Burden of Proof: What Makes a Nutrient, a Nutrient?

December 14, 2025

Welcome to Issue 158 of Science Says! Our weekly newsletter where you’ll learn the latest healthy aging and C15:0 research news that our team of doctors, scientists, and experts are most excited about—without having to go search for it.

Eric and Steph
Co-Founders, Doctors, Nerds

What Dr. Stephanie Venn-Watson, our co-founder and author of The Longevity Nutrient and over 80 peer-reviewed scientific publications, is reading.

Healthy Aging

Nutrient: A simple molecule with a big impact

While there is important overlap between medicine, pharmaceuticals, and nutrition, there is a need to recognize differences between traditional drugs (used to treat diseases) and nutrition (used to protect health). In this issue, we cover a position paper published in Nutrition Reviews by a consortium of experts to help answer the question: Should drugs and nutrients be judged using the same criteria?

Let’s start by defining “nutrient”.

Following the old school Oxford Dictionary definition (and pretty much any other source defining “nutrient”), a nutrient is a substance that provides nourishment essential for growth and the maintenance of life.

Easy enough. We can further break that definition down into three sections.

First up, substances are classified into the following six nutrient categories (plus, a bonus category of fiber is making its way onto this list):

Carbohydrates
Proteins
Fats
Vitamins
Minerals
Water

Next, providing nourishment essential for growth means there is evidence that a nutrient is needed during our earliest, developing years… and without this nutrient, our growth and development would be compromised.

Finally, providing nourishment essential for the maintenance of life means there is evidence that a nutrient is needed to support health throughout our lives… and without this nutrient, our long-term health would be compromised.

With this understanding of how a nutrient is defined, let’s move on to Blumberg et al.’s thoughts on how to assess the value of a nutrient.

How can we best determine the value of a nutrient?

A consortium of experts with long-standing careers in nutritional science, policy, and practice met for two days in Omaha, Nebraska, to discuss evidence-based nutrition (EBN) versus evidence-based medicine (EBM). Here, they wanted to differentiate between the criteria needed to demonstrate the effectiveness of treating a specific disease (aka, EBM) versus protecting long-term health (aka, EBN). The product of this consortium was the Blumberg et al. paper.

As a primary theme of this paper, they call out the rising popularity of randomized clinical trials (RCTs), which have been the long-term gold standard to demonstrate a pharmaceutical drug’s safety and efficacy in treating a disease.

While RCTs are great for determining whether a specific compound treats a specific disease, Blumberg et al. conclude that, in isolation, RCTs can be limited and even unfeasible for determining the long-term protective benefits of nutrients.

Nutrient RCT #1 for Kids: Show that 1) providing a given nutrient is essential to the growth and development of infants and children, and 2) withholding the nutrient compromises the growth and development of infants and children.

Nutrient RCT #2 for Adults: Show that 1) providing a given nutrient is essential to the maintenance of long-term health in adults, and 2) withholding the nutrient compromises the long-term health in adults.

It should be pretty clear that these types of clinical trials would either be unethical to do with infants and unfeasible to do over decades with adults. Understanding that, Blumberg et al. sought to provide solutions beyond just RCTs.

The totality of evidence.

In their paper, Blumberg et al. emphasize the need to understand the totality of evidence beyond RCTS to fully validate the core benefits of nutrients. This totality of evidence includes:

Prospective cohort studies
Case-control studies
Biological plausibility
Replication and multiplicity of studies
Dose-response relationships
Presence of low-intake groups
Correct temporal sequence
Low between-subject variance
Intake estimate validation
Evidence of supporting early stage growth
Evidence of neonatal disease caused by nutrient deficiency
Evidence of protecting long-term health throughout life
Evidence of diseases in adults caused by nutrient deficiency

The bottom line? Meeting the evidence-based criteria of a nutrient that is essential to healthy development and maintaining our overall health throughout our lives is a whole lot harder than meeting the criteria of a drug that is targeted to treat a disease. For nutrients, it’s the totality of data that repeatedly point to the same story that counts.

The totality of evidence behind C15:0 as an emerging essential nutrient.

C15:0 (pentadecanoic acid) has long been sidelined as a simple, inactive saturated fatty acid biomarker of dairy intake. We now know that C15:0 is not only a beneficial fat, but one that is emerging as an essential nutrient.

Our bias aside, this really is an incredibly exciting discovery, backed by 100+ peer-reviewed studies and with the rare potential to meaningfully and relatively quickly improve global health.

