More than a decade ago, when I was just beginning my exploration of bioenergetics, one of the first indications that Ray’s writings were onto something when it came to SFA vs. PUFA was the fact that while mainstream medicine ruthlessly bashed SFA in general and promoted PUFA, virtually very little bad publicity was directed at dairy fat. In fact, it seemed even back then that medicine had\u00a0 already resigned itself to the existence of the “dairy fat paradox” and periodically published articles about the “surprising” or “paradoxical” benefits of dairy in bastions of medical propaganda such as NEJM, BMJ, Nature, etc that were often given even bigger publicity by mainstream media.<\/p>\n
https:\/\/www.npr.org\/sections\/thesalt\/2016\/04\/18\/474403311\/the-full-fat-paradox-dairy-fat-linked-to-lower-diabetes-risk<\/a><\/p>\n https:\/\/pubmed.ncbi.nlm.nih.gov\/29951411<\/a><\/p>\n That fact that it is dairy fat (and not the protein or calcium in dairy) that has unique beneficial effect is easily surmised from the studies with ice-cream, where the primary ingredient is fat, and mostly of the SFA kind.<\/p>\n https:\/\/www.theatlantic.com\/magazine\/archive\/2023\/05\/ice-cream-bad-for-you-health-study\/673487\/<\/a><\/p>\n https:\/\/www.deseret.com\/23683767\/ice-cream-health-benefits<\/a><\/p>\n As part of its studies on dairy, medicine even developed a test for quantifying dairy consumption and that test consists of measuring blood\/tissue levels of two odd-chain SFA found primarily in dairy. Namely, pentadecanoic acid (PA, C15:0) and heptadecanoic acid (HA, C17:0). The latter is also known as margaric acid. Their average concentrations in dairy are about 1% and 0.5%<\/strong><\/span>, respectively, of total fats in dairy.<\/p>\n https:\/\/en.wikipedia.org\/wiki\/Pentadecylic_acid<\/a><\/p>\n https:\/\/en.wikipedia.org\/wiki\/Margaric_acid<\/a><\/p>\n After that initial interest in researching dairy fats, I moved onto other research and almost forgot about the existence of PA and HA. Years later, while researching succinic acid as part of the development of our product SolBan, my attention was drawn to a pair of Japanese studies for treating hair loss by topical application of PA. As those studies described, due to its odd-chain, PA is only partially metabolized via the beta-oxidation pathway, through which even-chain fatty acids get metabolized to ultimate form acetyl-CoA and then enter the Krebs Cycle. The terminal metabolism of odd-chain fatty acids, including PA, forms succinic acid, and ultimately succinyl-CoA, which then enters the Krebs Cycle. Since rising levels of acetyl-CoA has an inhibitory effects on pyruvate dehydrogenase (PDH), eating a diet high in fat with mostly even-chain fats would result in reduction of glucose metabolism, even if all the fats are of the SFA type, as per the Randle Cycle. However, if those fats are of the odd-chain species and enter the Krebs Cycle as succinic acid (i.e. without effect on the acetyl-CoA\/CoA ratio), then virtually no such reduction of glucose metabolism is expected to occur and, in fact, PA was described in the Japanese studies as stimulating mitochondrial function and ATP production, which ultimately resulted in improved hair growth. The Japanese reseachers even filed a patent for treating hair-loss with PA and in that patent they opined that other odd-chain fatty acids with similar length, especially the C17:0 fat HA mentioned above, would have similarly beneficial effects on hair-growth through increasing mitochondrial function (OXPHOS).