The Ancient Remedy: Lactoferrin’s 160-Million-Year Evolutionary History

Some of the most interesting discoveries in modern science begin with something nature has been doing for millions of years, and lactoferrin is a perfect example. Today, scientists can study this protein molecule by molecule, investigate how it interacts with microbes and even infer what its ancestors may have looked like. Yet mammals were producing lactoferrin long before we had the tools to understand it.

 

Our own introduction to lactoferrin came relatively recently. In 1939, the Danish scientists Jens and Niels Sørensen reported an unusual iron-containing red protein in bovine milk. Its properties were characterised more fully over the following decades, and the protein became known as lactoferrin.

 

Scientists went on to find lactoferrin beyond milk. It is present in saliva and tears, as well as other secretions protecting parts of the body regularly exposed to the outside world. It is also stored inside neutrophils, white blood cells that respond rapidly during infection.

 

What started with an unusual red protein in cow’s milk became the subject of decades of research. Then, in 2026, scientists used modern evolutionary techniques to infer the origin of the lactoferrin lineage at around 160 million years ago.

 

Mother Nature had quite the head start.

 

First, there was iron

 

One of the first clues to lactoferrin’s role came from iron. We need iron to function, but many microorganisms need it too. Controlling access to this valuable resource is one of the ways our bodies can make conditions less favourable for microbial growth.

 

Lactoferrin binds ferric iron with high affinity, helping limit the iron available to some microorganisms. Scientists call this nutritional immunity, where the body restricts access to nutrients that microbes need to survive and multiply.

 

Iron is only part of the picture. Lactoferrin can also interact directly with microbial surfaces, while its presence in saliva and tears places it at some of the body's busiest contact points with the outside world. Inside neutrophils, lactoferrin can be released when these immune cells are activated.

 

Scientists had started with an iron-binding protein. They were gradually discovering that its biology extended much further.

 

Another defence within lactoferrin

 

In the early 1990s, researchers discovered another interesting feature of bovine lactoferrin. When the protein was exposed to pepsin, an enzyme involved in digesting proteins in the stomach, it could be cleaved to release a much smaller antimicrobial peptide called lactoferricin.

 

Lactoferrin and lactoferricin are related, but they are not the same thing. Whole lactoferrin can bind iron and has antimicrobial properties of its own. Lactoferricin is a shorter, positively charged peptide with a different way of acting against bacteria.

 

In laboratory experiments, lactoferricin was able to interact directly with bacterial membranes. Early research showed that the peptide could damage the outer membrane of susceptible Gram-negative bacteria and display direct bactericidal activity under the conditions tested.

 

This opened up another area of lactoferrin research. Breaking the protein apart did not necessarily mean that all of its biological activity disappeared. Proteolysis, the process of cutting proteins into smaller pieces, could release an embedded peptide with properties of its own.

 

What happens during human digestion is more complicated. Pepsin can generate lactoferricin under laboratory conditions, but that does not mean the same amount of lactoferricin is always produced, or behaves in the same way, throughout the human digestive system. Digestion can produce a mixture of lactoferrin-derived fragments, while some of the original protein may remain intact.

 

A 2024 study gave us another clue. Researchers recreated gastrointestinal digestion in the laboratory and then tested digested bovine lactoferrin against E. coli. After the simulated stomach stage, the digested material showed greater antibacterial activity at low concentrations than undigested lactoferrin. That activity decreased again following further intestinal digestion.

 

This was an in vitro experiment, not a human trial, so it cannot tell us that consuming bovine lactoferrin will kill E. coli in the gut. However, it does show that digestion can change the biological activity of bovine lactoferrin and generate fragments that behave differently from the intact protein.

 

Looking back 160 million years

 

In 2026, researchers publishing in PLOS Biology investigated the evolutionary history of lactoferrin and the antimicrobial peptide sequence embedded within it. They were not digging up ancient lactoferrin or extracting it from fossils. Instead, they used a technique called ancestral sequence reconstruction.

 

The basic idea is surprisingly intuitive. Scientists compared protein sequences from living mammals and looked at how those species are related. From those differences, they could infer what likely ancestral sequences looked like, rather like working backwards through a molecular family tree.

 

Their analysis suggested that lactoferrin arose through duplication of an ancestral transferrin gene in the ancestor of placental mammals approximately 160 million years ago.

 

So when we talk about lactoferrin having 160 million years of history, we do not mean that the lactoferrin found in mammals today has remained unchanged for all that time. We mean that its evolutionary lineage can be traced back to that period, with the protein continuing to change as different mammalian lineages evolved.

 

The researchers then zoomed in on lactoferricin. They inferred likely ancestral versions of this region, synthesised selected peptides in the laboratory and tested their activity against bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus agalactiae.

