Fatty acids play major roles in supporting physiological health, including energy storage and transport, gene regulation, and thermal and electrical insulation in cells. They also act as building blocks for cell membranes and facilitate cellular signaling. Essential fatty acids, like pentadecanoic acid (C15:0), cannot be efficiently made by the body and must be obtained through diet or supplements to maintain physiological health.
What is Pentadecanoic Acid (C15:0)?
Pentadecanoic acid (C15:0) is an odd-chain saturated fatty acid present in trace levels in dairy fat and ruminant meat, as well as some types of plants and fish. It is emerging as an essential fatty acid with broad activities relevant to protecting cardiometabolic, immune, and liver health.
Why is C15:0 Important?
Mounting evidence suggests that C15:0 is essential for supporting cardiometabolic and liver health. People with low circulating C15:0 concentrations have a higher risk of developing type 2 diabetes, heart disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis, as well as specific types of cancer. Circulating C15:0 concentrations are reflective of dietary C15:0 intake, as it is primarily an exogenous molecule, present in 1 to 3% of dairy fat. Studies suggest that 100 to 300 mg of C15:0 is needed daily to effectively achieve and maintain active circulating C15:0 concentrations of 10 to 30 µM.
Mechanisms of Action
Pure C15:0 is a pleiotropic nutrient with broad-reaching mechanisms of action, including AMPK and PPAR-α/δ activation, as well as mTOR, JAK-STAT, and HDAC-6 inhibition. These mechanisms are aligned with the demonstrated anti-inflammatory, antifibrotic, and anticancer activities of C15:0 in vitro and in vivo. Beyond targeting key receptors, C15:0 is a stable saturated fat that is readily incorporated into the lipid bilayers of cell membranes, including red blood cells, to lower the risk of lipid peroxidation and premature lysis. Further, C15:0 has antimicrobial properties, including growth inhibition of pathogenic bacteria and fungi.
C15:0 and Longevity
There is tremendous interest in developing and testing interventions that can simultaneously prevent or mitigate multiple age-related diseases and thereby enhance healthspan and longevity. C15:0 activates AMPK and inhibits mTOR, both of which are core components of the human longevity pathway. As an essential fatty acid, C15:0 should, by definition, support healthspan and longevity. Further, C15:0 has mTOR-inhibiting and AMPK-activating activities shared with rapamycin and metformin, respectively.
Read also: The role of alpha-keto acids in metabolism.
C15:0 Compared to Other Longevity-Enhancing Compounds
To assess the potential for C15:0 to enhance processes associated with longevity and healthspan, human cell-based molecular phenotyping assays were used to compare C15:0 with three longevity-enhancing candidates: acarbose, metformin, and rapamycin. The BioMAP Diversity PLUS system includes a series of independently run and industry-standard pharmacological assays routinely used to screen and compare molecules for activity profiles and clinical indications as well as safety. The BioMAP Diversity PLUS system tests molecules across 12 primary human cell-based systems mimicking various disease states and measures the molecule’s effects across 148 clinically relevant biomarkers at four doses.
Study Design and Methods
The Eurofins BioMAP assay system, which has a long history of use in pharmaceutical development, evaluation, and comparisons of newly studied compounds with well-established pharmaceutical compounds, was utilized. The system consists of 148 assays across 12 primary human cell-based systems mimicking various disease states. C15:0 doses were based on circulating C15:0 concentration ranges from in vivo studies and similar effective concentrations related to PPARα/δ agonist and mitochondrial repair activities. The ascending doses for rapamycin (0.3, 1, 3, 9 µM), metformin (190, 560, 1700, 5000 µM), and acarbose (1.1, 3.3, 10, 30 µM) were based on previously established ranges by Eurofins/DiscoverX.
