Are there really chemicals inside us that could lead to some age-defying interventions in the future? Could our hormones hold the map to the fountain of youth?
This is Hormones: The Inside Story, the podcast from the Society for Endocrinology about the tiny things inside us pulling the strings.
Not to start on a bum note, but every single one of you listening to this podcast will die, we all will. And if we’re lucky - we get to grow old before that. But the ageing process can be cruel, wearing away at our strength, mobility and cognitive function, we can lose our eyesight, hearing or the memories that make us who we are.
The quest to cure ageing has been going on for thousands of years, and unless there are any old Arthurian knights in hiding we don't know about - it’s been largely unsuccessful. But could we finally be within reach of some genuine interventions that don’t cure a specific disease, but prevent the ageing processes that lead to them?
I’m Georgia Mills, and in this episode we’re finding out whether we can hack our hormones to slow down ageing?
Andrew: I actually changed career because of a graph, so I started out toward the end of my physics Ph.D. wondering what it was I was going to do with my life. And this graph is - it's actually quite a simple graph - it's the graph of how likely you are to die based on how old you are.
Georgia: This is Andrew Steele, scientist and writer, and author of Ageless, The New Science of Getting Older Without Getting Old
Andrew: And of course, all of us know that older people are more likely to die. But just how much really shocked me. So I'm currently in my 30s. That means my odds of death per year are somewhere in the region of one in a thousand. And I quite like those odds. But the problem is that those odds will carry on increasing as I get older and in fact they double in humans about every eight years. So that means if I'm lucky enough to make it into my 90s and there's no progress in medicine in the intervening time, my odds of death every year will be somewhere around one in six. That's sort of life and death at the roll of a dice. And so, you know, as a human, you can look at that. I think that's terrifying about this exponential wall of mortality coming towards me, you know, inevitably as time passes. But as a scientist, you can look at that and think, “oh, that's fascinating” because, you know, what is it that causes the human body to go wrong in this incredibly synchronised way? This eight-year mortality risk doubling time, it's called, is universal across populations, across time, wherever you look and whenever you look in the world, that's been a fact of human life. So the question is, can we understand that? Can we do something about it? And can we potentially prevent all of the horrible things that happen in the synchronised way in our biology that we call ageing?
Georgia: Would it be fair to say you're not the first person to be bitten by, let's say, the ageing bug? It’s a fairly old pursuit of humanity, isn't it?
Andrew: It definitely is. And I think, you know, for as long as humans have been humans, we've been sort of contemplating what it means to get old and what it means to die. The first funeral rituals in humans go back, I think, tens of thousands of years. And looking back a few thousand years, you got the pyramids, these enormous sort of icons to sort of life and mortality and death. And, yeah, throughout the ages, people have been searching for the fountain of youth, whether it's been, you know, looking for the Holy Grail or whether it's been alchemists trying to turn lead into gold and thinking that this Philosopher's Stone substance that could do that could also grant them eternal life. So there's this incredibly sort of long thread running through the whole of human existence. So it really is this incredibly universal phenomenon. So I guess it's natural that as soon as you get the ability to understand that that's coming for you, you do want to do something about it.
Georgia: When you were researching your book, did you come across any examples of people who really took this to the limit of this, trying to discover this Philosopher's Stone, this fountain of youth?
Andrew: There have been all kinds of bizarre interventions throughout history, and I think probably my favourite was one that was actually in the 1920s, sort of shockingly recent at the beginnings of the era of modern medicine. You know, we knew what germs, which by this point and yet a touted and actually practised anti-ageing treatment, was to take monkey testicles and surgically implant them into patients. And it was thought that would obviously improve their virility, but also slow their ageing to, you know, some very good for the person or for the monkey.
Georgia: People have an obsession with grafting testicles, and it's not the first time I’ve heard of someone doing that.
Andrew: The cure for all ills.
Georgia: And I know in the discourse about this, it ranges from the sort of the more mundane things that could increase your health years by five years. And then there's people saying we can download our brain into computers. So it is a big spectrum, isn't it, of research ideas.