 

This allowed them to do something rather clever: instead of only comparing the lactoferricin found in mammals today, they could experimentally investigate how its antimicrobial properties may have changed through evolutionary time.

 

Evolution did not follow a straight line

 

The earliest reconstructed lactoferricin-derived peptide already showed some antimicrobial activity, but what happened afterwards was not a simple progression from weak to strong. Different evolutionary branches accumulated different changes, and their activity also depended on which bacterium the researchers tested.

 

Changes in the amino-acid sequence altered properties such as positive charge and hydrophobicity, both of which affect how antimicrobial peptides interact with bacterial membranes. Some reconstructed peptides could disturb these membranes, while others produced stronger bactericidal effects.

 

One experiment showed just how much a small molecular change could matter. Researchers introduced the positively charged amino acid arginine into an earlier ancestral lactoferricin sequence and found that its antimicrobial activity against P. aeruginosa increased. When the same change was reversed in a later peptide, activity decreased.

 

A single amino-acid substitution had changed how the peptide behaved.

 

Some reconstructed ancestral peptides were also more active than modern human lactoferricin against particular bacteria, while modern bovine lactoferricin showed especially strong activity in several of the assays. There was no single ladder leading neatly from an ancient, weak peptide to a modern, powerful one.

 

That messiness is part of what makes the study so interesting. It gives us a glimpse of evolution at work, with small molecular changes producing different effects across different mammalian lineages and against different microorganisms.

 

And where does bovine lactoferrin come in?

 

There is something rather fitting about the fact that our scientific understanding of lactoferrin began with cow’s milk. Bovine lactoferrin has since become an important part of lactoferrin research, with scientists studying its iron-binding properties, antimicrobial activity, digestion and the smaller peptides that can be released from it.

 

The 2026 study added another interesting piece. When the researchers tested modern lactoferricin peptides against bacteria, bovine lactoferricin was particularly potent in several of their laboratory assays.

 

That does not tell us that bovine lactoferrin is universally better than other forms. These experiments involved isolated peptides and bacteria under controlled laboratory conditions, which is very different from someone consuming whole bovine lactoferrin.

 

But it does give us good reason to be interested in bovine lactoferrin on its own terms.

 

Human research adds another layer. Lactoferrin has been studied in relation to immune function, inflammation, iron metabolism and respiratory health. Results vary depending on the population, dose, formulation and outcome being measured, so laboratory mechanisms and human health outcomes need to be kept separate.

 

For us, that distinction matters. Nature gives us something interesting to investigate. Science tells us what the evidence truly supports.

 

 

Why lactoferrin is the hero of Leapfrog

 

At Leapfrog, we love the combination of nature and science, and lactoferrin gives us both.

 

This is not an ingredient invented for a wellness trend. Its evolutionary lineage stretches back towards the earliest placental mammals, while the protein itself naturally occurs in milk and several of the body's protective secretions. Modern science now allows us to investigate that biology right down to individual amino acids.

 

That is why lactoferrin is the hero ingredient across Leapfrog: with 250mg in IMMUNE, 100mg in DAILY and 50mg in both FOCUS and SNOOZE.

 

We use bovine lactoferrin because we can follow research on the ingredient itself. Scientists have studied the intact protein, its iron-binding and antimicrobial properties, what happens when it is digested, the peptides that can be released from it and its use in human research.

 

And we are still learning. There are questions around dose and delivery that deserve more research, while scientists continue to investigate which lactoferrin-derived peptides are produced during digestion and what they might do inside the body. Lactoferricin itself is a perfect example. Researchers identified it more than 30 years ago, yet in 2026 scientists were still finding completely new ways to investigate its evolutionary history.

 

For us, that is far more interesting than pretending every question has already been answered. Lactoferrin has a remarkable biological history, decades of modern research behind it and plenty left for science to uncover.

 

Our Ancient Remedy

 

When you see lactoferrin on the side of a supplement, it is easy to miss how much history sits behind that one word. Scientists began studying the protein less than a century ago, but the lactoferrin lineage stretches back 160 million years.

 

Since then, research has taken us from iron binding to immune biology, from digestion to lactoferricin and now back through mammalian evolution. Scientists can infer likely ancestral sequences, recreate selected peptides and test how tiny changes in their molecular structure altered what they could do.

 

That is what we mean when we call lactoferrin our Ancient Remedy. We are not using “ancient” to suggest that lactoferrin was a historical medicine, or that something is effective simply because it comes from nature. We mean that this is a naturally occurring protein with an evolutionary history stretching back millions of years, which modern science is only continuing to uncover.

 

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