Here are some of the studies that are helping to check off Blumberg et al.’s totality of evidence list supporting C15:0 as a true nutrient:

Prospective cohort studies. Meta-analyses (studies of multiple prospective studies) tracking tens of thousands of people over many years repeatedly show that people with higher C15:0 have better protected long-term cardiovascular and metabolic health.
Case-control studies. Similarly, case-control studies in numerous animal models repeatedly show that oral C15:0 actively results in protected cholesterol, immune, red blood cell, liver, glucose handling, and gut health compared to non-C15:0 controls. That means, beyond association, C15:0 can actively protect health.
Biological plausibility. Further, we know that C15:0 directly activates AMPK, AKT, and PPARs, which are mechanisms of action well known to protect cardiometabolic health. Thus, we have a direct link between how C15:0 works and observed long-term benefits in humans.
Replication and multiplicity of studies. Across prospective cohort studies, cell-based studies, mechanistic studies, and RCTs, C15:0’s beneficial role as a nutrient has been successfully repeated using a multiplicity of studies from different research teams. There’s just no explaining C15:0 away due to one-off studies.
Dose-response relationships. Mechanism of action studies, human cell system studies, prospective cohort studies, and RCTs have all shown that the higher the C15:0 level, the greater the benefit (aka dose-response relationship). This is compound efficacy 101.
Presence of low-intake groups. Thanks to global dietary recommendations to decrease our intake of whole dairy fat, there are large swaths of populations that have had low C15:0 intake since the late 1970s. So, no lack of low-intake groups. We’ll talk more about this 50-year experiment below.
Correct temporal sequence. The benefits of prospective control studies? They are prospective and can show that people who start with higher C15:0 levels at Day 1 are more likely to have protected cardiometabolic health at Year 10. Controlled animal studies and RCTs also prove that providing C15:0 directly resulted in health benefits that weren’t seen in non-exposed controls.
Low between-subject variance. A large genetic study by Otto et al. showed that there are no detectable genetic drivers for C15:0 levels, meaning that C15:0 levels are likely ubiquitously raised among individuals. As an essential nutrient, C15:0 appears to be intended to help all mammals. This ubiquitous benefit of C15:0 as an essential nutrient has been emerging across species too, including C. elegans, mice, rats, piglets, dolphins, and humans.
Intake estimate validation. Numerous large scale studies support that the average person needs 100 to 200 mg of C15:0 a day to maintain healthy C15:0 levels of > 0.2% (> 20 uM, > 5 ug/ml). Based on reports from the USDA and declining whole fat milk intake over the past 50 years, the average person in the U.S. today may be getting as little as 25 mg of C15:0 per day.
Randomized clinical trials. Across seven randomized clinical trials, higher C15:0 intake has been shown to increase C15:0 levels, and these higher C15:0 levels have been associated with protected red blood cell, liver, cholesterol, gut microbiome, and vascular health.
Evidence of supporting early stage growth & the presence of poor growth caused by nutrient deficiency. Both prospective cohort studies of mother-infant pairs and controlled studies with multiple hallmark deficiency models support that lower or no dietary C15:0 among infants results in poorer growth, and restoring normal C15:0 levels results in healthier body growth and cognitive development. This is one of the rarest and toughest criteria for a candidate nutrient to meet.
Evidence of protecting long-term health & the presence of diseases in adults caused by nutrient deficiency. Well, all the above supports how C15:0 protects long-term health. Additionally, in 2024, we published the detailed pathophysiology of a C15:0 nutritional deficiency syndrome, called Cellular Fragility Syndrome, that involves a new form of cell death called ferroptosis and may be impacting as many as 1 in 3 people globally. Importantly, the ability for C15:0 to reverse this syndrome was recently validated, in detail, by a second team.

Alas, due to the 1977 Congressional recommendations to dramatically lower whole dairy fat intake for all Americans, we have undergone a 50-year experiment of decreasing our C15:0 intake – including infants, children, and adults. Thus, the ultimate RCTs (#1 and #2 defined above) for C15:0 as a nutrient have kind of been done.

This half-century experiment helps to explain why prospective cohort studies have been so reliable – and why studies have repeatedly shown that 1) infants and children with lower C15:0 intake have poorer body growth and cognitive development, and 2) adults with lower C15:0 have poorer long-term cardiometabolic health. The emerging hypothesis, now from multiple research teams backed by 100+ peer-reviewed studies, is that nutritional C15:0 deficiencies may be contributing to the rise in poorer cardiometabolic health, including among younger and younger people. More importantly, studies are supporting that getting C15:0 back into our lives can help protect healthy development during our earliest years and our long-term health.

Here’s another way to gain a healthy perspective on the excitement behind C15:0: How many other substances, be they in supplements or pharmaceuticals, are able to check off the evidence-based criteria boxes above?
Answer: Very few.

As shared by Blumberg et al., a failure to ignore the totality of evidence specific to an essential nutrient, paired with nutrients’ safety and accessibility, could result in a greater risk of not implementing recommendations that could meaningfully improve public health.

Our movement has gained tremendous momentum in 2025 and will continue into 2026, along with science. Thanks for being with us, and here’s to evidence-based nutrients. Have a fantastic week, everyone!