Lessons from lactose intolerance: Investigating epigenomic aging

New insights into lactose intolerance may give scientists more than a better understanding of why some people lose the ability to digest dairy. They also could help uncover why some neurodegenerative diseases such as Parkinson’s disease arise later in life.

Key Terms

Lactose: A sugar found in milk and other dairy products
Lactase: An enzyme found in the gut that breaks down lactose so that it may be absorbed
Lactose intolerance: A condition marked by the inability or the decreased ability to digest lactose and therefore dairy products. Symptoms can include gastrointestinal discomfort, bloating, diarrhea and nausea.
Neurodegeneration: The gradual loss of nerve cells in the brain.
Parkinson’s disease: A progressive neurodegenerative disease marked by slowing and eventual loss of voluntary movement, tremor, rigidity and non-motor symptoms such as cognitive impairment. Symptoms typically arise after age 60.

Although vastly different, lactose intolerance (the inability to digest a key milk sugar) and many neurodegenerative diseases have an important point in common—symptoms aren’t present at an early age but appear after many years.

It’s a perplexing problem. The genetic code written in our DNA is largely the same code that we have all throughout our life. So what changes to allow these conditions and illnesses to crop up later on? According to a recent study led by Van Andel Research Institute’s (VARI) Viviane Labrie, Ph.D, and University of Toronto’s Art Petronis, Ph.D., it all comes back to aging and a second code that lays overtop of our DNA called the epigenome.

Simple to complex

Compared to neurodegeneration, lactose intolerance is a relatively simple condition to study. It is caused by a single gene called LCT, one version of which causes a gradual decline in lactase production, the enzyme required to digest the milk sugar lactose. About 65 percent of the global population has this version of LCT and, as a result, eventually becomes lactose intolerant.

“Given the way lactose intolerance develops with age, we thought perhaps the epigenome was involved due in part to its ability to change over time. We also believed genetic mutations may be setting the stage for how a person will age epigenetically,” said Labrie, a VARI assistant professor and first author on the study. “As in late-age onset neurodegenerative diseases, we knew there had to be something acting as a timer of sorts for triggering a person to become lactose intolerant. Epigenetic factors made sense.”

The epigenome is a set of molecular marks and factors that tells genes when to turn “on” and “off,” ultimately determining cell type and function. In lactose intolerance, the LCT gene gradually accumulates certain types of these marks throughout life, a process called epigenetic aging. As silencing epigenetic marks build up, the gene is slowly turned off. Once lactase levels get low enough, individuals develop lactose intolerance.

A matter of time

Labrie and her collaborators think a similar epigenetic program could be occurring in neurodegenerative and other late-age onset diseases but on a much larger and much more complex scale.

“Conceptually, we can borrow a lot of the same lessons we’ve learned from this story and apply them to neurodegenerative diseases, which are far more intricate,” says Labrie. “You can carry certain mutations that puts you at a higher risk for developing Parkinson’s, for example, and then 60 to 70 years down the line, enough marks have accumulated near these mutations to switch key genes on or off, triggering the disease.”

The picture still isn’t clear and will require much more work to fully unravel. However, the lessons garnered from how epigenetic aging occurs in a simple condition like lactose intolerance has broad implications for better understanding Parkinson’s, Alzheimer’s and many other diseases.

“It’s still the early days for this work,” Labrie said. “If we can uncover how epigenetic aging affects risk and onset for neurodegeneration, perhaps we can develop new ways to effectively stop the clock and give people more symptom-free years.”

Labrie V, Buske OJ, Oh E, Jeremian R, Ptak C, Gasiunas G, Maleckas A, Petereit R, Zvirbliene A, Adamonis K, Kriukiene E, Koncevicius K, Gordevicius J, Nair A, Zhang A, Ebrahimi S, Oh G, Siksnys V, Kupcinskas L, Brudno M, Petronis A. 2016. Lactase nonpersistence is directed by DNA-variation-dependent epigenetic agingNat Struct Mol Biol 23:566–573.