C15:0 & Long-Term Metabolic Health

Healthy Aging

C15:0 Rises To The Top

Last week, we touched on a newly published prospective cohort meta-analysis in Advances in Nutrition, which looked at relationships between different fatty acids and one’s ability to protect their long-term metabolic health. This week, we take a deeper dive into this study, its findings on C15:0 and other fatty acids as they relate to protecting our metabolic health over time – and what made it so robust.

I’m in! What did they find?

Here is a breakdown of their key findings:

• Odd-chain fatty acids led the health-protective pack. Of all 27 fatty acid types and groups included in this study, higher levels of C15:0 and C17:0 were – by far – the strongest predictors of not developing type 2 diabetes over time. Both are dietary odd-chain saturated fatty acids. Specifically, for every 0.1% increase in C15:0 and C17:0, the associated risk of developing type 2 diabetes was reduced by a massive 32% and 36%, respectively. These were assigned the highest “Moderate Confidence of Evidence (CoE) category.”
• EPA, DHA and an omega-6 (linoleic acid) came in second. In addition to C15:0 and C17:0, higher levels of specific omega-3s and an omega-6 were associated with better long-term metabolic health. For every 0.1% increase in omega-3s (specifically, EPA and DHA) and omega-6s (linoleic acid), the associated risk of developing type 2 diabetes was reduced by 3% and 7% respectively. These were also assigned the highest “Moderate” CoE category.
• A few mono- and polyunsaturated fatty acids made the naughty list. On the flip side, higher levels of specific monounsaturated fatty acids (palmitoleic acid and oleic acid) and polyunsaturated fatty acids (gamma-linolenic acid, dihomo-gamma-linolenic acid, and arachidonic acid) were associated with a higher risk of developing type 2 diabetes.
• Even-chain saturated fatty acid C16:0 also misbehaved, maybe. Higher levels of C16:0, an even-chain saturated fatty acid, were associated with a higher risk of developing type 2 diabetes. These associations, however, had CoEs of “Low” or “Very Low”.
• The truth is in the cell membrane. The strongest associations between fatty acids and long-term metabolic health were based on measurements in red blood cell membranes and plasma phospholipids (which are the form of fatty acids in cell membranes). This is particularly important, given fatty acids’ differing roles in physically strengthening (like C15:0) or compromising  (like some polyunsaturated fatty acids) cell membranes as they relate to lipid peroxidation and age-related breakdown.

This latest study further backs multiple previously published cohort meta-analyses repeatedly linking higher C15:0 to not only better long-term metabolic health, but cardiovascular health, too.

Impressive. What made this study so robust?

There are five reasons why this Schaefer et al. study deserves extra attention for its credibility:

• First, they combined data from 27 prospective cohort studies that followed hundreds of thousands of people over periods of time, which ranged from 2.5 to 43 years. The mean age of participants ranged from 49 to 82 years old, and the cohorts included people from the U.S., Europe, Asia and Australia. So, this analysis included a lot of studies with many older adults over many years and global locations.
• Second, they included a full fatty acid panel: from saturated fats to monounsaturated fats to polyunsaturated fats (including omega-3s and omega-6s). They not only looked at total amounts of fatty acids from each of these categories, but they also included specific types of fatty acids within each category. All in, 27 different fatty acids and their groups were included in this study.
• Third, not only did Schaefer et al. include a full list of fatty acids – they both combined and differentiated between studies that measured fatty acids in different parts of our blood and cells: namely, fatty acid levels in red blood cells, phospholipids (a proxy for cell membrane-bound fatty acids), or plasma.
• Fourth, Schaefer et al. looked at dose-response relationships between fatty acid blood levels and the risk of developing (or not developing) type 2 diabetes. While many prospective cohort studies evaluate people with “high” versus “low” fatty acid levels, this paper used a more sophisticated approach to draw more powerful and applicable conclusions: “For every X increase in fatty acid Y, one’s risk of developing type 2 diabetes was Z.”
• Fifth, they assigned Certainty of Evidence (CoE) categories to their analyses, by fatty acid type and group, based on the quality of cohort studies used. Specifically, CoE category options were “Very Low”, “Low”, and “Moderate”. Schaefer et al. limited their summary conclusions to findings that met their highest threshold of “Moderate”.

We’d say this all adds up to a robust study.

How much C15:0 is needed to raise my C15:0 levels by 0.1%?

According to extensive clinical trials from Mascarhenas et al. and Stallings et al., every 100 mg of pure C15:0 is expected to raise our circulating C15:0 levels by about 0.1%.

Wait, aren’t prospective cohort studies about association, not causation?

Good question. Any time a cohort study is evaluating associations between fatty acid levels and a given outcome, it is indeed showing relationships that are based on associations and does not prove direct causation. When you add in the dose-response prospective components, it adds the benefit of timing: for every 0.1% increase in C15:0 level one has at baseline, the associated ability to protect one’s metabolic health over time increases, too.

Why this latest study is so compelling.

This latest study becomes even more compelling when combined with our knowledge of how C15:0 directly and actively protects long-term metabolic health, including C15:0’s:

• Mechanisms of action. Fu et al. showed that C15:0 directly activates AMPK and increases insulin sensitivity in cells, which are well-established mechanisms for glucose control. Bishop et al. demonstrated that C15:0 activates AKT, which also aids in glucose control.
• Preclinical studies. Studies have shown that C15:0 directly protects healthy body weight and glucose control in relevant preclinical models.

Large-scale population studies, paired with gold-standard experimental studies, support that C15:0 has a direct role in supporting our long-term metabolic health.