Cellular Fragility Syndrome: A Deep Dive on Nutritional C15:0 Deficiencies and How to Fix Them

A big paper was just published on a newly discovered nutritional C15:0 deficiency syndrome, called Cellular Fragility Syndrome. This is a big deal because nutritional deficiency syndromes (like vitamin C deficiency and scurvy, or vitamin D deficiency and rickets) are rarely discovered.

This latest paper describes how deficiencies in C15:0, an essential fatty acid, can cause fragile cells and a phenomenon called ferroptosis. In turn, ferroptosis accelerates aging and impacts our metabolic, liver, and heart health.

The good news? This paper published in the peer-reviewed scientific journal Metabolites, shows that fixing C15:0 deficiencies effectively strengthens cells, fights ferroptosis, slows cellular aging, and protects our long-term metabolic, liver, and heart health. Even better news? There is support for optimal C15:0 levels that can help us live even healthier and longer. We’re talking Longevity Blue Zone levels, folks.

So, let’s take a deeper dive into this groundbreaking news, including 1) understanding C15:0 and Cellular Fragility Syndrome, 2) definitions for “low”, “healthy”, and “optimal” C15:0 levels, 3) how our world became C15:0 deficient, and 4) how much dietary C15:0 we need to strengthen those cells and support our long-term wellness.

Well, this sounds exciting. But what is C15:0? 

C15:0 (pronounced see-fifteen) is an odd-chain saturated fatty acid. While our primary source of C15:0 is from whole fat dairy foods, this healthy fat can also be found in some types of fish and plants. Dr. Stephanie Venn-Watson, a veterinary epidemiologist, surprisingly discovered that C15:0 is an essential fatty acid - the first to be found in over 90 years.

What does C15:0 do?

Good question. C15:0 (also called pentadecanoic acid) actively repairs, restores and revitalizes our long-term health at the cellular level by:*

• Strengthening our cell membranes (and us) against age-related breakdown.
• Repairing mitochondrial function, which keeps our cells' energy-producers going.
• Naturally activating receptors (including PPARs and AMPK) that regulate our metabolism, immunity, mood, sleep and appetite.
• Naturally inhibiting damaging pathways (including mTOR and JAK-STAT) as a means to support longevity.

All in, C15:0 provides 36+ cellular benefits to support our long-term health. Wow!

How is C15:0 an essential fatty acid?

Essential fatty acids are nutrients that our bodies must have to maintain our baseline health. Since our bodies can’t make enough C15:0 on their own, we must routinely get adequate amounts from our diet or supplements.

There are now three known essential fatty acids: C15:0 (pentadecanoic acid), linoleic acid (an omega-6 fatty acid), and alpha-linolenic acid (an omega-3 fatty acid).

C15:0 is considered essential because:

• Our bodies cannot make enough C15:0 on their own.
• Our C15:0 levels are directly tied to the amount of C15:0 in our diet.
• People with lower C15:0 levels have poorer metabolic, heart, and liver health.
• Supplementation with C15:0 improves metabolic, heart, and liver health.
• C15:0 has an active metabolite, called PDC, that supports brain health and joint comfort.
• And now: Too-low C15:0 levels can cause a nutritional deficiency syndrome.

Now that you have the 101 on C15:0, let’s get to the latest scientific paper, which describes a newly discovered nutritional C15:0 deficiency syndrome, called Cellular Fragility Syndrome. This syndrome starts with fragile cells.

What are “fragile cells”?

Well, each and every one of our cells is protected by a cell membrane. Our cell membranes are made of different fatty acids, which determine the strength (or fragility) of our cells.

• C15:0 is a sturdy fatty acid that serves as an armor for our cells. Because C15:0 has no double bonds in its structure, it is particularly resistant to damaging lipid peroxidation. Studies have shown that C15:0 can strengthen cell membranes by 80%. Our cell membranes need C15:0 levels greater than 0.2% of total fatty acids to keep them healthy and strong.

• Unsaturated fatty acids are fragile fatty acids that can weaken our cell membranes. This is because unsaturated fatty acids have double bonds that are susceptible to lipid peroxidation.

The higher the C15:0, the stronger the cell membrane. The higher the unsaturated fatty acids, the more fragile the cell membrane. And the more fragile the cell membrane, the greater the risk of ferroptosis. Now seems like a good time to talk about ferroptosis.

A new cellular enemy: ferroptosis

If our cell membranes have too little C15:0 and too many fragile fatty acids, our cell membranes get attacked by oxygen. The result? Damaging lipid peroxidation and a phenomenon called “ferroptosis”.

