'We can identify these really early, before the clinical diagnosis': Epigenetic markers may help explain why Native Hawaiians are aging faster

Epigenetics, which means "above genetics," results in changes to the way an individual's genes act without involving changes to the DNA itself. For example, by adding molecules called methyl groups to DNA — a process called DNA methylation — epigenetics may turn genes on or off, or increase or decrease their activity.

Environmental factors ‪—‬ such as stress, diet and smoking ‪—‬ can fuel epigenetic modifications which can, in turn, lead to conditions such as colorectal cancer and heart disease.

But some of these epigenetic modifications can be reversed. This means that epigenetics can reveal potentially new and targeted ways of modifying disease risk, Alika Maunakea, a professor of anatomy, biochemistry and physiology at the University of Hawaii at Manoa, told Live Science.

Having grown up subsistence-living on a homestead in Hawaii, Maunakea said he learned from a young age that the environment plays a major role in shaping the health of the community.

Now, Maunakea has been researching epigenetics for over 20 years and heads the Maunakea Lab, which focuses on how environmental and epigenetic factors act at the molecular level to fuel health disparities. Live Science spoke with Maunakea to unpack how epigenetics affects health and what his research is uncovering about how epigenetics plays a role in driving health disparities in Native Hawaiians.

Sophie Berdugo: Can you explain how genetics and epigenetics interact in a health context?

Alika Maunakea: It's a little complicated because there's a lot of nuanced differences and variability in understanding the context behind disease risk that's not just shaped by genetic predisposition but also environmental factors and lifestyle, and even things that our grandparents experienced. That's where epigenetics comes in.

Epigenetics is this intermediate state between the environment and the genome, and it helps to regulate the genome. So, even if you carry a genetic risk, it doesn't necessarily mean that risk will play out.

They [genetics and epigenetics] relate to each other because there are certain regions in the genome where if there's a polymorphism — a change — in the sequence, that can sometimes cause a change in the epigenetic patterning. So there's this intertwined connection between the two. In some cases, it's hard to separate completely the genetic variability that's conferring a risk of a particular outcome with epigenetic variability that's contributing to that same risk.

If a lot of the epigenetic variability is contributing to that risk — rather than genetic variability — then there's a chance that there are lifestyle changes, things that you can modify at the individual level to reshape the epigenome, that would then help to reduce that risk. So there's still a lot of work [to be done] around understanding that connection, and it will require a multidisciplinary approach and integrating multiple types of data.

SB: What got you interested in this field?

AM: My great-grandmother was a Hawaiian healer — what we call "kahuna la'au lapa'au" — and she taught me "nā mea Hawai'i," so "all the things Hawaiian." There was a deep understanding and recognition for how maintaining a healthy built and natural environment around us actually does shape our own health and well-being.

I was really interested in understanding why our population, Native Hawaiians, has a higher prevalence of specific chronic conditions which we never had before Westernization, and trying to understand, why do we see it earlier, at a younger age, in our population compared to other populations? That was something that really bothered me. I wanted to understand that more at the cell and gene level, so I think I just gravitated naturally towards epigenetics because I think it explains that phenomenon.

My main goal is really to apply that information into more of a clinical, community-based setting where that information can be used to enable tools and approaches that would help reduce the onset of these disorders in our community.

What we're learning now is that, indeed, epigenetic processes can precede disease symptoms. We can actually identify some of the earlier indicators of disease trajectories before our clinical diagnosis, using epigenetic analyses. Trying to understand how that can play a role in enabling prevention is a real big thing in my lab right now.

SB: Which health conditions do you look at in your research?

AM: One of the conditions that we're looking at is type 2 diabetes, which has such a high prevalence amongst Native Hawaiians. It's three times higher than in other populations in the state, as well as an earlier onset of disorder: about 10 to 15 years younger where Native Hawaiians are diagnosed with type 2 diabetes compared to other populations in the state. [They also have] higher rates of mortality due to type 2 diabetes and other chronic conditions.

Pre-colonization [pre-Western contact in 1778], we never had [chronic conditions like type 2 diabetes] as an issue in our population. Our "kahuna la'au lapa'au" [Hawaiian healer], like my great-grandmother, had to invent new terms for them based on the phenotype [how the condition is presenting]. So we call it [type 2 diabetes] "mimi koko," which is "sweet blood."

