Human hearts grow stiffer with age, allowing less blood to fill the chambers for each beat. While much research has investigated components of heart stiffness at the tissue level, less is known about the contribution of the cellular components.

This has drawn the attention of two scientists from the National University of Singapore (NUS) who are investigating how the heart ages with the hope of being able to counter this process.

“If we understand how ageing works at the cellular and molecular level, we might be able to slow it down and reduce ageing as a risk factor for diseases,” explained Professor Rong Li from the NUS Mechanobiology Institute (MBI) who co-leads the project with Professor Roger Foo from NUS’ Yong Loo Lin School of Medicine.

“Our hope for this collaboration with clinical scientists is to bridge the gap between what we study in the lab and clinical observations. So, when clinical scientists like Prof Foo tell us that they see stiffness in the heart, we get excited because we see that in cells.”

Professor Rong Li

 

Unearthing the secrets to immortality in cells

Cardiac stiffness—one of the most recognisable properties of an ageing heart— starts at the molecular and cellular levels.

The researchers hypothesised that chronic mechanical and metabolic stressors lead to molecular and biomechanical changes that result in cardiac stiffness over time, which in turn contributes to heart muscle disorders and heart failure.

Foo noted that heart muscles respond to increased stress by becoming larger. But new muscle cells are not added to the heart when this happens. Instead, existing cells become larger and the resulting tissue might scar because the heart does not have stem cells and is hence incapable of growing new healthy tissue. A common consequence of this scar tissue, which also forms as a result of heart attacks, is a degree of stiffness that afflicts the heart.

While researchers at Duke-NUS have been using laminin-221 to regenerate heart muscle cells, Foo and Li have assembled an interdisciplinary team to look into the molecules and structures of the heart as related to heart stiffness, highlighting NUS Medicine’s exciting recent discovery of a novel protein molecular chaperone involved in heart disease associated with the Singaporean population. With this as an entry point, the MBI team will investigate the molecular control of protein homeostasis and how this affects the heart’s ability to pump.

 

Growing model organs

The same team will also be examining how cardiomyocytes—cells that make the heart pump—lose their function with age while looking into how a heart cell’s ability to communicate with its own components is affected. A novel hypothesis that they hope to test is whether the misfolding of proteins in cardiomyocytes is linked to chronic mechanical stress experienced by force-bearing structural proteins.

“This is the beauty of science today, because we have the tools to fix problems at the cellular level,” said Li. “We just need to know what the problems are, which is where clinicians come in.”

Similar to how the researchers at Duke-NUS have been growing mini-brains, the scientists at MBI are currently able to grow miniature heart muscle in petri dishes. These organoids can be grown from samples originating in both the young and the old, allowing scientists to study the differences and learn if they can reverse certain processes in older organoids or cells.

At the tissue and organ level, the scientists will be studying the behaviour of cardiomyocytes in the context of complex cardiac tissue microenvironments in the ageing heart.

All in all, the entire joint MBI and NUS Medicine project will encompass everything from molecules to tissues, resulting in an integrated framework that will explain age-associated cardiac stiffness.

“MBI’s strong expertise in proteins as the building blocks of cells (is particularly relevant) ... because the cardiac apparatus is contractile. So cardiac stiffness really lends itself to being studied from a bioengineering perspective,” said Foo.

 

Adapted by Dionne Seah from Staying ‘young at heart’ with science.