Discovered in 2012 by scientists at Columbia University, ferroptosis is a newly recognized threat to our cells. Here’s how ferroptosis goes down:

• Ferroptosis starts with fragile fatty acids in our cell membranes, which result in lipid peroxidation. 
• This lipid peroxidation mixes with unwanted iron in our cells to create massive amounts of reactive oxygen species (aka, ROS). 
• High levels of ROS attack our mitochondria, resulting in cells that power down and stop working.

Over 10,000 scientific papers have been published on ferroptosis since its discovery. Thanks to all that science, we now know that ferroptosis accelerates our aging and negatively impacts our metabolic, heart, liver, and brain health. In fact, ferroptosis may explain why so many young people have been developing older-people conditions.

Despite all these studies, no one has really understood what causes ferroptosis, or why it showed up on our front door.

Wait, weren’t we talking about Cellular Fragility Syndrome?

We were! The latest paper provides scientific support behind a giant discovery:

Nutritional C15:0 deficiencies can cause ferroptosis, which results in accelerated aging and compromised metabolic, heart, and liver health. This syndrome is called Cellular Fragility Syndrome.

Cellular Fragility Syndrome occurs when a person does not routinely get enough C15:0 via their diet or supplements. Specifically, the following process occurs when:

• We don’t get enough C15:0 from our diet.
• Our cell membrane C15:0 levels hover near or below 0.2% of total fatty acids (aka “low” C15:0 levels)
• These low C15:0 levels can result in weakened cell membranes and increased lipid peroxidation, including in our red blood cells and liver cells.
• Fragile red blood cells are then engulfed by macrophages in our liver, which result in excess iron in our liver tissues.
• Lipid peroxidation + excess iron in the liver result in ferroptosis, which can spill over to affect our vessels, heart, pancreas, and brain.
• Aging is accelerated in cells, resulting in compromised metabolic, heart, and liver health.

Studies support that Cellular Fragility Syndrome may be impacting as many as 1 in 3 people globally.

I thought nutritional deficiencies were a thing of the past. How are so many people susceptible to nutritional C15:0 deficiencies today?

Well, for over 50 years, we have been told to decrease our intake of saturated fats by decreasing our intake of butter and whole fat milk. As a result, we have not only decreased our intake or proinflammatory even-chain saturated fatty acids (like C16:0 and C18:0), we have also lowered our daily intake of C15:0 from 100 to 200 mg per day in the 1970s to less than 50 mg per day in the 2000s. 

This decrease in dietary C15:0 explains why population-wide average C15:0 levels have declined from 0.23% to 0.20% of total fatty acids. In addition, our C15:0 levels naturally decline as we age. These are the primary two reasons why many of us are sitting on that 0.2% breaking point of nutritional C15:0 deficiency.

Since these dietary recommendations were implemented, there has been an alarming rise in metabolic, heart, and liver conditions. Especially among younger people. The latest Metabolites paper supports that this disturbing trend may be driven, at least in part, by nutritional C15:0 deficiencies.

Yikes. What are healthy vs. deficient C15:0 levels?

Let’s start with how C15:0 is measured. C15:0 blood levels can be measured in three ways: µg/ml, µM, or % of total fatty acids. Additionally, C15:0 may be measured in your serum, plasma, or red blood cell membranes.

Because there is some variation across different laboratories using µg/ml or µM, results that report the percentage of C15:0 (% of all fatty acids) is a good place to start. Further, red blood cell membrane C15:0 levels are the most relevant and reliable measurements to detect Cellular Fragility Syndrome. The recent paper provides the following reference ranges for C15:0 levels:

• Low Zone: C15:0 ≤ 0.20%. Low C15:0 levels can cause weakened cell membranes and Cellular Fragility Syndrome. Numerous studies have shown that people with low C15:0 levels are more likely to have impacted metabolic, heart, and liver health.
• Healthy Zone: C15:0 > 0.20% - 0.4%. Most people have C15:0 levels in this range, which can protect against Cellular Fragility Syndrome and support metabolic, heart, and liver health.
• Optimal Zone: C15:0 between > 0.40% - 0.64%. People living in the Longevity “Blue” Zone of Sardinia have average C15:0 levels of 0.64%. Another extensive study showed that C15:0 levels > 0.4% are associated with the most protected heart health.

Is there a test for C15:0 levels?

Yes. You can determine your C15:0 levels using either a test at your doctor’s office or an at-home test. These tests typically report C15:0 results as either a percentage (%) of total fatty acids, or as an amount (in µg/ml or µM).

Now that you know that, let’s talk about how C15:0 fixes Cellular Fragility Syndrome.

So, how do I know that raising C15:0 fixes Cellular Fragility Syndrome?

