Full text of biomedical scientist Georgina Ellison-Hughes’ talk titled “What Becomes Of The Broken Hearted: Rejuvenating Hearts” at TEDxRoyalTunbridgeWells conference. In this talk, she offers a personal touch to her journey of discovering the regenerative potential of the adult heart and describes the use of senolytics to rejuvenate heart repair and regeneration, enabling people to live longer, fuller, healthier lives.
Georgina Ellison-Hughes – Biomedical scientist
My first love was my grandfather. He was the kindest, most generous and loving man, and my brother and sisters used to say that I was his favorite.
He suffered a fatal heart attack at the age of 79 when I was 16, and I was mortified. At the time, my mother told me that he died because it was his age, he was old, and he had a bad heart and it just couldn’t hold out any longer. And the classic that you always hear: ‘He had a good innings.’
My heart hurt.
Like his grandfather, my grandfather would have liked me to have gone into law. He was so proud that out of seven grandchildren, I was the one to be the lawyer. His favorite, the lawyer.
I liked the idea. But after his death, I had other ideas. I had many questions. I wanted to understand, why couldn’t his heart hold out any longer, and what role does age play in the health of our hearts?
What if we could have a better and longer innings? If I could find out the answers to my questions, I could stop grandfathers and grandmothers being taken away from us too soon.
I wanted to be a scientist. So my journey began with a PhD sponsored by the British Heart Foundation, and it was during this time that I discovered something remarkable.
So rather than cardiac or heart muscle, it all started with skeletal muscle, which are the muscles that allow us to move. I was investigating the ability of skeletal muscle to repair and regenerate and form new muscle cells after injury.
With a microscope, I was identifying these small, immature regenerating muscle cells that express proteins that were reflective of them being newly born or newly formed, and they look like this.
Now, switching to the heart, which, at this time, which was 2002, was considered to be a postmitotic organ. Now, this means that your heart doesn’t have any abilities to make new heart muscle cells. So the heart cells you’re born with are the same ones that you are going to die with.
At this time, it was thought there was no heart muscle cell regeneration or renewal taking place in the adult heart.
So in every experiment, you need a control sample, a sample where you do not expect anything to happen, and then you compare to the sample where you do expect something to happen to your control sample.
So my PhD supervisor advised me to use heart tissue in my experiments as my control sample, because the heart cannot make new heart muscle cells, so I did.
I did my experiment. But every time I did my experiment, I kept seeing these small, immature, regenerating muscle cells that express those same proteins, and they look like this.
So I went to my PhD supervisor. He told me to repeat the experiment, so I did.
And being a scientist, I repeated the experiment many, many, many, many times, but I just kept seeing them, they just kept popping up. I mean there wasn’t loads of them, but there was like one or two of them per field of view, and hey, for an organ that can’t regenerate, there’s definitely something going on here.
So I went to literature and I did some reading, and I read a paper that had been published by a group in America, where they have showed these small, immature, regenerating heart muscle cells in the adult human heart after injury.
Well, could I be seeing the same cells in my experiments?
Now, it just so happened that my PhD supervisor, he knew one of the investigators that was doing this work in America. So he wrote to him and he told him about my findings.
The next thing I knew, I was on a plane to New York for a three-month lab visit to understand more about the regenerative capacity of the adult heart. That three months turned into four years. I graduated my PhD, and I trained with some of the greatest scientific and inspiring minds to discover that the adult heart has a rare population of resident stem cells that can give rise to new heart cells.
My biggest and strongest contribution to understanding the role of cardiac stem cells in heart repair and regeneration came through exploring a rare cardiac condition called ‘broken heart syndrome’.
Now, I’ve suffered a broken heart, and I believe that some time or another, we’ve all suffered a broken heart. So your boyfriend or your girlfriend dumps you, your whole world’s going to end, literally.
Loved one dies, grandfather dies suddenly, and your whole world comes crashing down. Your heart hurts, or something biological does actually happen to your heart following emotional distress, and people can literally suffer from a broken heart.
