,59,60,61,62,63,64,65,66,67,68,69,70,71].
In summary, the demonstrated benefits of C15:0 supplementation, including evidence of reversing key stages of the proposed Cellular Fragility Syndrome, support that this syndrome is not only caused by C15:0 deficiencies but can be fixed with C15:0 supplementation.

7. Conclusions

In summary, C15:0 is a newly discovered essential fatty acid that has a core role in physically strengthening cell membranes and protecting cells against lipid peroxidation. There is abundant evidence that lower circulating C15:0 concentrations are associated with a higher risk of having type 2 diabetes, cardiovascular disease, and NAFLD. As part of a Cellular Stability Hypothesis, it is proposed that adequate C15:0 concentrations are needed in cell membranes to prevent ferroptosis, a newly discovered method of cell death involving the lipid peroxidation of cell membrane fatty acids and intracellular iron—which has also been linked to type 2 diabetes, cardiovascular disease, and NAFLD.
Based on numerous studies provided in this review, a definition of nutritional C15:0 deficiency is offered (circulating C15:0 ≤ 0.2% total fatty acids). A description of the pathophysiology behind this nutritional C15:0 deficiency syndrome (Cellular Fragility Syndrome) is provided that explains how low C15:0 may accelerate the progression of aging-associated diseases, including dysmetabolic iron overload syndrome (DIOS), type 2 diabetes, cardiovascular disease, and NAFLD. Finally, controlled interventions in relevant models demonstrate that C15:0 supplementation can reverse key components of ferroptosis and Cellular Fragility Syndrome. Historical and recent human data support a daily dietary C15:0 intake of around 100 to 200 mg to achieve circulating C15:0 levels > 20 µM (>5 µg/mL, or >0.2%).
Beyond fixing nutritional deficiencies, there is evidence that optimal circulating C15:0 concentrations (>0.4% to 0.64% total fatty acids) may support long-term cardiovascular health and longevity. Continued studies, including clinical trials, will help further test the Cellular Stability Hypothesis and the proposed definition of nutritional C15:0 deficiencies. Given global declines in dietary C15:0 intake, further studies are needed to better understand the depth and breadth of the proposed C15:0-deficiency-driven Cellular Fragility Syndrome across different human populations and how this syndrome may be contributing to rises in aging-associated diseases, especially among younger people.

8. Patents

Patents relevant to this manuscript are available at https://fatty15.com/pages/patents [143,144,145].

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

Stephanie Venn-Watson is an employee of Seraphina Therapeutics, Inc. and Epitracker Inc. This paper reflects the views of the scientist and not the company.

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