<\/p>\n https:\/\/doi.org\/10.1111\/j.1468-2494.1993.tb00592.x<\/a><\/p>\n https:\/\/www.jstage.jst.go.jp\/article\/skinresearch1959\/37\/6\/37_6_800\/_article\/-char\/en<\/a><\/p>\n Those studies above were performed in the early 1990s and since then there have been quite a few additional studies discovering remarkable benefits of odd-chain SFA, with the bulk of the research focusing on PA and HA. Several studies have compared PA and HA to the “essential” omega-6 fatty acids, as well as to omega-3 fats, and have concluded that PA and HA are much more deserving of the label “essential” than the omega-6, let alone the omega-3. In fact, at least one study demonstrated that the omega-3 are cytotoxic when used in concentrations that are lower than concentrations typically achieved when eating cold-water fatty fish or taking fish oil supplements, while the odd-chain PA and HA were not only not cytotoxic but their cellular benefits were dose-dependent. Such effects are reminiscent of pregnenolone, progesterone, vitamin K, etc for which the body seems to have remarkably high affinity and accumulates them inside cells in concentrations exceeding blood levels by several orders of magnitude.<\/p>\n https:\/\/doi.org\/10.3945\/an.115.011387<\/a><\/p>\n “…The robust inverse association of 15:0 and\/or 17:0<\/span> concentrations in plasma phospholipids or RBCs with<\/span> cardiovascular disease (CVD<\/span>) and type 2 diabetes mellitus (T2D) risk is quite impressive<\/span><\/strong><\/span>. The latter is observed in various European populations with different dietary backgrounds (5<\/span><\/a>). This review brings forward hypotheses about the possible sources of 15:0 and 17:0 and their potential involvement in metabolic pathways. They may be used for synthesis of odd-numbered VLCFAs, provide anaplerotic intermediates for the CAC, or store away excess propionic acid.\u00a0”<\/p>\n https:\/\/pubmed.ncbi.nlm.nih.gov\/32424181\/<\/a><\/p>\n “…Further, an 18-year longitudinal study including over 25,000 individuals demonstrated that children fed whole fat milk had a lower risk of having obesity compared to children who were provided fat-free or 1% fat milk<\/strong><\/span>, and multiple studies have demonstrated associations between higher dietary intake of full-fat dairy and reduced risk of type 2 diabetes and cardiovascular disease<\/strong><\/span>7<\/a>\u20139<\/a><\/sup>. As such, there is a need re-evaluate potential health risks versus benefits of dietary dairy fats10<\/a><\/sup>.”<\/p>\n “…While dietary ECFAs have been associated with increased risk of inflammation, heart disease, and type 2 diabetes in humans12<\/a>\u201315<\/a><\/sup>, higher dietary intake and circulating levels of OCFAs have been associated with lower risks of adiposity, chronic inflammation, cardiovascular disease, metabolic syndrome, type 2 diabetes, nonalcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease, pancreatic cancer<\/strong><\/span> and other conditions14<\/a>\u201327<\/a><\/sup>. In a prospective cohort involving over 14,000 people followed for an average of 14 years, increased dietary intake of <\/strong>OCFAs was associated with lower mortality in both men and women<\/strong><\/span>, while higher ECFA intake was associated with higher mortality in women28<\/a><\/sup>.”<\/p>\n “…Since fatty acids can affect mitochondrial function45<\/a><\/sup>, the effects of OCFAs and ECFAs on repairing mitochondrial function<\/span> and reducing mitochondrial ROS<\/strong><\/span> were evaluated in serum starved HepG2 cells. Here, C15:0 had a dose-response u-curve effect on mitochondrial function, including lower mitochondrial ROS production<\/strong><\/span> in cell systems supplemented at 10\u2009\u00b5M (17.8\u2009\u00b1\u20092.7%, P\u2009=\u20090.04), 20\u2009\u00b5M (12.9\u2009\u00b1\u20093.2%, P\u2009=\u20090.005) and 50\u2009\u00b5M (15.4\u2009\u00b1\u20092.6%, P\u2009=\u20090.007) compared to non-supplemented control cell systems (23.4\u2009\u00b1\u20094.3%) (Fig.