Norman Swan: Hello, Norman Swan here with this week's Health Report. Life expectancy has been rising about three months a year since the mid 19th century. We do well in Australia and are usually in the top five or six most long-lived nations. When we personalise this to the individual although, life expectancy, which is a national average, becomes irrelevant. What many of us really want to know is how long we are going to live and how much of that will be in good health. Living longer is an obsession and there are pills galore being offered to slow ageing and maybe even reverse it. Even so, the increase in longevity may be stalling, and you've heard a lot about that on the Health Report over the last two or three years because our metabolic health is declining and our abdominal girth is increasing.

So what works in slowing ageing? Well, that's been the life work, at least so far, of Luigi Fontana, an international authority on the biology of ageing and the dietary interventions, especially calorie restriction, which in fact is what many of the anti-ageing pills seek to emulate without having to cut back on what you eat. Luigi Fontana is Professor of Medicine and Nutrition and has a chair in translational metabolic health at the University of Sydney, and I spoke to him recently at length.

Luigi Fontana: When I was a medical student we had a professor in geriatrics who gave a very interesting lecture about the effects of dietary restriction in mice being the most powerful intervention to extend lifespan and health span. And so I was fascinated. I said, ah, so there is something in mammals that is able to extend lifespan up to 50%. It is like for human beings instead of living 80 years, to live 130, 140 years. The data back then, so we're talking about 25 years ago, were showing also a huge increase in health span with the prevention of cancer, cardiovascular disease and kidney disease, autoimmune diseases

Norman Swan: And before you go on we should just define our terms here. So, lifespan, just crudely, is how long you live, it's not life expectancy, it's just the absolute number of years you have on the planet, and health span is how many healthy years you've got before disability and other diseases start to encroach on your life.

Luigi Fontana: Absolutely. I wasn't happy with being a practitioner where you go to the emergency room because there is a patient with a myocardial infarction, a stroke, and you try to minimise the damage. I said, is it possible to understand if humans, like animals on calorie restrictions, they live at least healthier and possibly longer if we can slow down ageing and accumulation of damage? And so I started to search and there was nothing in humans

Norman Swan: And the important caveat here isit's bloody obvious when you think about it, but mice are not humans, although dietary restriction does spanthey've shown it in fruit fly, in yeast, in other animal species.

Luigi Fontana: In monkeys now, rhesus monkeys.

Norman Swan: But the holy grail is humans because humans are a lot more complicated.

Luigi Fontana: Just to give you an example, mice or rats, they live on average 2.5 years, human beings live on average for 80 years. Rhesus monkeys, they are primates, they live on average 26, 27 years. So even if they are primates, they live a third of what a human being nowadays lives. And so basically I decided to search and I discovered that there was a Professor John Holloszy in the US at Washington University who was starting a program on calorie restriction in humans, and he replied to me and said, come on, come to the US. So I took my luggage and then I fell in love with what I was studying. John, he just died a couple of years ago, was one of the guys who discovered that exercise increases mitochondrial biogenesis, is improving insulin sensitivity, preventing diabetes. So he was a brilliant mind, a pioneer.

Norman Swan: And we will come back to mitochondrial biogenesis in a minute because these are the energy sources in the cells, possibly the source of ageing, and regenerating, revivifying these mitochondria might be one of the answers for delaying ageing.

Luigi Fontana: Exactly. And I spent the next 17 years working on humans, research on calorie restriction. So we studied people who were practising calorie restriction, so what is called technically a cross-sectional study, you compare these people with people who are master athletes or sedentary men and women consuming Western diets. And then we did two big randomised clinical trials, the calorie where we randomised people on calorie restriction. The first one, the step one calorie randomised clinical trial was comparing people randomised to 25% calorie restriction without malnutrition, so with all the vitamins and minerals.

Norman Swan: So what with the outcomes you were looking for, because you can't hang around for 90 years to see whether or not they live longer.

Luigi Fontana: Exactly, so lifespan is impossible. Even in monkeys, the monkeys study now we have finished 20 years to get data on survival, and so it's feasible but for humans it's impossible. In terms of longevity what we are trying to do is to develop biomarkers of ageing, what is called biological ageing, can we measure biological age and with some biomarkers. Right now the most common one, the most trendy one is epigenetic ageing. So you measure DNA methylation, and there are some DNA methylation clocks that are

Norman Swan: So, just to explain, epigenetic changes are not mutations in the actual DNA, they are chemical reactions around the side of the spiral, the helix, which changes its shape and changes its function. And this DNA methylation that you are talking about is one of these chemical reactions that changes the shape, for better or for worse.