The BioMAP assay system uses human primary cells at early passages (passage 4 or earlier) to minimize adaptation to cell culture conditions and to preserve physiological signaling responses. All cells were from a pool of multiple donors (n = 2 to 6), commercially purchased, and handled according to the recommendations of the manufacturers. Human blood-derived CD14+ monocytes were differentiated into macrophages in vitro before being added to the lMphg system. The assays were based on either single-cell types or co-culture systems. Adherent cell types were cultured in 96- or 384-well plates until confluence, followed by the addition of PBMC (SAg and LPS systems). The BT system consisted of CD19+ B cells co-cultured with PBMC and stimulated with a BCR activator and low levels of TCR stimulation. Test agents prepared in either DMSO (small molecules; final concentration ≤ 0.1%) or PBS (biologics) were added at the indicated concentrations 1 h before stimulation and remained in culture for 24 h or as otherwise indicated (48 h, MyoF system; 72 h, BT system (soluble readouts); 168 h, BT system (secreted IgG)). Direct ELISA was used to measure biomarker levels of cell-associated and cell membrane targets via absorbance. Soluble factors from supernatants were quantified using either HTRF® detection (Eurofins Panlabs, St. Charles, MO, USA), bead-based multiplex immunoassay, or capture ELISA. Overt adverse effects of test agents on cell proliferation and viability (i.e., cytotoxicity) were detected by sulforhodamine B (SRB) staining, for adherent cells, and alamarBlue® (Eurofins Panlabs, St. Charles, MO, USA) reduction for cells in suspension. For proliferation assays, individual cell types were cultured at subconfluence and measured at time points optimized for each system (48 h: 3C and CASM3C systems; 72 h: BT and HDF3CGF systems; 96 h: SAg system). Cytotoxicity for adherent cells was measured by SRB (24 h: 3C, 4H, LPS, SAg, BF4T, BE3C, CASM3C, HDF3CGF, KF3CT, and lMphg systems; 48 h: MyoF system), and by alamarBlue staining for cells in suspension (24 h: SAg system; 42 h: BT system) at the time points indicated.
Data Analysis
Quantitative readouts of biomarkers in treated systems were considered “hits” if a biomarker readout was outside the significance envelope. The significance envelope was defined as symmetrical upper and negative lower bound values of log10 transformed historical vehicle controls at a 95% confidence interval. Biomarker activities were annotated when two or more consecutive concentrations changed in the same direction relative to vehicle controls, were outside of the significance envelope defined by legacy and accepted use of the BioMAP platform and had at least one concentration with an effect size >20% (|log10 ratio| > 0.1). Biomarker key activities were described as modulated if these activities increased in some systems but decreased in others. Cytotoxic conditions were noted when total protein levels decreased by more than 50% (log10 ratio of SRB or alamarBlue levels <−0.3) and were indicated by a thin black arrow above the X-axis. A compound was considered to have broad cytotoxicity when cytotoxicity was detected in three or more systems. Concentrations of test agents with detectable broad cytotoxicity were excluded from biomarker activity annotation and downstream benchmarking, similarity search, and cluster analysis. Antiproliferative effects were defined by an SRB or alamarBlue log10 ratio value <−0.1 from cells plated at a lower density and were indicated by grey arrows above the X-axis. Cytotoxicity and antiproliferative arrows only required one concentration to meet the indicated threshold for profile annotation. The optimal concentrations for each of the evaluated compounds were defined as which of the four tested concentrations had the highest number of clinically relevant biomarker hits. Biomarker hits were defined by a measurement outside of the significance envelope and an effect size > 20% (|log10 ratio| > 0.1).
Results
C15:0 (n = 36 activities in 10 of 12 cell systems) and rapamycin (n = 32 activities in 12 of 12 systems) had the most clinically relevant, dose-dependent activities. At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies.
Read also: Facial Toner with Hyaluronic Acid
Of the four compounds tested, pure C15:0 (FA15) had the most dose-dependent annotated activities (i.e., had 2 or more consecutive concentrations changed in the same direction relative to vehicle controls, were outside the significance envelope, and had at least one concentration with an effect size >20% (|log10 ratio| > 0.1)) (n = 36), closely followed by rapamycin (n = 32). Metformin had 17 annotated activities, and acarbose had five. As an added reference from a prior study, omega-3 fatty acid eicosapentaenoic acid (EPA) had seven annotated activities. Rapamycin had positive effects across all 12 cell systems, while C15:0 positively affected 10 out of 12 (83%) cell systems. C15:0 (1.9-50 µM) shared 12 annotated, dose-dependent cell-based activities with rapamycin (0.3-9 µM) across 7 (58%) out of 12 cell systems. In contrast, C15:0 (1.9-50 µM) shared only four annotated cell-based activities with metformin (190-5000 µM) across 2 (17%) out of 12 cell systems. Specifically, both C15:0 and metformin had significant, dose-dependent effects on lowering: HLA-DR in the 3C system relevant to cardiovascular disease and chronic inflammation; and CD38, CD69, and T cell proliferation in the SAg cell system relevant to autoimmune disease and chronic inflammation.
