C15:0 deficiency may explain accelerated aging in younger people

C15:0 deficiency syndrome – or Cellular Fragility Syndrome – is first nutritional deficiency syndrome discovered in over 75 years.

What we eat is inextricably linked to our health and longevity, and just as too much of certain things (sugar, salt, fat, alcohol) can have a negative effect on our healthspan, so too can not enough of certain things.

Now, for the first time in over seventy-five years, researchers have identified a syndrome linked to nutritional deficiencies – Cellular Fragility Syndrome [1].

Longevity.Technology: Cellular Fragility Syndrome, as recently reported in the scientific journal Metabolites, is caused by low body levels of pentadecanoic acid (C15:0), a stable, odd-chain saturated fatty acid. Given that Cellular Fragility Syndrome and may be impacting as many as 1 in 3 people worldwide, this new finding holds significant implications for understanding – and potentially mitigating – the processes of aging and chronic disease development.

“The discovery of a nutritional C15:0 deficiency syndrome is the culmination of over a decade of rigorous studies,” said Dr Stephanie Venn-Watson, the lead author of the paper and co-founder of Seraphina Therapeutics, a company that manufactures a C15:0 supplement. “As a hopeful inspiration to fellow and future scientists, this shows that there are still simple and impactful discoveries to be made that can meaningfully improve global health [2].”

Pentadecanoic acid (C15:0) is primarily found in whole fat dairy products, certain types of fish and some plants. Studies have consistently shown that individuals with low levels of C15:0 are at a heightened risk of developing type 2 diabetes, heart disease and nonalcoholic fatty liver disease (NAFLD) [3], but changes in agricultural practices and the demonization of whole fat dairy products has led to a population-wide decline in C15:0 levels [4]. Despite the prevalence of these conditions in contemporary society, the daily intake of cow’s milk has worsened with each generation, a trend that the United States Department of Agriculture describes as “difficult to reverse” [4].

The Metabolites paper notes that C15:0 plays a critical role in maintaining cellular integrity. When levels of C15:0 in cell membranes fall to or below 0.2% of total fatty acids, cells become increasingly fragile; this fragility is closely associated with ferroptosis, a form of cell death first described by Columbia University researchers in 2012 [5]. Ferroptosis is implicated in accelerated aging and the pathogenesis of several chronic diseases including CVD and type 2 diabetes, but its precise trigger remained elusive until now.

Small but mighty: the fatty acid that packs a considerable longevity punch
Dr Stephanie Venn-Watson is lead author on the paper

“A somewhat mysterious type of cell death, called ferroptosis, showed up as our C15:0 levels have been declining,” explained Venn-Watson. “We have demonstrated not only that low C15:0 can lead to ferroptosis and its downstream complications, but that replenishing these levels directly halts all core components of this new cell killer [2].”

The studies led by Venn-Watson demonstrate that a deficiency in C15:0 precipitates cellular fragility and ferroptosis – conversely, supplementing diets with C15:0 can reverse these adverse effects. The evidence indicates that C15:0 supplementation stabilizes cell membranes, prevents liver iron deposition, repairs mitochondrial damage and reduces reactive oxygen species. These cellular improvements translate into measurable health benefits, including lower glucose, cholesterol, and triglyceride levels, enhanced liver function and improved red blood cell health.

The typical C15:0 levels in modern populations hover around 0.2% of total fatty acids, which is alarmingly close to the threshold for cellular fragility. Research suggests that maintaining C15:0 levels between 0.2% and 0.4% is necessary to mitigate the risk of Cellular Fragility Syndrome. A study involving over 4,000 individuals monitored over sixteen years found that those with C15:0 levels between 0.40% and 0.55% had the lowest incidence of heart disease [6]. Intriguingly, populations in high longevity zones (also known as blue zones), such as Sardinia, exhibit significantly higher C15:0 levels – up to 0.64% [7]. This higher level correlates with the region’s remarkably high percentage of centenarians, particularly among men, and lower mortality rates from heart disease.

The Sardinian diet, rich in C15:0 due to the consumption of cheeses made from the milk of local, mountainous grazing goats and sheep, presents a stark contrast to modern dietary habits that favor reduced-fat dairy products. This dietary pattern spotlights the potential benefits of C15:0 in promoting longevity and cardiovascular health. Notably, C15:0 demonstrates a range of cellular benefits surpassing those of well-known longevity-enhancing compounds such as rapamycin, metformin and acarbose.

Natural declines in C15:0 levels with age further exacerbate the risk of deficiency-related health issues, and the discovery that C15:0 deficiency contributes to a spectrum of chronic diseases will fuel the debate on the need to reassess current dietary guidelines and agricultural practices. The identification of C15:0 as a crucial nutrient highlights the interconnectedness of diet, cellular health, and chronic disease prevention, and as research progresses, it becomes increasingly evident that a holistic approach to nutrition is essential for mitigating the effects of aging and enhancing long-term health outcomes.

“There are two big benefits of a discovered nutritional deficiency syndrome,” shared Dr. Venn-Watson. “The first is that C15:0 can be measured to identify people who have low levels. The second is that we can drive meaningful changes in our diets and global nutritional guidelines to help replenish population wide C15:0 levels and fix these deficiencies [2].”

[1] https://www.mdpi.com/2218-1989/14/7/355
[2] https://www.prweb.com/releases/nutritional-c150-deficiency-syndrome-may-explain-accelerated-aging-in-younger-people-302181722.html
[3] https://www.discoverc15.com/application/
[4] https://www.ers.usda.gov/amber-waves/2022/june/fluid-milk-consumption-continues-downward-trend-proving-difficult-to-reverse/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367386/
[6] https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003763
[7] https://link.springer.com/article/10.1007/s11357-021-00342-0

Photograph of Stephanie Venn-Watson courtesy of Seraphina Therapeutics