Well, science. The recently published paper shows how C15:0 reverses all core components of ferroptosis and Cellular Fragility Syndrome. This includes studies demonstrating how C15:0 supplementation directly:*

• Raises C15:0 blood levels
• Strengthens red blood cell membranes by 80%, and stabilizes them against premature breakdown
• Lowers lipid peroxidation & iron deposition in the liver
• Lowers reactive oxygen species (ROS) levels by 45%
• Repairs mitochondria

That’s like, 5 for 5. Go, C15:0.

How does C15:0 support longevity?

Extending healthspan and longevity by strengthening cell membranes isn’t a new idea. In fact, A.J. Hulbert’s Cell Membrane Pacemaker Theory of Aging shows that nature has used this trick for millions of years. 

In his studies, Hulbert demonstrated that long-lived mammals (like humans and elephants) have cell membranes with the sturdiest fatty acids. These strong cell membranes result in lower lipid peroxidation and longer lives. Poor mice have fragile cell membranes with lots of polyunsaturated fatty acids, resulting in higher lipid peroxidation and short lives.

The latest paper shares the Cellular Stability Hypothesis, which states that cell membrane strength dictates not only a species’ longevity, but the longevity of individuals within a species - including humans.

Pure C15:0 (aka fatty15) longevity-enhancing activities include:*

• 36+ cellular benefits, which was better than three leading longevity-enhancing molecules: rapamycin, metformin, and acarbose.
• Targeting six out of 12 hallmarks of aging, including cellular senescence, inflammaging, mitochondrial dysfunction, gut dysbiosis, impaired cellular signaling, and epigenetic alterations
• AMPK activation and mTOR inhibition, both of which support longevity 
• Raising LPE C15 levels, which have been associated with slower biological aging rates
• Improved growth of the healthy gut microbe, Bifidobacterium adolescentis, which has been shown to increase longevity in multiple species

As shared earlier, people who live in the Sardinian Longevity Blue Zone are healthier longer and are more likely to live 100+ years. Sardinia has the world’s largest percentage of men who live to at least 100, which has been attributed to their good heart health. Studies found that this long-lived population has high C15:0 levels: a whopping 0.64%. As a reminder, the rest of the world has an average C15:0 level of only 0.2%. 

I’m in. How much C15:0 do I need in my diet to not be deficient? 

Most people have a baseline of around 0.2% of C15:0 in their red blood cells. This means that our bodies are likely giving us a kick start with some low-level C15:0 production. Additionally, there may be a consistent minimum most people get in their current diets.

To achieve your desired C15:0 level, here’s a good rule of thumb: For every added 100 mg of C15:0 to a daily diet, most people can raise their C15:0 levels by about 0.1%. Most people need an added 100 mg of C15:0 per day to stay in the “Healthy Zone” (C15:0 levels > 0.2% to 0.4% of total fatty acids).

People who have a nutritional C15:0 deficiency (< 0.2%) will need higher amounts of daily C15:0. That amount will depend on their current C15:0 levels.

Now that I know how much daily C15:0 I need in my diet, any recommendations?

While simply eating more dairy doesn’t translate to the metabolic, liver, and heart-health benefits of C15:0, the Longevity Blue Zone Sardinian diet provides some important clues on how to achieve optimal C15:0 levels, good heart health, and supported longevity. 

The Sardinian diet is low in meat (which is typically eaten only once a week) and high in dairy (primarily cheese, which is part of their daily diet). Importantly, Longevity Blue Zone Sardinians make their own cheese from local goats and sheep that graze on mountainous grass. Not only have studies shown that grass-fed animals produce higher-C15:0 milkfat, but that mountainous grass-fed animals produce the highest-C15:0 milkfat. 

Longevity Blue Zone Sardinians typically eat their locally made pecorino cheese, which has double the C15:0 levels of cow’s butter. They also eat an aged goat cheese that has a higher amount of free fatty acids - which translates to more bioavailable C15:0. 

Ah, now we know how Longevity Blue Zone Sardinians achieve C15:0 levels that are 3x higher than the rest of us.

Why can’t I just eat more of any food that contains C15:0?

While there are foods that contain C15:0, there is a balance between getting enough good C15:0 versus getting too many proinflammatory even-chain saturated fatty acids. Here are the top limitations of many food-based sources of C15:0:

• While milk fat contains only 1% C15:0, it also has more than 40% proinflammatory fatty acids (such as C16:0 and C18:0). Higher levels of C16:0 and C18:0 have been repeatedly associated with poorer metabolic, heart, and liver health.
• This unfavorable ratio is present in just about all foods that contain C15:0.
• Some studies have shown that high fat diets may actually limit absorption of food-based C15:0.
• The amount of C15:0 in dairy fat is dependent on what animals are fed. As shared above grass-fed animals produce milk that has more C15:0 compared to animals fed corn.

