Manel Esteller, director of the Josep Carreras Leukemia Research Institute (IJC-CERCA), ICREA researcher and Professor of Genetics at the Faculty of Medicine of the University of Barcelona, is recognized as one of the most prominent scientists in the world by the prestigious Stanford University. Together with Salvador Macip, doctor and researcher and director of Health Sciences at the UOC, he has just published The Secret of Eternal Life. Everything we know to live longer and better (Grijalbo; in Catalan, Rosa dels Vents). We talked with him about longevity, genes, habits, aging and health.
The secret of the eternal life. Are we close to revealing it?
The book could also be titled The Secrets of Eternal Life, because there are more than one; Some are revealing themselves, others are not yet. In the last 10 years we have discovered many keys to aging, why cells die. It is now possible to find biomarkers of aging and perhaps we can begin to intervene in the process to slow it down. One of the ideas of the book is to explain the bases for adding more life to years and not more years to life. We do not want to make a Guinness record for survival, if not with quality of life.
Are we living longer than expected and that is why we get so sick at the end of life?
As a human species, homo sapiens, we are living much longer than we should. It's not long since we came down from the trees, we started running, escaping from other carnivores... Our brain has not yet adapted to those changes. Perhaps this has to do with the appearance of neurodegenerative diseases such as Alzheimer's. It has only been a short time since our body has the technical capacity to survive so many years, and this is because, in the last 50 years, technological and biomedical progress has been incredible.
How is the investigation going with Maria Branyas, the oldest woman in the world, at 116 years old? What have you been able to observe so far?
First of all, I would like to thank María and her entire family for their collaboration. Its biological material can give us very important keys to healthy aging. Maria does not have arteriosclerosis or dementia, nor has she had cancer. She has osteoarthritis and hearing defects, which is expected when you are over 116 years old. We can see, for example, how her DNA is, what her biological age is versus her chronological age, look at markers in her blood. We can know how her oxidation system is, her chromosomes, see if she has stem cells left, which regenerate tissues...
Is all this data already collected?
We're on that. On the one hand, in your family history there are more people over 90 years of age than would be expected. Therefore, there will surely be a genetic component to their longevity. There are more than 200 genes involved in aging and we are going to see them; Maybe you don't have risk genes for diseases like Alzheimer's, for example. Apart from this, we have also measured their biological clock. Using epigenetics, the control of DNA, we have seen that he has a biological age of 106 years, ten less than his chronological age.
Can we all know our real biological age?
It is becoming more and more popular. Just as we can now go to a center and find out what geography your DNA comes from, there are already companies where you can privately request your biological age.
What markers are there to determine biological age?
There are many, but perhaps the simplest markers are epigenetic, which is how the environment talks to your genes. When you insult them, then the epigenetic marks are worse. When there is a comfortable environment that allows you to develop, your epigenetic marks are better and you are sometimes even younger than your chronological age. Heavy smokers, heavy drinkers, or those who have a chronic infection age much sooner. The solar reaction also causes aging and even people who do extreme sports continuously age much sooner. They are external factors that act on our cells.
There is a part of aging that is genetic and another part that is environmental. Which one has more weight?
It depends on the people, their habits and their genetics. For example, we have published an article in Science where we discovered that there is an environmental agent called formaldehyde, which changes your epigenetics and worsens it, and is associated with diseases such as cancer and others. But there are genetic factors: if your parents have lived more than 90 years, you have a high probability of living it. Even so, there are genetic factors that are sometimes due to mutations, and accumulating mutations in your DNA early is not good.
So what percentage of aging is genetic and what percentage can we vary with habits?
It is difficult to calculate. I like to think that it is 50%, that is, half is determined by what we do. It was proven in a study with twin brothers. One stayed on earth and another went to space. The genetics were the same, what mattered was weightlessness, radiation, etc. The one in space obviously aged more, since it is a very aggressive environment for humans. We are not prepared to run on the savannah or to go to space.
So, half of our aging is in our hands?
At least half, if not more. That's clear. An example: cardiovascular disease. A high-fat diet damages the walls, making us age inside and out. Excess food, sweets... Type 2 diabetes and obesity make us age a lot.
Avoid tobacco and alcohol, avoid a sedentary lifestyle... Do we already know it all?
Now we know the decalogue of healthy living, but we also know the cellular pathways where this acts.
In food, fasting and “calorie restriction” are fashionable...
In mice, staying a little hungry makes them live a little longer, and this may be the key. But this has not been clearly demonstrated in humans and, therefore, we must avoid uncontrolled or regulated diets. Intermittent fasting? You have to avoid all those kinds of things because there is no clear demonstration that they contribute. The balance would be in the middle, neither eating too much nor too little.
In Japan they follow the 'hara hachi bu', eating only up to 80%, not until you are full...
The oldest people in the world are usually in Japan and are usually women. There are two factors. One has to do with diet: in Japan there is more consumption of oily fish, which is beneficial for health. The second factor is that they are women and women typically live longer than men.
