Issue 127 | Oct-Dec 2021

Staying ‘Young at Heart’ with Science

Is the ‘pump’ that powers our bodies capable of repairing itself? Current research offers some promising evidence that the lifespan of our hearts can be extended.

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Keeping A Steady Beat

Cardiac stiffness is all too common in ageing hearts, and research shows a similar situation at the cellular level. A collaboration between the Mechanobiology Institute and the Yong Loo Lin School of Medicine at NUS will attempt to bridge the gap between basic science and clinical practice to find practical solutions.
    
   
Ageing is a feature of life, and all organisms experience it. Lifespans vary greatly from species to species — bowhead whales live for an estimated two centuries, while mice might live only a few years. This does tend to make one wonder why this happens, and then, to perhaps ask why ageing is a feature of life anyway. Professor Li Rong of the NUS Mechanobiology Institute (MBI) and Professor Roger Foo (Medicine ’92) from the NUS Yong Loo Lin School of Medicine (NUS Medicine) are looking into this fascinating research area, and asking that very question, with a specific focus. “We are trying to understand ageing as a real science,” says Prof Li. 

As co-leaders of this project, Prof Foo (the Director of the Cardiovascular Disease Translational Research Programme, NUS Medicine) and Prof Li (who is MBI’s Director) both have considerable expertise in their respective areas. Prof Li’s work in examining cellular dynamics has employed integrated approaches that encompass biochemistry, genetics, quantitative imaging and fluorescence spectroscopy, mathematical modelling, quantitative genomics and proteomics (the large-scale study of proteins). A clinician, Prof Foo has led researchers from NUS Medicine and the National University Hospital in creating the world’s first map of the heart’s genes, and the switches that control them, and also established Singapore’s first Cardiac Genetics clinical service.

This collaboration is attempting to unlock the secrets behind how heart tissues, molecular and mechanical functions of heart cells, change as we age. What the teams discover could launch the development of innovative diagnostic methods and more effective treatments for age-related cardiovascular diseases (CVD). These might have direct applications in Singapore, where one in five persons will be above 65 years of age by 2029. “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,” explains Prof Li. The project’s main aim is to understand cardiac stiffness, one of the most recognisable properties of the ageing heart, at the molecular and cellular levels. 
 
Prof Li Rong
Prof Roger Foo

What does ageing really mean?

“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,” says Prof Li. 

Their hypothesis is that chronic mechanical and metabolic stressors lead to molecular and biomechanical changes that, over time, result in cardiac stiffness. This in turn contributes to accelerated pathologies of cardiomyopathy and heart failure. It is the word ‘chronic’ in the aforementioned description that refers to ageing. The scientific consensus is that ageing is the biggest risk factor for CVD in general, and Prof Li and Prof Foo agree. “We cannot prevent ageing — we are not going to become immortal,” says Prof Li. “The question is: What does ageing really mean?” When it comes to CVD, multiple ageing processes meet comorbidities and disease modifiers to create a complex story. 

To unpack this, the joint team is embarking on a journey into the microscopic core of the matter. This, of course, refers to the cell, and it immediately confronts observers with a conundrum. “We don’t know why cells age,” says Prof Li. “We know that cells have enormous ability to fix themselves, and replace damaged parts, and this is ongoing. So why can’t a cell be immortal?” When one scales this up to the level of an organ like the heart, the questions multiply. For example, do we know if cells in the heart can repair themselves, and if they can, do we lose that ability as we age?
   

We know that cells have enormous ability to fix themselves. So why can’t 
a cell be immortal?

Scar tissue

According to Prof Foo, there is good evidence in the animal kingdom that heart cells can and do regenerate. The zebrafish and the newt are only two examples of animals whose hearts can heal themselves. Even if one slices part of the zebrafish’s heart off, it can be regenerated to be as good as new. Of course, zebrafish and newts aren’t even mammals, but Prof Foo notes that researchers have seen something similar in mice. The NUS Medicine project is looking for answers there. 

The researchers have discovered that mice below a week old could heal from a heart attack. They form a bit of fibrotic tissue, just as the zebrafish and newts do, but it heals nicely and their hearts are as good as new eventually. Past this one-week window, a heart attack results in a permanent scar, says Prof Foo. We all learn that the heart is a muscle, so it is made up of muscle tissue. Given that our other muscles do heal, it seems intuitive that the heart should heal in much the same way. Of course, the heart is made up of specialised cells, so it does exhibit properties different to the skeletomuscular system. 

Prof Foo notes that heart muscles respond to increased stress by becoming larger. New muscle fibres are not added because cell division does not happen. Instead, existing cells become larger and the resulting tissue might scar. This is because the heart is incapable of growing new healthy tissue, which one might expect given that there are no stem cells involved, as there are in the skeletomuscular system. 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.
   

From Mice to Men?

This is what makes the historical research finding in mice particularly impressive, because mouse hearts do not have stem cells either. It is not the case that stem cells were present in the young mice, and then disappeared or atrophied. That healing happened without stem cells warrants further investigation. “When we looked at neonatal mice, the healing was from endogenous cells. There is now emerging evidence that this capacity is not entirely lost (as the mice age). So we will be looking for where these cardiac cells are, and how we can resuscitate this healing capacity. These are the research questions we’ll be looking at,” says Prof Foo.  

To find the answers, Prof Foo and Prof Li have assembled an interdisciplinary team. This joint team aims to conduct a rigorous study that looks into the molecules and structures of the heart, highlighting NUS Medicine’s exciting recent discovery of a novel protein molecular chaperone involved in cardiac pathology associated with the Singaporean population. With this as an entry point, the MBI team will investigate the molecular control of protein homeostasis and the heart’s ability to contract. 

Growing model organs

The team will also examine how cardiomyocytes (cells that generate contractile force in the heart) lose biomechanical function due to ageing, while looking into how the heart cell’s ability to communicate with its own components is affected. A specific novel hypothesis to be tested is that 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,” says Prof Li. “We just need to know what the problems are, which is where clinicians come in.”

The scientists at MBI are currently able to grow miniature organs in petri dishes. These organoids can be grown from samples originating in both the young and the old. In this way, the scientists can study differences and learn if they can reverse certain processes in older organoids or cells. This is one of the tools that might be useful in the collaboration between basic science at MBI and clinical research at NUS Medicine. 

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 told, this project will cover everything from molecules to cells and tissues, resulting in an integrated framework explaining 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,” says Prof Foo. 

Text by Ashok Soman. 
 
 
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