Luigi Fontana: Yes, exactly, and so basically these epigenetic changes is basically the regulation of which part of the DNA is translating into proteins. And what we have discovered is that what you do in your life, what you eat, if you exercise, if you smoke, if you are stressed, is changing the transcription of DNA. And new data is suggesting that as you age, basically there are changes in this transcription

Norman Swan: Which may well measure your clock as opposed to how many days or months you've been on the Earth, it's really how many days or months it affects your biology.

Luigi Fontana: Exactly, you can compare basically your chronological age, how many months and years you've been living, compared to the biological age. So you can be biologically younger. Let's say you are 50 years old, biologically you are 40, or biologically you are 60. And so these are experimental tools that we are training, that we are working on, and it looks like they are good. And so ideally we hope that in the next few years we are going to refine these biomarkers of biological age and then we can do an intervention, it can be exercise, it can be diet, it can be a supplement, it can be a drug, and we can say, okay, your body has rejuvenated. Or if you are smoking or if you have other unhealthy lifestyles, you have been getting older than your chronological age.

Norman Swan: And what about the telomeres? We've spoken about that a lot on the Health Reportby the way, you are listening to the Health Report on RN with me, Norman Swan, and I'm speaking to Professor Luigi Fontana, world authority on ageing, slowing ageing, the biology of ageing. So we've spoken about the telomeres, these bits on the ends of the chromosomes, almost like the plastic bits on your shoelaces, to protect the chromosomes which get shorter as you age, as each cell goes, and also if you seem to have less damage of ageing they seem to be longer. Are they good as markers for ageing?

Luigi Fontana: Look, we don't use them in our research. In the past there was a lot of hope that good biomarkersbut Elizabeth Blackburn who got the Nobel prize for telomere and telomerases, she is a friend, and I sent her some samples of these people doing calorie restriction, and we don't see changes. And even in animals on calorie restriction we are not able to use those as a biomarker. It doesn't mean that what you just said, that as you age, every time the cells are dividing or replicating the telomere gets shorter. So, no doubt about it, it's real. I'm just saying that

Norman Swan: It's not a good clock.

Luigi Fontana: Exactly.

Norman Swan: So, come back to the trials now; what do the trials show?

Luigi Fontana: So the first one we compared people who were doing 25% calorie restrictions without malnutrition, or people who were exercising to increase their energy expenditure by 25%, and then we had the control sedentary group. And we found that of course they were leaner, they had less visceral fat. Interestingly, both the CR and exercisers lost around 9% of their body weight, and 40% on average of their visceral fat.

Norman Swan: The dangerous fat in your tummy.

Luigi Fontana: Yes, the dangerous abdominal fat. And then we found improvements in inflammation, reduction of inflammation, we found improvement in insulin sensitivity.

Norman Swan: And just again, so inflammation, which is really an overactive immune system which causes thickening and damage to your internal vessels, is probably part of the ageing process.

Luigi Fontana: Yes, inflammation now we know is a key factor in the development of cancer, cardiovascular disease, stroke and many other diseases, including ageing. So it's one of the major players in ageing and many chronic diseases. So we saw an improvement in insulin sensitivity. Insulin is very important, based on many animal models of longevity. So nowadays we can play with genes and we can knock down one gene or we can over-express one gene in rodents, and then we can look at what are the physiological or lifespan effects of these genetic manipulations. And so I will say that 80% of the animal models of longevity, meaning mice that are living longer than the wild type, they have a mutation in the insulin IGF-1 pathway, so they have less insulin biding, less insulin transduction. And what we know is that as you get older, especially as you accumulate belly fat, visceral fat because you are in a positive chronic energy balance, you are becoming insulin resistant. So there are a number of hormones produced by the adipose tissue called adipokines that are making the skeletal muscle but also the adipose tissue and other cells resistant to the effects of insulin.

Norman Swan: And you get growth hormones that can stimulate cancer, so a lot of focus is on insulin, it's much more than diabetes in terms of how it affects the body.

Luigi Fontana: Yes, a lot of people think about insulin when they talk about diabetes. In reality, before you become diabetic you have many years of insulin resistance and hyperinsulinaemia. So the beta cells of the pancreas that are the cells that are producing insulin, they are trying to over-produce insulin to overcome the peripheral insulin resistance, and this hyperinsulinaemia is driving cancer and ageing.