So what I discovered was that in broken heart syndrome, a small number of heart muscle cells in a particular location in your heart, they die, and then this can affect the ability of your heart to pump blood, and your heart goes into failure for a small amount of time.
But remarkably, in broken heart syndrome, the resident stem cells in your heart are able to regenerate and replace those cells that are lost, and your heart recovers.
Now, this whole process can take between two to three months to fully get back to normal, which ironically, could be about the same time it takes your emotional state to recover too.
Now I know what you’re thinking. You’re thinking to yourself, ‘Well, if there’re stem cells in the heart that can regenerate new heart cells and the heart recovers, then why do people actually die from a heart attack?
Why can people actually die from broken heart syndrome?
Well, I ask myself these questions all the time, and they’re in the back of my mind in every experiment that we do. And I can tell you that there are many, many, many reasons, but one of those reasons is age, old age.
So aging is the greatest risk factor for many life-threatening disorders, including cardiovascular disease, neurodegeneration, and cancer. As we age, our cells age. They become dysfunctional or abnormal.
Aging leads to an increase in a phenomenon known as cellular senescence in several tissues, including the heart. These senescent cells, they have a limited ability to replicate. They build up in our bodies, and they refuse to die.
The main problem with a senescent cell is that it releases chemicals that can then be harmful to nearby cells, eventually making them become senescent and dysfunctional too.
The build-up of senescent cells in our bodies promotes aging and the conditions that come with it, like osteoporosis, dementia, and cardiovascular disease.
Recently, I’ve been working with clinicians and scientists at the Mayo Clinic in America, who have discovered a new class of agents called senolytics.
‘Senolytics’ comes from the words ‘senescent’ and ‘lytic’, which means destroying. They disable or eliminate senescent cells.
Now, many classes of senolytics have already been discovered and not all of them are pharmacological. Some of them are flavonoids, which are present in fruit and vegetables.
So senolytics have been shown to disable and eliminate senescent cells, leading to improved physical function and extended lifespan and healthspan.
Specifically, senolytics have been shown to improve conditions such as cataracts, diabetes, Alzheimer’s disease, kidney problems, osteoporosis, clogged arteries, and the age-related loss of skeletal muscle.
So why not cardiac muscle as well?
So in terms of the heart, work by us and others has shown the senescent cells accumulate in your heart and blood vessels with age, contributing to cardiovascular disease.
My team have recently shown that old age impairs the ability of your heart to regenerate and repair. We have found that as a person ages – so, in the human heart – their cardiac stem cells become senescent and dysfunctional.
In fact, by the time a person reaches the age of 75 years old, approximately 50% of your cardiac stem cells are senescent. This means the ability of your cardiac stem cells to regenerate and replace cells that are lost as a result of damage, injury, or through broken heart syndrome declines with age.
So we wanted to understand, like the other age-related diseases where senolytics have shown an effect, could they also have an effect on heart repair and regeneration?
So together with our colleagues from the Mayo Clinic, we published a paper last year, where we showed that if we disable or eliminate senescent cells in the aged heart using senolytics, we can rejuvenate the heart’s regenerative potential. In that we see cardiac stem cell activation, new heart cell formation, and improved cardiac function.
So considering ours and other people’s findings, senolytic approaches could be therapeutically relevant in treating patients. And the first clinical trial on senolytics was published last year. They used patients who have idiopathic pulmonary fibrosis. This is a cell senescent-driven fatal disease.
And they showed that after giving just a short course of senolytics, these patients had improved physical function as evidenced by increased walking speed and endurance.
With the research and the clinical trials that we are currently undertaking, we have a very real chance of improving lifespan, but more importantly, healthspan.
Ultimately, we hope to be able to delay the onset of multiple chronic age-related diseases, including cardiovascular disease, enabling people to live longer, fuller, healthier lives.
Perhaps grandmothers and grandfathers can have a longer and better innings; fewer hearts will be broken. But even if we do suffer from a broken heart, we will know ways to rejuvenate the heart’s regenerative capacity, which I’m sure you’ll all agree is really exciting.
And by the way, Grandpop, I became a scientist. And I think I did all right.