Andrew: It really is. And I think that the things I'm most excited about, are the things that are more like pills or treatments that are basically extensions of things we already do. So there are quite a lot of ideas that are just, you know, medicines that just drugs and in the way, you know, we currently understand them in the same way that people take a preventative starting if they are at risk of heart disease, to try and, you know, reduce the level of cholesterol in their blood and make them less likely to have a heart attack. We could imagine taking a preventative pill slows down your ageing. And, you know, I think sort of lumping it together, as it often is in the media with things like mind uploading. That's just a zany far future idea, really, because if you think about it, we don't even know where the mind is stored in the brain. We don't even know where and how the memories are stored. Exactly. So potentially you're going to have to make these, you know, ridiculously precise microscopic slices through the whole brain, and download its whole structure onto your computer. It's going to require petabytes of data potentially. I think we're going to have cured ageing biologically and, you know, got people living much, much healthier, longer lives long before we're in a position where we can start to emulate humans inside computers.
Georgia: And I know we need computers to be a lot more consistent if we were to be happy with that.
Andrew: The blue screen of death in your uploaded mind.
Georgia: And so, I mean, this is a hormones podcast, but ageing is a massively complicated thing. Is there a single mechanism behind ageing? Is there a big clock inside us old ticking away? Do we know what causes it?
Andrew: I think that probably isn't a single clock. It's not to say that definitely because we're still digging into exactly what causes ageing, but it looks more likely that it's a whole range of processes and hormones are definitely a sort of part of those processes.
Paul: The kind of aging principle probably boils down to DNA changes in our cells. In some ways, the endocrine system might just be an innocent bystander for all of that. So I don't think for one minute that, you know, the endocrine system is controlling ageing. No, but it does change with age.
Georgia: This is Professor Paul Stewart, professor of endocrinology and medicine at the University of Leeds - who is interested in slowing down or even halting the ageing processes
Paul took me through some of the hormonal changes that mark our life course. Of course, a huge one is the menopause, but that’s getting its own episode so let’s park it for now. BUT there are some changes in our hormones as we age that affect every one of us.
Paul: Growth hormone changes quite dramatically, actually. So our peak growth hormone levels - the clues in the title, the fact that I'm over six foot, means I have had a bit more growth hormone than most because growth hormone effectively is how we achieve our skeletal height and bone maturity. But from the age of 30 onwards, we progressively have a decline in growth hormone, around about 10 percent every decade because growth hormone is what we call an anabolic hormone. It's building muscle mass. It's building some of our metabolic processes. It's easy to see how that fall in growth hormone has been associated with things like muscle wasting with age, with a reduction in bone mineral density, you know, an increase in fat mass. So huge excitement there in terms of the changes of growth hormone with age.
Georgia: There’s another hormone Paul is particularly interested in - and it’s one you might recognise if you were paying attention to series one of our podcast.
Paul: Cortisol is a fascinating hormone. It's slightly different with ageing because we know actually in the circulation that cortisol levels don't really change very much. We all make more cortisol in times of stress. It's a stress hormone. It's the way we cope with stressful situations, with infection. But it's also a key hormone determining our day to day living, well-being, the way we handle food and nutrients, the way we control our body composition. So you might think, well, why is this relevant then in ageing? Well, what's important here in the cortisol story is not what's going on in the circulation, but what's going on in tissues. So there's a very crucial enzyme that's actually important for generating cortisol locally in tissues such as muscle fat, liver, independent of what's going on in the circulation. So circulating levels don't change. But we know that in some of these key tissues, such as bone, such as liver, such as muscle, cortisol levels are increasing because of the expression of this enzyme that we're interested in. It's got a very long name, 11 beta hydroxysteroid dehydrogenase. Let's just call it 11-beta HSD1 for simplicity.
Georgia: That's the nickname? That’s the short one!
Paul: That's the short one. And that's the enzyme that's exciting in terms of the ageing process, because that's an enzyme that's going up with age and probably delivering more cortisol locally in some of these key tissues. And we've shown certainly in animal models and in preclinical experiments that that is really bad news. That does give you an unfavourable, you know, propensity to diabetes. It does result in some of the changes in our body composition with a predilection to central obesity as opposed to, you know, the earlier fat distribution and something I'm particularly interested in, you know, the integrity of things like skin, of bone and of muscle, which we see slowly wasting away with ageing. Is it important in that process?
Georgia: The reason this lengthily-named enzyme is so important isn’t actually directly to do with cortisol, but with its shadowy relative.
Paul: So although I've talked about cortisol as the active stress hormone, in our circulation we actually have two hormones circulating at any one time, one of which is cortisol, which is the active hormone. The other one is a hormone called cortisone, which is like a shadow cortisol but is inactive. And what this enzyme, this clever enzyme can do is it can take the inactive cortisone in the circulation and generate active cortisol from that. So that effectively is what's key. And as I say, this enzyme is expressed at very high levels in in our liver, where we've shown its importance in modulating glucose output from the liver, in bone, where it's regulating osteocalcin and other key bone markers of bone formation in the skin in terms of regulating collagen breakdown and also in muscle, where we think it's got a key role in terms of, you know, muscle, bulk and muscle function. So those are the main sites of its expression, which is obviously exciting, again, in terms of the ageing changes.