These limitations are why experts have concluded that simply eating more dairy products does not holistically and reliably improve our health. And why these experts concluded that individual beneficial ingredients in milk (ahem, C15:0) can perform better when they are isolated and pure.

Fatty15 to the rescue.

Fatty15 is a pure, science-backed, bioavailable, and tiny vegan-friendly C15:0 supplement. This award winning ingredient was developed by doctors and scientists to supplement our diet and help us maintain healthy C15:0 levels.

Numerous studies have demonstrated broad health benefits of the pure C15:0 ingredient in fatty15, including optimal metabolic, heart, liver, and LDL cholesterol health.* To boot, more than half of fatty15 customers report feeling better within 2 weeks, including deeper sleep, calmer mood, and improved joint comfort.*

Each capsule contains 100 mg of C15:0, which allows you to tailor a C15:0 supplement regimen to your specific needs. As a reminder, most people need an added 100 to 200 mg of C15:0 per day to maintain healthy C15:0 levels.

So long Cellular Fragility, hello Cellular Stability.

Wait a minute. This paper was authored by one of the founders of Seraphina Therapeutics, which sells fatty15. Doesn’t this make it a biased review?

Let’s start with the science that led to the discovery of C15:0 as a good fat. 

Dr. Stephanie Venn-Watson is a veterinary epidemiologist who, back in 2015, initially discovered C15:0 as an active and beneficial ingredient while working for the U.S. Navy. This surprising finding happened when Steph was studying how to help older Navy dolphins live their longest, healthiest lives possible.

Specifically, Steph and her team at the Navy recognized that some dolphins, all of which live in the open ocean, aged healthier than others. Since dolphins eat an all-fish diet, her team reasonably hypothesized that higher omega-3 fish diets likely predicted the healthiest aging dolphins.

Turning the healthy fat pyramid on its head, however, Steph and her team unexpectedly discovered that it was not higher levels of omega-3s, but instead higher levels of C15:0, that predicted the healthiest dolphins. 

With this exciting discovery, Steph and her Navy physician husband, Eric, founded Seraphina Therapeutics and worked cooperatively with the Navy to develop a pure, vegan-friendly C15:0 ingredient (FA15) and the world’s first C15:0 supplement, fatty15.

As a military family of doctors, Steph and Eric have started a movement to improve global health - one amazing person at a time.

This movement includes continuing the team’s rigorous science around C15:0, including identifying the pathophysiology behind nutritional C15:0 deficiencies that, if fixed, can truly help improve global health.

To address concerns of bias, Steph and her team make a concerted effort to go above and beyond typical studies to ensure that their science is responsible, valid, and transparent, including the following for the current paper:

• Peer-reviewed publication. All of the science in the current paper was peer-reviewed and independently published by reputable journals, which have strict publishing guidelines. This includes extensive reviews by an editor and two independent experts, who must concur that the science was done with the utmost care and that the findings and conclusions were valid.
• Third-party study. The laboratory-based studies in this review were conducted, and data interpreted, by contracted third parties with extensive expertise.
• Control systems. The laboratory-based studies included non-treated control systems, which enabled statistical comparisons of effects of fatty15 against non-treated controls, as well as comparisons with omega-3 (EPA) and longevity-enhancing molecules.
• Repeated results. To ensure that the results were repeatable, similar outcomes are shared across multiple studies, including meta-analyses.
• Federally funded. Much of the work in this review was part of an Office of Naval Research funded study (N00014-21-9-002), the proposal of which was reviewed and approved by the Department of Defense.
• Conflict of interest disclosure. In this paper, it is disclosed that fatty15’s company has licensed the commercialization of C15:0 from the U.S. Navy, and it is shared that this company has a C15:0 supplement product on the market.

What’s next?

There are now numerous peer-reviewed scientific publications supporting C15:0 as the first essential fatty acid to be discovered since the omegas (which was 90 years ago), and the science around C15:0’s specific health benefits is continuing to grow.

With the discovery and explained pathophysiology of nutritional C15:0 deficiencies (Cellular Fragility Syndrome), C15:0 tests can be routinely used by physicians and consumers to measure C15:0 levels, tailor their daily C15:0 regimens, and support their long-term health.

Updates to the growing list of studies around C15:0 can be found at DiscoverC15.com.

As a featured 2022 TEDx San Diego talk, a 2022 & 2024 Fast Company World Changing Idea, and the 2024 Mindful Award for Overall Supplement of the Year, the fatty15 team’s movement to improve global health is well underway! 

Read the study:

Venn-Watson, S. The Cellular Stability Hypothesis: Evidence of Ferroptosis & Accelerated Aging-Associated Diseases as Newly Identified Nutritional Pentadecanoic Acid (C15:0) Deficiency Syndrome. Metabolites 14 (2024): 355.