Epigenetics and Aging: A Conversation with Dr. Patrick Allard

It is commonly stated that we are the product of both our genes and our environment. The newly emerging field of epigenetics, therefore, can be thought as a bridge between this “nature” vs “nurture” perspective, providing insight into the murky ways we are shaped into being outside of our own genome (CDC). More specifically, epigenetics refers to changes to gene expression, through a mechanism like DNA methylation, histone modifications, or changes to RNA, caused by environmental exposure. It can be a product of the conditions we were exposed to prenatally, the foods we eat, the chemicals we are exposed to, and the life experiences we are granted, among an assortment of other potential determinants (CDC). Only more recently are we gaining a better understanding of such factors and also the ways in which these epigenetic markers, and changes to gene expression, can potentially be passed onto future generations, further cementing the importance of the field. In an effort to learn more about this field, and particularly the overlapping influences of the environment, aging, and epigenetics, I was fortunate enough to sit down for a conversation with Dr. Patrick Allard. Dr. Allard heads the Allard Lab for UCLA’s Institute for Society and Genetics and the Molecular Biology Institute, and conducts research covering the transgenerational effects of environmental chemicals, epigenetics, and toxicology among other topics. He was awarded the Global Toxicology Scholar award by the Society of Toxicology in 2011 and was governor-appointed to California’s Developmental and Reproductive Toxicant Identification Committee in 2014 in recognition of his research contributions. At UCLA, Dr. Allard serves as an Associate Professor in the Department for Society and Genetics at UCLA, teaching courses that tackle many of the same questions he explores in his research.

Below is a transcribed conversation, edited for clarity, I had with Dr. Allard about his work researching epigenetics through the context of the piece he published in Epigenetics Insights in 2020, along with Rio Barrere-Cain, entitled “An Understudied Dimension: Why Age Needs to Be Considered When Studying Epigenetic-Environment Interactions.”

Maxwell Grollman: Hello Dr. Allard, thank you so much for taking the time to speak to me about the work you and Rio Barrere Cain published in Epigenetic Insights and the larger topic it covers. I wanted to first start the conversation by asking what sparked your interest in researching the intersection of epigenetics and aging?

Dr. Patrick Allard: So first of all, I just want to make it clear that the piece that you're referring to is not an original research paper, it is a perspective piece. In it, we wanted to take a look at three intersections: epigenetics on one hand, aging on the other hand, and also the environment as a third component. To answer where the question came from, across my own training, I bounced between different fields during my undergrad, my masters, my PhD and then my postdoc. As a master student, when I was still in France, I did a master's in biology of aging, and then I completely changed course, and eventually went into toxicology and epigenetics. This article presented a great opportunity to bring all of these components together.

Max: As you note in the article, there seems to be a fairly large gap in the literature on the topic studied for your piece. Did this research gap cover all intersections on the topics of epigenetics, aging, and the environment?

Allard: So there is a lot of literature on the intersection between aging and epigenetics, but there's not a lot on how the environment can play into that. When we started digging a bit more into how aging is included in studies, especially in clinical trials, we then realized that it's really an understudied dimension. It is not just us saying that either, there are reviews and other perspectives that picked up on this fact as well, with an often mentioned cause being the underrepresentation of elderly patients in clinical trials. For those reasons, we felt it was important to bring forth this intersection in our own research, and also hopefully in other people's research as well.

Max: I just wanted to quickly touch on that last point you brought up about the underrepresentation of elderly patients in clinical trials. Is there a clear understanding of what's causing this discrepancy and does this lack of representation pose an issue to answering fundamental scientific questions?