Norman Swan: So, high levels of insulin.

Luigi Fontana: Yes.

Norman Swan: So you've got a signal that reducing calories by 25% seem to be doing similar stuff to

Luigi Fontana: Exactly, so if we have to summarise what we did find, many of the metabolic hormonal adaptations that we have described in long-lived dietary restricted animals are also occurring in humans. So humans are adapting to calorie restriction similarly to animals. Another important one, we found a major reduction in oxidative stress markers, biomarkers like F2-isoprostanes.

Norman Swan: This is biological rusting, which goes along with inflammation and drives those mitochondria that we were talking about as well.

Luigi Fontana: We also saw an increase in autophagy proteins in genes. Autophagy is another important mechanism.

Norman Swan: So again, to explain, your cells get old and they should die but some cells don't die and they just sit there causing havoc and you want the body to get rid of them

Luigi Fontana: But that's senescence. Autophagy is different. So as we get older, we have accumulation of garbage in our cells because our cells are becoming less efficient to remove misfolded proteins, old mitochondria, so mitochondria that get oxidised, they become dysfunctional, and so if you are in energy restriction, the cells, they are trying to say, okay, now where do I get the material to create energy for cell functioning, and they start to digest the garbage, and so that's called autophagy.

The other factor we found in humans as well is what you are saying before, cell senescence. As we get older, we have an accumulation of DNA damage, and when you have accumulation of DNA damage that can be stimulated by smoking or radiation and many other stuff, you have two different options. One is this DNA damage ends up in oncogenes, you have cancer. Otherwise, this DNA damage can cause cell senescence. And what other colleagues have found is that these senescent cells, these old cells, these zombie cells, they are producing pro-inflammatory cytokines. So this is a major source of inflammation itself. They are also secreting pro-cancer factors, and we found that in humans and in animals on calorie restriction, there is a reduction in senescent cells.

Norman Swan: So, popular books out there being sold as the solution to ageing, and I'll declare a conflict of interest here as I've got one coming out in August, but hopefully reasonably scientificlet's just take fasting. So, fasting has been touted as the answer here, and what they do is they say, look, if you look at fasting in animals it prolongs their lifespan, it emulates dietary restrictions. So if you look at the chemical pathways, I'll just use some technical terms like SIRT1, they recapitulate that and work in the same way. So what's your view on fasting as a surrogate for dietary restriction?

Luigi Fontana: The story of fasting, really at least the commercial part, started with the Michael Mosley documentary Eat, Fast and Live Longer, I was one of the two characters on the documentary, and he came and interviewed me in St Louis and then he interviewed Valter Longo in Los Angeles. And back then he put together a nice story, but without scientific data because there were no human studies. And even right now, the data on the effects of fasting, intermittent fasting or time restricted feeding in humans, the data are very, very slim. I'm talking about humans. In animals, yes, the data are overwhelming that intermittent fasting is extending lifespan and health span.

Norman Swan: But isn't there evidence in humans and larger animals that it increases ageing, speeds it up?

Luigi Fontana: No, but we have dataI shouldn't talk about it but I'll give you justwe have a paper submitted now in a major journal for publication, and we were able to do intermittent fasting for six months plus six months, and we see a beautiful reduction in body fat, in body weight and body fat, 8% weight loss, so it's very good for the standards of calorie restriction, but we don't see improvements in inflammation, no improvement in inflammation, a very tiny improvement in insulin sensitivity in many factors. So despite the fact they lose the same amount of body weight that we achieve with classical calorie restriction or with exercise, metabolically we don't see the same responses. Why? Well, what we are finding is that a calorie is not a calorie, that the quality of the food you are eating influences the metabolic response to weight loss, okay? So the shortcut that many think, okay, you know

Norman Swan: So if you're having bacon and eggs, it's not the same as a Mediterranean diet.

Luigi Fontana: Exactly. It's a balance between exercise, the amount of calories you are burning and the metabolic adaptations that you are triggering with exercise, the quantity of calories and the quality of those calories, they are three pillars. Before we were discussing about these easy-fix types of books or solutions that are very, very trendy, it's like if you go to the director of a symphony orchestra and you say, 'Tell me, what is the most important instrument in the symphony?' I don't know, he likes violin or cello. Okay, now I create an orchestra only with violin

Norman Swan: It's funny you should say that, actually one of my chapters in my book says anti-ageing is orchestral.