Georgia: As we get older our levels of cortisol and cortisone don’t change enormously - unless of course we’re very stressed - but the activity of this enzyme is on the up, so cortisONE is converted into cortisOL in some of our organs, meaning that the levels of this stress hormone start to rise.
To find out what this does, Paul did an experiment in mice, using genetic engineering to knock out the genes that code for the enzyme to see what happens when it isn’t there at all.
Paul: These mice have accelerated wound healing. They have differences in muscle metabolism and muscle mass, changes in body composition. And some of the preclinical work we've gone on to do in man suggests that might be important in bone changes as well with ageing. So there's little snippets of the jigsaw starting to fit into place. The mouse studies are very powerful, but the enzyme is very different in mouse to man.
Georgia: Do you think this could hold the key to an intervention which could increase health span?
Paul: Well, I genuinely do, you know, as we go back to the principles I was talking about of ageing, I mean, most of the reasons why we aged badly now are because of all the chronic diseases we accumulate with ageing. Of course, lifestyle has to still be a major end game there. But actually manipulating tissue levels of cortisol, I think could play a huge role in being beneficial in that process. And that's what we're aiming to do here. Of course, persuading a pharmaceutical company to then embark on what would be long term phase three clinical trials is another issue. So that's why we're now carving it up and going down: let's look at a wound healing programme. Let's separately look at a muscle wasting programme or a bone osteoporosis programme, because that's more easily divisible to do rather than just how are we going to age, you know, which would be an impossible study to fund and execute. But yes is the answer to that question. We're certainly committed that we think this might be a key part of the ageing process.
Georgia: Cortisol obviously is associated very strongly with stress. Do we know anything about how stress impacts this ageing process? If you have a very stressful life, does that make you get older?
Paul: You know, it's a really good question, the whole role of stress and ageing and, I remember seeing those dreadful pictures of Tony Blair ageing when he was prime minister. You know, that level of people with these huge demanding jobs and you see a dramatic change in them so yes, of course, there's something in it. Whether it's cortisol, I think is more guarded. Yes, if you've got repeated stress, you could end up in that prolonged situation. But the kind of stresses that you and I would be exposed to on a normal day, the rapid onset and rapid offset. So I can't believe that that kind of stress would have a big impact acting via cortisol to cause some of those changes except in very unusual situations.
Georgia: So there may be a cortisol related intervention coming, and in the meantime - probably don't become prime minister.
And Paul’s work is not about upping our years alive, but making those years better, which is a really important part of this type of research.
Janet: So with improved healthcare lifespan has been increasing at approximately two years per decade, really for the last century. And this is quite dramatic, if you think of it in another way. A child born yesterday has about five hours more lifespan expectancy than one born today. So very dramatic, but the time we spend in good health, which is called health span, hasn't been keeping space. So this has only been increasing about half of the same rate. So now, on average, adults will spend the last decade of life in ill health. So big impacts for us socially with an older population if it’s unwell.
Georgia: This is Professor Janet Lord, the director of the Institute of Inflammation and ageing at the University of Birmingham - she looks at how hormones, ageing and our immune system all intersect.
Janet: Naturally, as you get older, our ability, for example, to repair damage in our tissues declines. So you do get a build-up of damaged cells and organs in your body. And certainly a decline in your immune system means you're less able to fight infections. And of course, we're all aware with coronavirus of the impact of that, because over 90 percent of our patients who've had serious covid-19 or passed away are over the age of 65. So, the endocrine system really does interact very closely with your immune system.
Georgia: Now cortisol, which we just talked about, has a central role in our immune systems in dampening it down. But there’s another, much less well known hormone, that’s no less important.
Janet: It's called dehydroepiandrosterone or DHEA for short. DHEA generally enhances our immune system. So they try and keep in balance. So they work together to either suppress or support our immune system.
Sadly, what happens with age? So the viewers will have heard of menopause, the decline in the sex hormones with age. But there's another pause: Adreno-pause. And this is the decline in DHEA with age, which begins at around the age of 30.
So those in the audience thinking, I'm fine, I'm young. No, it begins around thirty and it's a very gradual decline. But unfortunately, what happens is the production of cortisol doesn't change with age. If anything, it goes up slightly with age. So you've got the same.
