Can we prevent the heart from aging? This landmark genetic study is a start

Hearts are not made to be broken. But with age, it happens. Even with a healthy diet and exercise, as our age slowly increases, the risk of clogged arteries, fragile blood vessels, and ultimately heart failure also increases.


Scientists have long sought to unravel the mystery of how aging is linked to an increased risk of heart disease, a predominant killer of our time. It’s a difficult problem: many biological aspects, ranging from nature to diet, can subtly influence heart health. To unravel the mystery, some experiments spanned more than half a century and involved hundreds of thousands of people.

The good news? We have clues. With age, heart cells drastically change their function, eventually finding it difficult to contract and release. A new study published in natural aging took an in-depth look at the genetic code to understand why this happens.

From a dozen volunteers aged 0 to 82, the team sequenced the entire genome of 56 heart muscle cells, or cardiomyocytes. The result is the first landscape painting of genetic changes in the aging heart. As we age, the heart suffers a double whammy at the DNA level. The genetic code of cells physically breaks down, while their ability to repair DNA is eroded.

It’s a huge surprise. Like brain cells, cardiomyocytes are the biological end game, in that they can no longer divide into newer, younger offspring. These types of cells usually have a kind of protective “armor”, in that they are less susceptible to mutations.

This is not the case for cardiomyocytes. Compared to neurons, cells accumulate DNA damage rapidly with age, and at a rate three times faster, although neurons are a very complex and particularly delicate type of cell.

“As you get older and get more mutations, you add deleterious effects that could push the heart past a tipping point toward disease,” said study author Dr Ming Hui Chen, cardiologist at Boston Children’s Hospital. “It can get to a point where so much DNA is damaged that the heart can’t beat well.”

The results give us an overview of the aging heart. Like a puzzle, they “provide a paradigm for understanding the influence of aging on cardiac dysfunction,” the authors write.

give your heart a break

Cardiomyocytes are tough creatures. Imagine a pump that automatically and reliably injects just the right amount of blood, with reasonable pressure, to flood your entire body with nutrients. If you’ve done any plumbing work, it’s tough. Yet these cells work in sync, mostly without a hitch, for your entire life. It’s a delicate balance: too little pressure or speed robs your brain and other extremities of blood. Too much, and it’s like squirting a big hose of liquids, at high pressure, into a little weed growing in a starter pot.

Like a rubber garden hose, cardiomyocytes wear out with age. Most cases of heart failure occur in people over the age of 65, even when they are relatively healthy, i.e. without high blood cholesterol, blood pressure or any other risk factors running. But not at all.

“Some people at low or intermediate risk, according to traditional risk factors, still have heart disease, suggesting that additional, unidentified factors may be important,” the authors wrote. What else causes heart disease in the elderly population?

Free the DNA from my heart

To tackle the question, the team turned to a powerful genetic tool: single-cell sequencing, which transcribes the DNA string of each cell analyzed. The technique captures individuality – for example, genetic and other changes – that would otherwise be obscured by analyzing and averaging hundreds of cells simultaneously.

The diversity of a cell’s genome was central to the study design. “This is the first time that somatic mutations have been examined in the human heart at the single-cell level,” said study author Dr Sangita Choudhury.

The team looked at how the DNA signature of heart cells changes with age. These types of mutations are called “somatic mutations” because they cannot be passed on to the next generation.

Not all cells are built the same. Some, like liver cells, can take a fair amount of damage and rebuild themselves. Others, like cardiomyocytes, can no longer divide and must sustain any DNA damage themselves. With age, these cells can accumulate genetic mutations. They’re tricky: most don’t have obvious effects, but some, like a horror movie villain, can silently trigger cancer cells, or even kill them. These mutations have previously been linked to coronary heart disease, a major cause of heart problems as we age.

Trying to capture the mutational signatures leading to heart disease, the team dove deep into the genes of donated hearts from people ranging from infancy to the elderly. By isolating the nuclei – the round, apricot-seed-like structure that houses DNA – they evaluated their method and then compared the genetic sequences of three different age groups.

They focused on one main difference: single nucleotide mutations (also called single nucleotide polymorphisms or SNPs). These changes are simple: they are a single letter swap in the genome rather than, say, an entire piece that is reversed or duplicated. SNPs, when evaluated as a whole, contain a wealth of information. They are the most common form of somatic mutations.

Like pins marking journeys on a world map, with enough SNP mutations, it is possible to construct a complete “map,” or signature, related to specific biological processes or diseases. For example, there is a map of cellular changes related to smoking or DNA repair issues.

“Understanding mutational signatures and their mechanism of formation could lead us to uncover the mechanism of DNA damage and disease progression in the aging heart,” the authors said.

Sequencing nearly 60 samples, the team then worked on an algorithm to analyze the data, comparing it to a well-known cancer signature database called COSMIC. DNA changes increased with age, with mutation types falling within four different signature types. Signature A, for example, swapped the DNA letters C and T. While that might not seem like much, imagine replacing all the Cs in this article with Ts, or vice-versa, that would break up the whole text.

By digging deeper into the molecular underpinnings of the signatures, the team found a potential culprit of aging and heart dysfunction: oxidative stress. An unfortunate byproduct of a cell’s normal metabolism, these molecules act like little cannonballs, wreaking havoc inside cells, DNA and their membranes. While younger cells normally have a way of repelling vicious attacks, older ones gradually lose this ability. The result is not pretty. Heart cells, for example, can end up with damaged DNA letters while simultaneously destroying their genome repair mechanism.

In a way, it’s not that surprising, Chen said. “Because the heart is always pumping, it uses a lot of energy,” which produces chemicals that can damage DNA. What came as a shock was the heart’s special ability to parry damage. Cardiomyocytes have the power to double their chromosomes, buffering themselves against relentless attacks on their DNA.

So far, the study only shows that somatic mutations increase with age, which correlates with damaged heart cells. If the DNA letter exchanges cause cardiac injuries are yet to be determined. But the study is a first for dissecting heart disease at the single-cell level on a large scale. It’s like going from amateur binoculars to the James Webb Space Telescope: we can now analyze every cell, like a star in the sky, by analyzing its DNA inside an aging heart.

Aside from cardiomyocytes, “we also want to look at different types of cells in the heart,” Choudhury said. “We have only touched the tip of the iceberg.”

Image Credit: AnaitSmi /

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