Luigi Fontana: Exactly, we agree. So to have a beautiful symphony, I don't know if you like Shostakovich, whatever symphony, or Mahler or Beethoven, you need a balance of all the instruments. If you have an overwhelming violin section, then you kill the beauty.

Norman Swan: So then this translates to the individual substances that people say can influence the pathway like resveratrol or NAD boosters, Fisetin and so on, they should work but they don't when you actually study them.

Luigi Fontana: That's what is coming up, that basically in experimental animals some of these molecules, not the ones you mentioned but, for example, rapamycin and others, they are extending lifespan, but we know, for example, that rapamycin in humans is causing type 2 diabetes, is causing immune depression. So if you are mice who are living in a pathogen-free facility, well controlled, in an environment where you are not exposed to viruses, to bacteria, then it may work. But if you are living in an environment like we do, where there is Covid and influenza and bacteria, then you know some of these molecules are dangerous.

Norman Swan: One of the things I'm interested in is the concept of homeostasis. So homeostasis, just to explain to the audience, is this balance. You talk about the balance in the orchestra and you talk about rapamycin, which is a fascinating substance discovered on Easter Island and taken back and having all these effects and used in people with kidney transplants to stop rejection and so on, is that when you look at ageing, some people would argue that ageing is a disruption of homeostasis, so we have a balance, and the balancesay we don't eat well, we don't get much exercise, we put on weight, the balance just tips towards ageing. So it's like the leaning Tower of Pisa, to use an Italian metaphor. So you have this leaning Tower of Pisa, and then what happensso I'm putting a hypothesis to you, is that when you try and correct the leaning Tower of Pisa to vertical, the whole body wants to push it back to a leaning situation because the body knows it needs a balance. If you are laying down protein and making substances, you've also got to break it down. If you put down fat, you've got to be able to lift it up and use it for energy. And so it's very hard to shift that balance. Does dietary restriction restore the disrupted homeostasis of ageing, so, in other words, the leaning Tower of Pisa?

Luigi Fontana: It looks so, even if the sooner you start calorie restrictionso the classic experiments shows that if you start dietary restriction without malnutrition, and let me reinforce that, 'without malnutrition', so going back to the day of fasting where people say, okay, I fast a couple of days per week and five days a week I eat whatever I want. That is dietary restriction with malnutrition. But in the experimental models we found that if you start 30% dietary restriction in a very young animal, typically we were starting in post-weaning mice, you have an extension up to 50% of lifespan. If you start the same 30% dietary restriction in a 12-month-old mouse that is equivalent probably to a 40-, 50-year-old human being, you have a 15%, 20% increase in lifespan because in those 12 months that is like 40 years for a human being, you have accumulated damage. And yes, you can undo some of the damage but not all of it.

So the message is that at any age you can improve your health by exercising, changing your diet, counting your calories, controlling your calories, the quality of what you eat, but you cannot go back totally to the same effects of when you started calorie restriction when you were younger. So the message is that the sooner you start to counteract the damaging effect of ageingbecause, as you said, ageing is a mechanism where the repair mechanisms are getting old. When you were young you have a bone fracture and you're going to repair very quickly, when you are 70 years old you have a bone fracture, you are not repairingif you have a scar when you are young, you are able to repair very quickly the scar, and when you get older, less, because all these mechanisms, this autophagy, DNA repair mechanisms, the antioxidant mechanisms, the removal of senescent cells, they get old and less efficient to keep homeostasis.

Norman Swan: But there is still an effect.

Luigi Fontana: There is still an effect. What I'm saying is that your trajectory of ageing is the deterioration of 20% of these mechanisms per year. If you eat unhealthy, if you have excess belly fat, if you are not exercising, if you are smoking, if you are over-drinking, you are accelerating the accumulation of damage and the deterioration of these mechanisms instead of if you are exercising, you are eating well, you are eating good quality, you are eating the right amount of calories, you don't gain too much belly fat as you get older, you are decelerating these mechanisms and in some cases you are rejuvenating cells.

Norman Swan: So do you live in a monastic lifestyle then?

Luigi Fontana: No, I think it's noteverything dependsfor example, I exercise I would say one hour, probably 5 to 6 times a week, and here in Sydney it's beautiful because the weather is so nice all year long, that even in the winter, even at 6pm I take my bike and I go for an hour and for me it's refreshing. After one day using my brain, going on a bike, it's beautiful. So, one hour a day out of 24-hours is not a lot.