Georgia: Why is it called adrenopause, because I would associate “adreno” with adrenaline, is that just to confuse people?
Janet: No, not at all. So DHEA and cortisol are both made by the adrenal glands. And the part of the adrenals that makes DHEA is called the zona reticularis . And that begins to shrink as we get older. And that's why you make less of it as you get older. So that's why it's called Adreno pause because it's an effect on the adrenal glands.
Georgia: I love all these names, it sounds like something from a sci fi - the planet of zona reticularis.
Janet: And I know it's great, isn't it?
Georgia: Our immune system is full of white blood cells, and the most prominent type are called neutrophils. These neutrophils depend directly on the hormone DHEA.
Janet: We have shown in our research that DHEA is able to directly increase the ability of these cells to kill bacteria. So if you're older and times of an infection, you haven't you're not able to raise your DHEA levels, then your neutrophils don't function as well. And there's much more chance that you're not going to be able to fight that infection like pneumonia. So really powerful consequences for your immune system.
Georgia: Given how important DHEA is for maintaining immune function, Janet and her team are now running clinical trials at the Queen Elizabeth Hospital in Birmingham to see if it can help people recover from serious accidents.
Janet: So we've got older patients who have had a hip fracture and we've got young patients who, for example, have been in a road traffic accident because we know at times of stress that your DHEA falls really dramatically. Even if you're young, it really falls down and the cortisol goes up. But we don't know the results yet - we're in the middle of the trial, where we are giving the DHEA. But our hope is that it will help the immune system.
Georgia: Do you have to see this becoming not only an intervention, but seeing as it has always sort of ageing in? Do you ever see a stage where they will be popping a supplement just as par for the course?
Janet: I do personally, yes, I do. In fact, this does happen in the US. So another study reported in 2019 and they gave a cocktail of three agents, growth hormone in combination with DHEA and with a drug called metformin, which is used to treat Type two diabetes. And they gave this cocktail to older males for a year and they measured their biological age, not their chronological age. How old were these guys biologically? And they managed to reverse their age by, on average, two years.
So it's really interesting if you restore some of these hormones. So this is growth hormone, DHEA to the level that they were in a younger person. It actually slowed down the ageing in these older males. So although we need a lot more trials, actually, I could see that happening that we might just like where we’d pop a statin if we've got high cholesterol, we might pop DHEA to try and keep our hormone levels at the level they were when we were 30 years old.
Georgia: Just to be careful, we are not advocating going out and trying this, there’s lots more work to be done, but saying that, I honestly went into this programme expecting the usual science communication dance - the hopeful headlines and the cautious scientist telling us to all calm down - but really - everyone I've spoken to seems to be on the same page - there might be some genuine interventions which can reduce age-related decline on the horizon. But - lest we make the same mistakes as our testicle grafting for-bares, we still need to proceed with caution.
Janet: You can buy it over the counter in the US. The downside is because it's not a regulated drug in the US, it's not always, you know, sold correctly. For example, quite a few years ago now, we bought some DHEA for 10 different suppliers in the US and we found that only two of those actually contained the DHEA it should. So although it's good that it's readily available, it needs to be regulated properly.
Georgia: And so, maybe we’re well on the way to living without the problems ageing brings with it - in fact I'd go as far to say that the answer to the question “can we hack our hormones to slow down ageing”, may be a resounding “possibly soon”. But in the meantime, what can we do to live long enough to make it to a time when those interventions are ready?
The good news is that only 20% of how you age comes down to your genetics. The other 80% is lifestyle. So kick the cigarette habit, stop drinking, exercise more - no surprises there. And Andrew Steele has found lots of bits of advice
Andrew: And I think one of my favourite is to brush your teeth
Bad gums doesn’t just mean bad breath - they can wear your immune system out in a never ending battle against the bacteria which drives age related changes.
Andrew: It seems to be able to increase the risk of cardiovascular problems. There's also even a hint it might increase the risk of dementia because we found the bacteria associated with gum disease in the brains of people who have dementia. And it's not clear whether that's cause or effect. In any case, I'm not going to wait for the studies to find out the results to that question. I'm just going to carry on brushing and flossing and making sure I have a really, really Tip-Top oral hygiene to try and, you know, hopefully not just reduce my dentist bills, not necessarily use my teeth, but also increase my lifespan as well.
Thanks to Paul Stewart, Janet Lord and Andrew Steele.
This show was produced by me, Georgia Mills. Kat Arney is the executive producer and it was made by FIRST CREATE THE MEDIA. Thanks for listening, and goodbye.