At 40, 50 or 70 years old, can we still do something to age better? Or is there an age at which it is too late to act?
It is never too late to take care of yourself, slow down aging and have a longer life. It's never too late! Our cells are quite flexible. If behaviors are changed, cells can go back. If a smoker stops smoking, his or her lung, mouth, or throat cells return pretty much to what they were - although not completely. In the same way, it helps to start doing moderate exercise. As we age we lose skeletal muscle and exercise prevents that. Strengthening muscle and bone is key, especially in women, because due to hormonal deficiency there are alterations. But this is true for both men and women.
What role do social relationships have?
Active social life is very important. María Branyas always had a very valuable social life, many friends and a very beneficial family circle. This helps us age better for many reasons, because our brain is a very adaptable organ and the more different pathways it can use, the more circuits, the better. If you do the same thing every day and you do it alone, there is basically one circuit or at most two. If you have many neural circuits, that helps to achieve better old age, preserving maximum cognitive capacity.
Oxidation is an aging process. Does taking antioxidants work?
Oxidation means that, little by little, our proteins, which are the ones that perform the functions of our cells, change chemically and lose their activity because they become oxidized. Now there is a big business in antioxidants, but the scientific bases of this business are not so clear, most of these products are parapharmaceuticals, they have not been approved by a clinical committee or by a clear study. Therefore, its effectiveness is clearly under discussion. Some may be associated with excess disease: it is just as bad to be hypooxidized as hyperoxidized.
And as for anti-aging hormonal therapies (with capsules, subcutaneous chips...). Is its effect proven?
There are hormonal therapies, especially for women, that, under a doctor's prescription, may be appropriate. But it is true that there are many hormonal treatments that do not have a clear scientific basis. The cellular pathways, which have been discovered in the last 10 years, are going to generate much more specific drugs. There will be specific anti-aging drugs coming soon. They will be molecules with complex names, sometimes derived from natural products, but chemically modified. For example, they will have an effect by inducing specific caloric restriction where it touches, preventing the oxidation of the specific protein that needs it, or helping to repair the DNA it touches. Maybe they will be multi-pills.
How many years can it take us to see these drugs?
We believe that in ten years these drugs will be completely available, drugs that will reduce the aging of cells.
Will they be available for patients with specific diseases or for everyone?
If they are available for specific diseases, we will be giving a lot of life expectancy already with the three major chronic diseases of old age: cancer, cardiovascular disease and neurodementia. Treatments against these three already give us survival and healthier aging. This would add 10-15 more years and we would almost reach 100 years of life expectancy. These drugs will surely also be approved by public health, because they will eventually reduce the pathology, will be cheap, and will make us go to the hospital less, reducing public spending.
How is the research to slow aging with stem cells?
Stem cells are capable of regenerating tissue. As we get older, we lose them. There is more and more investment in this, it is very cutting-edge research to try to regenerate stem cells. This will surely arrive later than drugs, because it requires a slightly more complex biology.
Cancer is one of the diseases of aging. At what point are we in terms of survival?
Today 65% of tumors are cured and each year between 1.5 and 2% more global cures are usually added. In 10 years we may reach 75 or 80% cure of all cancer cases. Let us remember that the peak of cancer is at 62, 65 years, when more new cases appear.
The number of new cancer cases among those under 50 years of age increased by 79.1% worldwide between 1990 and 2019, according to BMJ Oncology. What's going on?
There are many factors. First, they are detected more when they are smaller, through the screening system. Second, there are good diagnoses, before we didn't know what it was and now we give it a very clear name. There are many new cases, but there are many cures. Uterus cancer was the leading cause of death from cancer in the state and now has a mortality rate of 5 or 10% of cases.
Will we soon be able to know if we have early-stage cancer with blood tests?
We must investigate for early detection, when the disease is minimal. Increasingly, thanks to liquid biopsy, which detects blood, it can be determined if there is a risk of cancer (because there is a certain gene) or if there is a small tumor. This is starting to be done now, there is a lot of investment in it, it would be a great advance.
Alzheimer's, the great brain disease, has no cure. What point are we at?
If we have a generation that frequently reaches 90 or 95 years old, but they have Alzheimer's, they will be in a pseudozombie state for many years. That is suffering for them, for the environment, for society, for everyone. This is a high priority investigation. Now we have a drug that slows down early cases, but it is still very expensive and experimental.
Can Alzheimer's prevention be done?
It is complicated, it is a disease associated with this dissociation between age as a species and the age we are, because our brain has still adapted us to that. There may also be environmental factors, such as small metals from air pollution. It is believed that more balanced diets (without excess sugar or fat) would help because there is a type of dementia due to fat deposits in the brain. Furthermore, if there are different alternative neural circuits, it takes a little longer for the disease to develop: many social contacts and many activities will help us.