And then I eat a very healthy Mediterranean diet, so very colourful, very tasty, with a lot of fresh fish and here in Sydney we are blessed, lots of different types of vegetables, whole grains and beans, so I have a range ofI think my diet is more diverse than many Australians and Americans because I have a lot of different recipes, very tasty. So I control my calories in two or three ways. One is to eat a lot of unrefined food, so whole grains and beans and vegetables and fish, and in this way you are already controlling your calories. We did a study in the USagain, we haven't published it but I'll give you the results, we are writing the manuscript right now, where we fed people in a randomised clinical trial for two months a Mediterranean diet comprising basically whole grains and vegetables and beans and fish, poultry once a week only, for two months. But I asked my dietician to clamp the body weight. So if the participant was, let's say, 80 kilos at baseline at the beginning of the study, I wanted the same person to be 80 kilos at the end of two months on this Mediterranean diet, you know, we provided the food.

Norman Swan: So they could see the pure effect of the diet rather than weight loss.

Luigi Fontana: Exactly, the results are going to be striking. But just to tell you the results, we had to over-feed people 250 calories to keep their body weight constant.

Norman Swan: You're kidding!

Luigi Fontana: Yes, and it was designed to be iso-caloric

Norman Swan: So it's hard work to maintain the weight.

Luigi Fontana: It was hard work, they were losing weight like crazy because the high-fibre diet compared to their typical American super-refined ultra-processed food, it was already able to make them lose weight like crazy. So this is a simple trick. You think about calorie restriction like, you know, having these tiny portions, an empty plateno. I'm eating huge amounts ofif you look at my plates, huge and big salads, very colourful, tasty, I do my dressing with orange juice or lemon juice with pepper and this and that, a lot of spices, so you can be very creative. It's science-based, it's not just fiction. So that's number one.

And then the other one is stop eating when you are 80% full. How do you do that? Typically we prepare these big portions and we have this plate full of food, and typically you try to finish everything because otherwise you feel guilty

Norman Swan: As you are told by your grandmother, you had to do it.

Luigi Fontana: Yes, you feel guilty to leave something on the plate, instead of one trick is to do small portions on your plate, you do a small portion, then you know you are still very hungry, you need another small portion, until you reach a point where you say, maybe I would eat another three or four tablespoons but I'll stop, I'm satisfied enough, I have a tiny bit of hunger but I'm satisfied, and that's a way to restrict your calories, the second one. Then, if you are overweight and you are trying to lose weight, then you can use a third trick which is basically fasting, vegetable fasting once or twice a week where you eat only

Norman Swan: Which is what the Greeks do.

Luigi Fontana: Yes, only raw or cooked vegetables, a wide variety, non-starchy vegetables, with a couple of tablespoons of olive oil per day because one tablespoon is 120 calories, and then you can use orange or vinegar, whatever you want. And the fourth one is eating everything in a window of six, eight hours.

So in this way if you put together high-quality plus fasting or this 80% filling, you don't have to be a monk orit's very easy, especially if you exercise, because we have clearly shown in these randomised clinical trials I was telling you about in the beginning, that if you lose weight, let's say 8% reduction in body weight with exercise or with calorie restriction, if you lose weight with calorie restriction you have a reduction in T3, triiodothyronine, it's one of the major active thyroid hormones. Therefore, you are lowering your resting metabolic rate. Whenever you are lowering your thyroid hormones

Norman Swan: So you are burning less calories, fewer calories at rest.

Luigi Fontana: Yes. Instead of if you lose the same amount of body weight and body fat by exercise you have no reduction in T3.

Norman Swan: So you balance the two.

Luigi Fontana: Exactly, so basically your metabolism is still very high, and therefore it's mandatory to always couple exercise with diet, otherwise you are lowering your resting metabolic rate, and then you are going to regainsooner or later you are going to regain all your body weight and body fat with the interests.

Norman Swan: Luigi, thank you, it's been fascinating.

Luigi Fontana: You're welcome, thank you for having me.

Norman Swan: We'll get you back when these results are published. Thank you very much.

Luigi Fontana is Professor of Medicine and Nutrition and has a chair in translational metabolic health at the University of Sydney. He has a book which came out in 2020, it's called The Path to Longevity: The Secrets to Living a Long, Happy, Healthy Life. This has been the Health Report, I'm Norman Swan.

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