C15:0 vs. Omega-3 Fatty Acids
Dose dependent and clinically relevant cell-based activities of pure C15:0 (FA15TM) were compared to eicosapentaenoic acid (EPA), a leading omega-3 fatty acid, as well as to an additional 4,500 compounds. These studies included 148 clinically relevant biomarkers measured across 12 primary human cell systems, mimicking various disease states, that were treated with C15:0 at four different concentrations (1.9 to 50 μM) and compared to non-treated control systems. C15:0 was non-cytotoxic at all concentrations and had dose dependent, broad anti-inflammatory and antiproliferative activities involving 36 biomarkers across 10 systems. In contrast, EPA was cytotoxic to four cell systems at 50 μM. While 12 clinically relevant activities were shared between C15:0 and EPA at 17 μM, C15:0 had an additional 28 clinically relevant activities, especially anti-inflammatory, that were not present in EPA.
C15:0 and Therapeutic Parallels
At 1.9 and 5.6 μM, C15:0 had cell-based properties similar to bupropion (Pearson’s scores of 0.78), a compound commonly used to treat depression and other mood disorders. At 5.6 μM, C15:0 mimicked two antimicrobials, climabazole and clarithromycin (Pearson’s scores of 0.76 and 0.75, respectively), and at 50 μM, C15:0 activities matched that of two common anti-cancer therapeutics, gemcitabine and paclitaxel (Pearson’s scores of 0.77 and 0.74, respectively).
C15:0 Deficiency and Cellular Stability
According to Stephanie Venn-Watson, DVM, MPH, deficiency in pentadecanoic acid of ≤0.2% total circulating fatty acids increases the risk of ferroptosis, which a type of cell death cause by the peroxidation of fragile fatty acids in cell membranes that combines with iron thus increasing reactive oxygen species, and disabling mitochondria. Ferroptosis is linked to a number of age-related conditions, namely type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Venn-Watson proposes the Cellular Stability Hypothesis, postulating that cell membranes need >0.4% to 0.64% C15:0 to support long term health.
Evidence from Human Studies
A prospective cohort study measured C15:0 levels at baseline for more than 4,000 adults with a median age of 60.5 years. On follow-up 16 years later, researchers found that higher C15:0 levels were associated with lower incidence of cardiovascular disease risk in a linear dose-response manner, and all-cause mortality nonlinearly. Another study of people living in Sardinia, Italy, which is known as a high-longevity zone (HZL), found that 60-70 year olds living in the HZL had the highest levels of C15:0 with 0.64% of total fatty acids, while people 80 years or older living in the HZL had 0.42% C15:0 of total fatty acids. People over the ages of 80 living in a low longevity zone had the lowest levels of C15:0 with 0.29% of total fatty acids.
Read also: Radiant Skin with Glycolic Acid
Sources of C15:0
C15:0 is found in trace levels in dairy fat and ruminant meat, as well as some types of plants and fish. One of the factors driving the decline of C15:0 in our diets is the decline in consumption of whole fat milk.
Supplementation with C15:0
Fatty15 is a supplement that contains pentadecanoic acid, a fatty acid with 15 carbon atoms that’s found primarily in dairy fat. Fatty15 is a once daily and easy to use supplement containing only one ingredient: FA15TM, the pure, vegan-friendly, sustainably-produced, award-winning, pure powder form of C15:0.
Benefits of C15:0 Supplementation
- Improving energy production.
- Helping cells stay resilient and functioning.
- Restoring communication between cells.
Fatty15 naturally binds to receptors, called PPARs (pronounced pee-pars) alpha and delta, that are found throughout your body and brain. PPARs alpha and delta orchestrate your metabolism and immunity, as well as your mood, appetite, and sleep.
Real-World Applications and Benefits
Cardiovascular Health
Emerging evidence suggests that C15 can positively influence cardiovascular health by lowering levels of low-density lipoprotein (LDL) cholesterol and raising levels of high-density lipoprotein (HDL) cholesterol.
Metabolic Health
C15 may improve insulin sensitivity and glucose metabolism, benefiting individuals with metabolic syndrome or type 2 diabetes.
Anti-Inflammatory Effects
Chronic inflammation is a root cause of many chronic diseases, including cardiovascular diseases, diabetes, and certain cancers.
tags: #pentadecanoic #acid #benefits