It's unclear how much of our genotype is really related to that disease risk, but we think that environmental factors and the changes that happened after colonization and Westernization, and the changes in our lifestyle and our society — disruption and especially displacement — really drove us to this state where there's this higher incidence now of these conditions. And so we're trying to understand what, at the molecular level, is shaping those outcomes and how we can use that information to prevent that from happening in the first place.

One of the questions that really immediately came out was, what's really behind the earlier age of onset? Why do we not only have a higher prevalence, but why is it happening at a younger age? That question still remains to be clarified, but we think that certain traits, like obesity, modify that risk.

To get at that question, then, we really need to understand, at the molecular level, are there disruptions to the aging process in this population? Are there differences in vulnerabilities to aging in this population versus other populations that might be influenced by these environmental factors?

There's a phenomenon called "epigenetic aging," which Steve Horvath back in 2013 initially published a paper around, and identified that there are certain sites in the genome that are epigenetically regulated — by DNA methylation, in particular — that correlate with chronological age really well in a healthy population.

But there were some individuals that exhibited what we would call outliers in this relationship, where there were cases where individuals seem to have higher estimated epigenetic age compared to their chronological age. So they would seem [to be] biologically aging faster than they should be normally. And then there were also people at the opposite end, where their estimated epigenetic age actually appeared younger than their chronological age. And we think that corresponds to health in general.

We found something similar in the Native Hawaiian population: There's a higher frequency of individuals in the Native Hawaiian population that seem to be, at the molecular level, aging faster than they should be compared to other populations, such as white populations and Japanese American populations in the state of Hawaii.

And we know that corresponds to the higher prevalence of these chronic conditions that we see, like diabetes in the Native Hawaiians compared to these other populations, as well as some of these risk factors, like obesity. And we've seen it in our community. Individuals that are in socioeconomically poorer neighborhoods tend to have this accelerated aging.

We're learning that there are certain individual-level lifestyle factors that can actually potentially modify that [epigenetic] risk. We have identified that even amongst Native Hawaiians that are living in socioeconomically poorer areas, at the individual level, if there's a higher degree of physical activity as well as education — and even in some cases, nutrition — there tends to be closer-to-normal biological aging amongst those individuals even within that population.

And so that told us that while there's a higher risk for individuals that have this accelerated aging of diseases like diabetes, that risk could be potentially modified by engaging in healthier lifestyle changes.

Now we're not only seeing that there's this disparity and potentially a mechanism that might underlie that disparity but some clues into potentially what types of environmental factors might be shaping that molecular process.

We have one pilot study that we published a few years ago showing clearly that amongst Native Hawaiians that are diabetic, when they engage in a lifestyle intervention that includes social support, in particular, they not only improve their glycemic control — which is the main purpose of this intervention, really — through this lifestyle modification over a 12-week period, but we also showed that the cells that relate to inflammation, the behavior of those cells, is actually modified by that intervention, and they actually seem to be less inflamed. [Glycemic control is the management of blood glucose levels.]

The epigenomes of those cells are also being modified to a pattern that's similar to a nondiabetic-like state.

So we think those cells play a role in the pathology and the etiology [cause] of the disease and metabolic dysregulation in diabetic individuals. But we also think that modifying their inflammatory state might actually help with improving the glycemic control. So we're trying to understand how much of the epigenetic patterning might be associated with that [inflammation].

We're finding very clear associations that indicate that potentially we can use that information also to identify more effective interventions that might actually target this [epigenetic] process, where we can reduce the inflammatory state of these individuals at the cellular and molecular level.

We're really hoping that it can be useful for prevention, because we can identify these really early, before the clinical diagnosis. [Editor's note: These findings have not been published in a peer-reviewed journal.] And we think that if we can do that at the individual level, especially in a high-risk population, then we can recommend appropriate interventions — or optimize those interventions that exist — to target changes in the epigenome that then have this effect on the physiology and the outcomes of the condition itself. So that's something we're trying to develop further.

SB: How resource-intensive is it to inspect an individual's epigenome?

AM: It is resource-heavy, unfortunately, at this stage. So I think that it will take time to develop new technologies and tools that are more targeted and that can be used in more of a clinical setting.

But with genome sequencing being more cost-effective than it ever was before and the reduced cost that it's now moving towards, that does increase the feasibility to adopt some of these approaches.

Editor's note: This interview has been condensed and edited for clarity.