\u00a01<\/a>). There were no differences in ROS production when comparing cells supplemented at higher C15:0 concentrations (100 and 200\u2009\u00b5M)<\/strong><\/span> compared to non-supplemented controls. Among a variety of other OCFAs and ECFAs evaluated (C13:0 through C18:0), C15:0 through C18:0 (20\u2009\u00b5M) had lower mitochondrial ROS<\/strong><\/span> compared to the non-supplemented control group, while C13:0 and C14:0 did not significantly lower mitochondrial ROS (Suppl Fig.\u00a02<\/a><\/sup>).”<\/p>\n “…Based on a definition of cytotoxicity in which more than 50% of total protein in the cell system was reduced, C15:0 did not induce cytotoxicity in any of the 12 cell systems<\/strong><\/span> (Suppl Table\u00a02<\/a><\/sup>).”<\/p>\n “…Here, C15:0 had dose-dependent, annotated anti-inflammatory activities<\/strong><\/span>, including reduced monocyte chemoattractant protein 1 (MCP-1) and secreted immunoglobulin G (IgG) (Fig.\u00a02<\/a>). C15:0 also had antifibrotic activities<\/strong><\/span>, including reduced Collagen I, plasminogen activation inhibitor 1 (PAI-1), and 72-hour fibroblast proliferation (Fig.\u00a02<\/a>). Anti-inflammatory and antifibrotic activities were present at both 6.7 and 20\u2009\u00b5M. C15:0 cell-based anti-inflammatory and antifibrotic activities at 20\u2009\u00b5M were better than C17:0 at the same concentration; other saturated fatty acids (C13:0, C14:0 and C16:0) had no anti-inflammatory or antifibrotic activities<\/strong><\/span> (Fig.\u00a03<\/a>). Because C14:0, C15:0, and C16:0 all had similar dual PPAR\u03b1\/\u03b4 agonist activities (reported above), results from our human cell phenotypic screening support that C15:0 activities go beyond C15:0’s\u00a0role as a natural PPAR\u03b1\/\u03b4 fatty acid ligand. This study also supports that a relatively minor increase in C15:0<\/span><\/strong><\/span> concentrations (e.g. from 2.2\u2009\u00b5M to 6.7\u2009\u00b5M) can positively impact its anti-inflammatory and antifibrotic activities<\/strong><\/span>.”<\/p>\n “…Thus, a single oral dose of C15:0 at 35\u2009mg\/kg succeeded in achieving our targeted active plasma concentrations<\/strong><\/span> in this rodent model, between 2.5 to 5\u2009\u00b5g\/ml (equivalent to 6.7 to 20\u2009\u00b5M), from 1 to 8\u2009hours post-dose. Plasma total C17:0 levels also increased<\/strong><\/span>, albeit less so than C15:0, following a single oral dose of C15:0; similar, sustained increases were not apparent with C13:0 (Fig.\u00a04<\/a>). These findings support\u00a0de novo<\/em>\u00a0elongation of C15:0 to C17:0<\/strong><\/span>.”<\/p>\n “…These levels are consistent with our studies, which demonstrated cell-based PPAR\u03b1\/\u03b4 agonist, anti-inflammatory, antifibrotic, and mitochondrial protective C15:0 activities between 10 and 50\u2009\u00b5M<\/strong><\/span>, with most of our studies demonstrating optimal activities at 20\u2009\u00b5M<\/strong><\/span>. Human<\/strong><\/span> pharmacokinetic studies support that a<\/span> <\/span>single dose of 200\u2009mg of C15:0 results in 20\u2009\u00b5M circulating C15:0<\/strong><\/span> concentrations (approximately 5\u2009\u00b5g\/ml)75<\/a><\/sup>”<\/p>\n “…To further evaluate the safety of C15:0 at increasing doses, Sprague Dawley rats (n\u2009=\u200910 per group, 5 females and 5 males, 7 to 8 weeks old) were dosed orally once daily for 14 days with C15:0 at 35, 175 and 350\u2009mg\/kg body weight<\/strong><\/span>. A non-dosed vehicle control group was included. Safety assessments included clinical observations, body weight, food intake, clinical chemistries, and histology (liver, kidney, heart, and adrenal glands). Additionally, total plasma C15:0 and C17:0 concentrations were measured at Day 14. There were no mortalities or observed abnormal behaviors in animals throughout the 14-day study across all study groups, and there were no significant differences when comparing body weights and organ weight-to-body weight ratios or the prevalence of abnormal clinical chemistry values or histologic observations<\/strong><\/span> between C15:0-supplemented and non-supplemented control animals (Suppl Table\u00a03<\/a><\/sup>).