Why are tumors more common as we age? Why are we more susceptible to infection? And why does everything continue to function just a little bit worse for every day of our lives?
This whole process inspired a great Kinks song. More topically, Manel Esteller thinks it might be possible to slow some of it down — maybe even reverse it. Among other roles, Dr. Esteller is editor of the journal Epigenetics and director of the Cancer Epigenetics and Biology Program at the Bellvitge Institute of Biomedical Research, known as IDIBELL.
Only last week, I got to talk with Dr. Esteller about the epigenetics of aging and research he just published with colleagues comparing the genome-wide DNA methylation of newborns with that of very old folks — nonagenarians and centenarians. (Find that full PNAS paper, “Distinct DNA methylomes of newborns and centenarians,” here.) Here’s what we talked about.
How did you get involved with this study of the methylomes of very old and very young people?
There were a couple of reasons. One is that for the first time, we have the technology to get complete DNA methylomes by bisulfite genomic sequencing. And we were wondering about which samples to sequence, because this is a very expensive, and [produces] very complicated bioinformatics data.
And I thought that this would be a good model — a model of aging showing both of the extreme points of life, newborns and centenarians, to find the difference between the extremes. There have been several attempts to study DNA methylation and aging, but this is the first one that does it on the complete, whole-genome level.
So, other researchers will be able to use your data?
Yes—all the information is publicly available, so they can compare the information with their own data, and have other types of analysis, metanalysis, etc. It’s in the Gene Expression Omnibus — the GEO.
So how do your group’s recent results compare to other studies of methylation and aging?
What we’ve found is that, at these extreme points of life, when you become a nonagenarian or a centenarian, your epigenome has changed, clearly.
There are a couple things that happen there. One is that at the whole-genome level, there’s a loss of DNA methylation — hypomethylation. This loss of DNA methylation can be associated with a higher chromosomal fragility and the wrong expression of genes.
For example, we did an analysis in lymphocytes, and these started to show the expression of genes from the testes, the kidneys, etc. There’s something wrong, because DNA methylation is important to maintain tissue-specific expression, and when you get old, this system doesn’t work so well.
Together with this global DNA hypomethylation, there are some genes that gain methylation, and those are associated with cancer development. It’s well known that the main risk factor for cancer is to be old — aging is the main risk factor for cancer. This association here is between epigenetics, aging, and cancer.
Many of those were in nuclear-lamina associated genes, right?
Yes, some of them. These genes are in a particular domain in the nucleus of the cell, and it may be more prone to have these aberrations in DNA methylations.
In addition to these genes that are cancer-related, we see changes in DNA methylation in genes that are involved in immunology. When we become old, we’re more prone to infections—that’s known — and this can explain that story.
At the same time, you have better methylation of genes that are involved in the processing of fat and associations with diabetes. And as you know, when you become old, you have a higher risk of developing metabolic disorders like diabetes and others.
What findings did you find most surprising?
First, that the changes are happening at a global level. It’s not just a few genes that change DNA methylation.
Another interesting finding is that when you become old, you’re really in the process of having cancer. Normally there’s not enough time, because you die from another disease. But you’re in the process, because this global hypomethylation — but gain of methylation at particular sites — is the same as we see in cancer cells. But in cancer cells it’s more bizarre — the changes are larger — while here it’s [relatively] minor. But it’s the same process: global loss of DNA methylation, and gain of methylation at particular CpG sites.
And it’s well-known that when people die and they do an autopsy of different tissues, they find small tumors. Usually these people didn’t realize they had a tumor, but almost everyone.
Can you tell me about the expression of particular, non-tissue-appropriate genes in older people?
It’s clear that DNA methylation is a way that we use to control the right transcription of genes, in a tissue-specific manner, to control genes to express only in the neuron, or only in lymphocytes, or only in the glial cells of the brain.
Here the analysis we’ve done with T-lympocytes, and these cells show a loss of DNA methylation in some genes that should never be expressed in a T-lymphocyte. So they express genes associated with the testes, or neurons, or the pancreas, although they should never be expressed in the blood.
This happens because after 100 years, your cells haven’t methylated your DNA [properly]. A lot of mistakes build up over time. This is a process that happens step by step. It’s not something that happens one day. It’s a progression.
I have samples from people who’re in the middle of the process. They’re around 40–50 years old, and their DNA methylation is in the middle [between newborn and centenarian patterns].
Is it essentially a linear progression?
Yes, it looks like a linear pattern.
That reminds me of research I’ve seen recently that tries to guess an individual’s age from DNA methylation.
Yes. Looking at the DNA methylation profiles that we obtained for this article, you can predict the biological age of a sample. Now, that doesn’t mean the chronological age, because you can have a really unhealthful life — a lot of tobacco smoking, drinking, drugs, etc. — and this speeds up the process, making your DNA methylation look older, in fact.
Any idea how much variation there can be between apparent “biological” age and chronological age?
We haven’t looked at that in the study — the people that we’ve included here were pretty average people without out extreme behaviors, so we don’t know. In this case, biological age and chronological age were very similar. But in particular cases we saw that there were some differences.
There are probably a lot of studies that you can do — maybe there are ways that you can slow the process. You might be able to try to maintain a DNA methylation pattern that’s younger then you are really, chronologically.
Are you going to follow up on this research at IDIBELL? If so, what’s next?
Yes. We’re studying the relationship between these patterns of aging with senescence [cell death]. And we’re also studying these types of DNA methylation patterns in people with aging disorders, like Werner syndrome and progeria.
And we’re using mouse models to see if it’s possible to slow this aging in DNA methylation. Are there drugs or something in food that can slow these changes in DNA methylation?
In that mouse study, what compounds will you be testing?
The compounds that there are right now, some of them are used in leukemias and lymphomas — tumors. And these types of drugs, they’re hypomethylating agents. They induce a loss of methylation.
And for context, what we have in aging is global methylation loss, but gain at particular sites. So we’re touching one of the parts of the study — one that may be good, but maybe not the other. So we’ll have to see how it looks.
So are you looking at the effects of HDAC inhibitors?
Yes — HDAC inhibitors and DNA methylation inhibitors.
When do expect to get some useful results?
Obviously mice always take time, so I think that in about a year, year and a half, we’ll know whether these [treated] mice live longer than the others.
We’ll also explore if, in the food, you can play with the amount of folates — it’s a methyl donor — to see if it increases lifetimes.
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[Photo of the three phases of a bike stoplight by Jeffrey Beall. It's reproduced here under a Creative Commons license.]
Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, & Esteller M (2012). Distinct DNA methylomes of newborns and centenarians. Proceedings of the National Academy of Sciences of the United States of America, 109 (26), 10522-7 PMID: 22689993