Allard: There is some rationale behind it. Elderly patients tend to have often a lot of what are called comorbidities, which refer to a set of larger underlying health issues, which could make pharmacological trials (i.e. testing drug safety/efficacy) more difficult. Take a cancer treatment clinical trial for example. If an enrolled person has a lot of other potential health issues or manages a chronic condition with drugs that could interact with the treatment in question, the effect of the drug may be masked by these complicating factors, and achieving clear research results might be much more difficult. Because the natural progression of aging often comes with these sorts of health issues, even a well-intentioned researcher might struggle to find healthy individuals over 65 who fit strict protocol requirements. And that gets to your second question. If we really want to have research that can be applicable to the real world, we need to start fully accounting for the ever growing elderly population and subsequently those with comorbidities and who take varying medications. Even though it’s difficult to implement, I think that is definitely the direction that we want to get into because elderly patients are often disproportionately facing conditions such as cancer and heart disease, and yet are still underrepresented in clinical trials trying to treat such issues. I understand the balance here is difficult between the scientific perspective of wanting to get clear interpretive data, and the medical perspective of obtaining results that translate directly for patients, but walking this thin line is necessary.

Max: In addition to this age disparity, one other aspect of your review I found interesting was the collection of articles about the intersection of epigenetics and aging that used model organisms as opposed to humans. How can roundworms and mice tell us anything useful about us?

Allard: In my lab we don't work with patients, but we do work with animal models, and these animal models can actually tell us a lot of different things. For example they can help provide insight into how chemicals are metabolized at different ages. Because working with patients is so complex, understanding metabolism at a molecular level is greatly facilitated with model organisms. These simpler species can model aging and chemical metabolism in such a way that it allows us to more broadly understand how the epigenome works. All of these things are so incredibly difficult, and of course there's ethical issues associated with it. To do in humans, it's a lot simpler to use alternative model systems to model all of this and understand the directions and the implications of those kinds of interactions.

Max: One use for this animal-based research as noted in your work is as a model for the epigenetic clock, which gives a mechanism for how we could quantify the relationship between aging and epigenetics. Could you explain a little bit more about the epigenetic clock, and is it a tangible measurement, or just like a helpful concept that we can use?

Allard: It's more than a concept; it is actually a tangible measure of aging in many organisms. There are actually several clocks, by the way, not just one clock, named after the different people/groups of people, who have proposed different sets of epigenetic marks to study after observing that they change over time.We first have to look at the clock developed by the UCLA researcher, Dr. Steve Horvath, which was one of the first ones and is perhaps still the most well known one. The Horvath clock looks at some DNA methylation sites around the genome, referred to as methylated CpG, that gain and lose in methylation with age. By studying the changes at all these different loci, or genetic sites, he was able to actually come up with a pretty accurate measure of chronological age. And that really opened the door to a lot of fantastic work by Horvath and other researchers who’ve since shown that not all tissues seem to run on the

same kind of clock and there's some tissues where the clock seems to be more as synchronous or desynchronized, especially tissues that seem to be more prone to cancer. More recently, the research has been progressing to answer questions such as how much the epigenetic clock itself could assess the likeliness of a tissue to lose normal function and enter a disease state. It's still a hot, ongoing topic of research with much left to understand but there is a sense that the epigenetic clock will have major implications in terms of disease.

Max: It definitely sounds like an exciting area of research! In a chart included in this area of the article about epigenetic clocks, you organize previous research by the species studied, the environmental factors considered, and ultimately the accelerating or decelerating effects observed. As a layperson, am I correct in assuming environmental exposures can act as both a gas pedal and brake in terms of being able to speed up and slow down the epigenetic aging process, but reversing the clock isn’t possible?

Allard: Are you asking if we can only slow things down versus being able to completely reverse them?

Max: Yes, so for example, someone’s epigenome is majorly impacted by PTSD or traumatic stress, could it be possible to fully undo that damage or just prevent it from getting worse?