\u00a0”<\/p>\n “…Mice supplemented with oral C15:0 for 90 days at low doses<\/strong><\/span> (5\u2009mg\/kg) had lower circulating levels of the proinflammatory chemokine, monocyte chemoattractant protein 1 (MCP-1), and the proinflammatory cytokine, interleukin 6 (IL-6)<\/strong><\/span> compared to non-supplemented controls (Fig.\u00a05<\/a>). The C15:0-supplemented group also had lower glucose, lower cholesterol, and lower percent body weight gain<\/strong><\/span> on the high fat diet compared to non-supplemented controls (Fig.\u00a05<\/a>, Suppl Table\u00a04<\/a><\/sup>). In contrast, mice supplemented with daily low dose C17:0 (5\u2009mg\/kg) had no significant differences in clinical chemistry values compared to non-supplemented, diseased controls, while high dose C17:0 (50\u2009mg\/kg) supplemented mice had lower serum MCP-1<\/strong> <\/span>compared to controls (Suppl Table\u00a04<\/a><\/sup>).\u00a0”<\/p>\n “…Specifically, C15:0 supplementation raised hemoglobin, hematocrit, and red blood cell count, and lowered nucleated red blood cells, red blood cell distribution width, and reticulocytes<\/strong><\/span>. In this model, these changes are consistent with decreased loss of fragile red blood cells and lowered need for new red blood cell production<\/strong><\/span>46<\/a><\/sup>. Further, C15:0-supplemented animals had lower cholesterol, triglycerides, globulins, and platelets<\/strong><\/span> compared to non-supplemented diseased controls (Fig.\u00a07<\/a>). Additionally, multiple liver health indices in C15:0-supplemented animals, including bilirubin and icterus were lower than<\/strong><\/span> non-supplemented diseased controls, matching that of healthy controls<\/strong><\/span> (Supplement Table\u00a06<\/a><\/sup>). Histologically, C15:0-supplemented animals also had less severe liver fibrosis and liver iron<\/strong><\/span> staining scores within Kupffer cells compared to non-supplemented diseased controls. Unlike the non-supplemented diseased controls, C15:0-supplemented animals did not progress from Stage 2 to Stage 3 (bridging) fibrosis<\/strong><\/span> (Suppl Table\u00a06<\/a><\/sup>).”<\/p>\n “…Here, we show C15:0 as an active dietary fatty acid that attenuates inflammation, anemia, dyslipidemia, and fibrosis in vivo<\/strong><\/span>, potentially by binding to key metabolic regulators and repairing mitochondrial function. This is the first demonstration of C15:0’s direct role in attenuating multiple comorbidities using relevant physiological mechanisms at established circulating concentrations. Pairing our findings with evidence that (1) C15:0 is not readily made endogenously, (2) lower C15:0 dietary intake and blood concentrations are associated with higher mortality and a poorer physiological state, and (3) C15:0 has demonstrated activities and efficacy that parallel associated health benefits in humans<\/strong><\/span>, we propose C15:0 as a potential essential fatty acid<\/strong><\/span>. Further studies are needed to evaluate the potential impact of decades of reduced intake of OCFA-containing foods as contributors to C15:0 deficiencies and susceptibilities to chronic disease.”