Allard: It is such an important question, and I do not think we have a good answer. I mean of course aging research is a huge field, and every few years you hear about a different molecule that has anti-aging properties. And I do not mean strange supplements you find on Amazon, I mean well established researchers from institutions like Harvard and MIT saying that resveratrol, for example, which you find in red wine, is a great to take to slow down aging. Then, it sort of falters in clinical trials and doesn't really do the things that you hope it would actually do. In terms of modifying our epigenome, one has to be very careful because right now most of the tools that we have to manipulate the epigenome, i.e. through DNA methylation, histone modification, and small mRNAse are non-specific; they are basically a giant hammer to the entire epigenome. We know how to bring up and down DNA methylation, and particularly we know how to bring down DNA methylation a lot more than we know how to bring it up, but these tools only work to modulate the genome from a very broad perspective. If you ever wanted to reverse things, however, you would need to find something that somehow could replicate what the cell used to be. And it's not like bringing up all DNA methylation, or bringing all DNA methylation down, you’d need to control how some specific loci gain or lose DNA methylation, which we’re not yet able to do. Luckily with the emergence of CRISPR, those sorts of tools are being developed, and there is hope they could be widely implemented in the future.

Max: I was actually going to bring up CRISPR because it seems like CRISPR has brought the level of precision to genetic engineering that the field of epigenetics could potentially benefit from. Are the tools in development that you mention, CRISPR-esque in their accuracy and ability to advance research?

Allard: Well, we are getting there. There is technology that uses enzymes which add and remove DNA methylation and modify histones, and you can bring that enzyme close to the actual gene that you are trying to change, but epigenetically speaking, you cannot have perfect precision. The issue is when you think about the effects of aging, it is something that is happening throughout the entire genome in different directions, and we do not have the tools to try to modulate things perfectly. Unless we can identify just very few specific loci that are responsible for most of the impact of age, on the epigenome, and therefore on the function of the cell, I am not sure we'll ever be there. I think what we can do though is really try to understand what seems to be impacting our epigenome the most, especially as we age, and if we can try to protect ourselves from that, then maybe just from a knowledge standpoint, maybe we have already made great progress. By achieving this, we will have gained some major, useful, and applicable insights. But beyond that, in terms of finding a pill to suddenly be younger, probably not too likely.

Max: So maybe this research won’t lead to a fountain of youth, but could a more realistic outcome be clearer guidelines on how safe it is for individuals of different ages to be exposed to a chemical with epigenetic potential? Could research potentially tell us, “here is a chemical that’s unsafe for older adults, or unsafe in certain dosages”?

Allard: I think that's a fantastic way to look at it. It might be difficult to compartmentalize products based on age, especially since you have to think about the life cycle of a product, and a product can degrade and be released into the environment and therefore affect a lot of people from different ages. I do not think you can easily compartmentalize chemicals, but I do think the idea is to bring up this issue of age, health and chemicals exactly to the level at which you're thinking at: meaning a much higher level. Ideally, age would become an integral part of what we call risk assessment, where, before you even put a product on the market or release it into the environment, you explicitly include age as a metric that’s being considered for safety purposes. This would impact clinical trials, chemical safety assessments, toxicity tests, manufacturing processes, environmental pollutants, basically a wide range of influential factors we all interact with every single day.

Max: Is it fair to contextualize the lack of understanding on how the chemicals we are exposed to impact the genome within a larger history of under-regulation and lack of testing by manufacturers and companies of these products?

Allard: Yes, absolutely. It's a very onerous process to assess the safety of a particular compound. We are ever-evolving, changing beings, so trying to assess the safety of every single thing that could happen to us is very difficult, and so the industry sticks to what the regulation asks for. And if the regulatory bodies that make the laws are not asking for that, the industry is not going to follow. They are not going to volunteer to perform extra studies to look at these other dimensions that are not written in the law, so we need to change the law first. The trouble is that in order to change the law first you need really, really good evidence that this is indeed something that is worth changing the law for, and we’re still building that evidence. More or less, my piece is ultimately a call for doing more of this research and collecting more of this evidence.

Max: Thank you so much for your time and your work on this important issue.

Allard: That’s what I’m here for.

References Barrere-Cain, R., & Allard, P. (2020). An Understudied Dimension: Why Age Needs to Be Considered When Studying Epigenetic-Environment Interactions. Epigenetics Insights, 13. https://doi.org/10.1177/2516865720947014 Centers for Disease Control and Prevention. (2020, August 3). What is Epigenetics? Centers for Disease Control and Prevention. https://www.cdc.gov/genomics/disease/epigenetics.htm.