<\/p>\n https:\/\/pubmed.ncbi.nlm.nih.gov\/35617322<\/a><\/p>\n “…Beyond population-based studies, experimental research has shown that C15:0 is an active and beneficial fatty acid with direct pleiotropic activities relevant to stemming chronic conditions, especially with age [26<\/a>\u201329<\/a>]. Specifically, C15:0 is a dual partial peroxisome proliferator-activated receptor \u03b1\/\u03b4 agonist, AMP-activated protein kinase activator, and histone deacetylase 6 inhibitor [26<\/a>\u201328<\/a>]. Further, C15:0 has been shown to repair mitochondrial function, improve the stability of red blood cells, regulate glucose metabolism, and decrease proliferation of cancer cells<\/strong><\/span> [26<\/a>\u201329<\/a>].”<\/p>\n “…In addition to MCP-1, C15:0<\/strong><\/span> and EPA effectively lowered CD40 and T cell proliferation<\/strong><\/span> in a single system relevant to T-cell driven inflammatory conditions. This cell system is used to discover potential therapeutics for autoimmune diseases, including rheumatoid arthritis, psoriasis, and Crohn\u2019s disease, as well as for hematological oncology<\/strong><\/span> applications. Although use of EPA has been proposed as a method to manage autoimmune diseases, supportive studies have been primarily limited to fish oil that did not discriminate between the effects of EPA versus other fatty acids [32<\/a>\u201336<\/a>]. Our study is the first to report the potential for C15:0 to manage autoimmune diseases<\/span><\/strong><\/span>.\u00a0”<\/p>\n “…While C15:0<\/strong><\/span> and EPA shared 12 common activities, our studies also demonstrated 35 differences between these two fatty acids, including substantially broader anti-inflammatory, immunomodulatory and antifibrotic activities caused by C15:0<\/span> that were not present with EPA<\/span><\/strong><\/span>. Of the 11 cell systems in which C15:0 had disease-attenuating properties that were not present with EPA<\/span>, three were relevant to atherosclerosis, vascular inflammation, and restenosis, as well as two others relevant to asthma, allergies, and metabolic diseases<\/strong><\/span>. Examples of biomarkers lowered by C15:0 and not EPA in these systems included sIL-10, CD69, HLA-DR, TNF-\u03b1, IL-17F, IL-17A, and IL-1\u03b1. Given these findings, further studies are warranted to evaluate if C15:0\u2019s broader therapeutic activities at the cellular level translate to broader health benefits to individuals and populations compared to EPA and other omega-3s fatty acids.”<\/p>\n “…Demonstrated mechanisms of actions for C15:0 and EPA may help explain both their shared and differentiated activities<\/strong><\/span>. C15:0 and EPA are endogenous peroxisome proliferator activated receptor (PPAR) agonists, including PPAR alpha and delta; their roles as PPAR agonists can explain their shared anti-inflammatory and antifibrotic activities [28<\/a>,\u00a039<\/a>]. Additionally, C15:0 and EPA have been shown to target the AMP-activated protein kinase (AMPK) pathway, which modulates glucose metabolism [23<\/a>,\u00a040<\/a>,\u00a041<\/a>], as well as inhibit histone deacetylase (HDAC), a proposed means of treating cancer by stemming cancer cell proliferation [26<\/a>,\u00a042<\/a>]. While C15:0 and EPA share several key mechanisms of action, they appear to have opposing effects related to MAPK and JAK-STAT signaling, which use oxidative stress to elicit cytokine and inflammatory processes<\/strong><\/span>. Specifically, polyunsaturated fatty acids, like EPA, induce MAP and JAK-STAT signaling, while C15:0 inhibits these pro-inflammatory pathways<\/strong><\/span> [29<\/a>,\u00a043<\/a>,\u00a044<\/a>]. JAK-STAT inhibitors have been proposed as promising therapeutics to inhibit cytokines and treat numerous inflammatory and autoimmune diseases, and this key mechanism of C15:0 may explain why it had broader anti-inflammatory effects in our study compared to EPA<\/strong><\/span> [45<\/a>].”<\/p>\n “…When assessing clinically relevant and dose-dependent activities of C15:0 and over 4,500 additional compounds, our study demonstrated common cell-based phenotypic profiles between C15:0 and therapeutics for mood disorders, infections, and cancer<\/strong><\/span>, based on concentration. At lower concentrations (1.9 and 5.6 \u03bcM), C15:0<\/strong><\/span> human cell-based activities closely matched those of bupropion<\/span><\/strong> <\/span>at 10 and 30 \u03bcM, respectively. Bupropion, sold as Wellbutrin\u00ae<\/sup>, is a dopamine-norepinephrine reuptake inhibitor<\/span> and commonly used antidepressant<\/strong><\/span> that is considered safe, well tolerated, and does not result in weight gain [51<\/a>]. Specific conditions managed by bupropion include major depressive disorder and seasonal affective disorder, and it has shown promise as a non-nicotine agent that promotes smoking cessation<\/strong><\/span> in clinical trials [51<\/a>]. Bupropion is a pill that is typically taken 2\u20133 times a day in doses ranging from 100\u2013150 milligrams. Based on human pharmacokinetic data with pure free fatty acid C15:0, approximate doses of 19 to 56 mg is expected to achieve circulating C15:0 concentrations with activities similar to bupropion<\/strong><\/span> [52<\/a>].”<\/p>\n “…A growing body of evidence supports that pentadecanoic acid (C15:0)<\/span>, an odd-chain saturated fat found in butter, is an essential fatty acid<\/span><\/strong><\/span> that is necessary in the diet to support long-term metabolic and heart health. Here, dose dependent and clinically relevant cell-based activities of pure C15:0 (FA15TM<\/sup>) were compared to eicosapentaenoic acid (EPA)<\/strong><\/span>, 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 \u03bcM) and compared to non-treated control systems. C15:0 was non-cytotoxic at all concentrations<\/span> and had dose dependent, broad anti-inflammatory and antiproliferative activities involving 36 biomarkers across 10 systems<\/strong><\/span>. In contrast, EPA was cytotoxic to four cell systems at 50 \u03bcM<\/strong><\/span>. While 12 clinically relevant activities were shared between C15:0 and EPA at 17 \u03bcM, C15:0 had an additional 28 clinically relevant activities, especially anti-inflammatory, that were not present in EPA. Further, at 1.9 and 5.6 \u03bcM, C15:0 had cell-based properties similar to bupropion<\/strong><\/span> (Pearson\u2019s scores of 0.78), a compound commonly used to treat depression and other mood disorders<\/strong><\/span>. At 5.6 \u03bcM, C15:0 mimicked two antimicrobials, climabazole and clarithromycin<\/strong><\/span> (Pearson\u2019s scores of 0.76 and 0.75, respectively), and at 50 \u03bcM, C15:0 activities matched that of two common anti-cancer therapeutics, gemcitabine and paclitaxel<\/strong><\/span> (Pearson\u2019s scores of 0.77 and 0.74, respectively). In summary, C15:0 had dose-dependent and clinically relevant activities across numerous human cell-based systems that were broader and safer than EPA<\/strong><\/span>, and C15:0 activities paralleled common therapeutics for mood disorders, microbial infections, and cancer. These studies further support the emerging role of C15:0 as an essential fatty acid<\/strong><\/span>.”<\/p>\n Now, if something has such a broad beneficial effects on health as the studies above describe, one would expect said substance to have an anti-aging and lifespan extending effects as well. While we still don’t have direct in-vivo evidence for such effects of PA and\/or HA, in-vitro evidence already exists. As the study below demonstrated, PA has anti-aging effects matching, and even exceeding, those of the standard drug for anti-aging research, rapamycin, the most widely used antagonist of the eponymous pathway mTOR.<\/p>\n