Pura Muñoz, biologist: ‘It is possible to reverse aging, to go back in time’

A year ago, a disconcerting project was presented to the world: a multinational company with four Nobel Prize winners on board, a huge $3-bilion budget and a very ambitious objective — to extend how long humans can live in good health. For months, the company, called Altos Labs, secretly signed dozens of the best scientists in the world, offering them salaries of more than $1 million a year. In March, Altos Labs — backed in the shadows by the Russian-Israeli billionaire Yuri Milner — recruited Spanish biologist Pura Muñoz Cánoves, winner of Spain’s National Research Award, who until then, was professor at the Pompeu Fabra University in Barcelona.

Muñoz Cánoves, 61, revealed the mechanisms of aging and muscle regeneration. Her Spanish laboratory designed strategies that managed to repair the muscle tissue of old mice, increasing the self-cleaning of their cells and eliminating damaged ones. At the Altos Labs headquarters in San Diego, Muñoz Cánoves and her colleagues are now focusing on a new paradigm: the aim is no longer to fix what is damaged, but to literally rejuvenate the human body.

One of Altos Labs’ advisors is Japanese doctor Shinya Yamanaka, who won the Nobel Prize for Medicine in 2012 for discovering that an adult cell — from the skin of a finger, for example — can be reprogrammed and return to an embryonic state, capable of becoming into any other type of cell, such as a neuron in the brain. The necessary chemical cocktail — consisting of four molecules known as Yamanaka factors — has already shown its effectiveness in mice, which have lived 30% longer and experienced apparent rejuvenating effects on their tissues, according to the results of pioneering experiments carried out by Spanish scientists Juan Carlos Izpisua, Manuel Serrano and María Abad. Altos Labs has also signed these three researchers to the team. Muñoz Cánoves explains the goals of her research after taking part in the Trends 2023 event, organized by EL PAÍS.

Question. A mouse lives three years, a squirrel can live 25 and the shaved mouse even exceeds 40 years, being quite similar animals. Can we dream of multiplying human life expectancy by 10?

Answer. And whales live 200 years. We do not know why some species have such a long lifespan and others have such a short lifespan. I don’t know the causes, but I think what we have to try is to live better. If we accept as a true premise that there is a greater risk of diseases with aging, a new branch of biomedicine focuses its interest on keeping the body young, as long as possible, to prevent diseases or make them appear as late as possible. This is also the premise of Altos: trying to keep cells, and organisms, young and healthy as long as possible. It is a new paradigm that involves preventing the appearance of diseases in a general way and not one by one. Altos’ strategy is to rejuvenate with reprogramming: try to turn back the clock a little, to delay the entire onset of diseases. It is very incipient and is still far from being put into practice.

Q. American experts Matt Kaeberlein and Brian Kennedy stated in 2009 in the journal Nature that a pill to extend life was science fiction. Is that still the case?

A. I think not so much anymore, almost 15 years have passed. The new philosophy is to try to stay young to generally stop the diseases associated with aging. It is the opposite of precision medicine, which is highly personalized. This is general medicine: keeping cells young so that the risks associated with the passage of time do not appear so soon. But it’s still early.

Q. Do you think it’s possible for a pill to stop cancer, Alzheimer’s and cardiovascular diseases altogether?

A. No, not a pill. They will have to be treated on different fronts. In Altos, what we are trying is to make the cells stronger. As time goes by, cells lose their weapons to stop stress and become more vulnerable. If they rejuvenate themselves with reprogramming methods, they will be able to better deal with stress and prevent illness. This is still early. We have to see how to reprogram cells safely.

Q. An injection?

A. We are not there yet. We are beginning to understand how to turn back the clock. Matt Kaeberlein and Brian K. Kennedy said in 2009 that there may be a pill that will make us stay younger longer, but it was still science fiction. They were likely referring to rapamycin or metformin pills, which prevent aging. What remains a long way off is actually reversing diseases associated with aging — turning back the clock.

Q. Reverse aging?

A. Reverse it, yes, but we already know that this has been possible in experiments with mice and in human cells. Shinya Yamanaka won the Nobel Prize for it. The proof of concept, with its risks, is there: aging can be reversed. A cell can become younger. Yamanaka managed to return it to the embryonic stage zero, but there is no need to return there. Juan Carlos Izpisua’s experiments show that controlled pulses of four Yamanaka factors, in a mouse model of premature aging, helped them to live longer and improved tissue function and regeneration in normal aging mice. That has already happened, Altos is working on ways to translate these approaches to humans but this will take some time.

Q. It is possible, conceptually, to go back in time in the cells of a human being.

A. I’m not talking about human beings, I’m talking about mice, but yes, it is possible in human beings, Altos and others have demonstrated this in human cells.

Q. In animals, then.

A. In animals. This has already occurred in a mouse model of progeria and normal aging mice. The proof of concept is there: it is possible to go back in time a little. And that proof of concept gives you hope of figuring out how to do it safely. But this is still a long way off. Altos, like other companies, wants to start from the basis of rejuvenating cells so that they are healthier, younger and with greater resilience to better cope with diseases associated with the passage of time. Deep down it is very simple, but it will not happen tomorrow.

Q. Izpisua announced in EL PAÍS in March 2022 his intention to rejuvenate monkeys by reprogramming their cells. It is the necessary step to jump from mouse to human.

A. Yes, but we also have to understand how it happens. Now we only have the proof of concept in mice and human cells. We do not know how these factors cause cells to go back in time but Altos is focused on understanding this.

Q. The Yamanaka experiments were almost two decades ago.

A. But that was going back to day zero, in vitro. It was returning to the embryonic state. Manuel Serrano’s team did it in mice [in 2013], returning to day zero, but there were tumors. Izpisua’s thing is to go back a little bit in time, without creating damage. Nobody wants to go back to the embryonic stage. Why would you? In that state the tissues do not function.

Q. Israeli doctor Nir Barzilai has been seeking funding for years for a large clinical trial with thousands of people to test whether metformin — a drug widely used to control the amount of sugar in the blood in patients with type 2 diabetes — delays aging diseases en bloc: cancer, Alzheimer’s, cardiovascular diseases.

A. Metformin and rapamycin are compounds that increase longevity in some species. And it all goes together: if the state of health is prolonged, almost consequently, there will be greater longevity. They are compounds that prolong functionality. What Altos is focused on is how to turn back the clock: reprogram the cells so that they return to a previous state and recover their function. It is a proof of concept that has already been demonstrated, but is very far from being applied. Rapamycin and metformin can be taken, but there are no cocktails that can be administered in humans to try to reverse the clock with cell reprogramming methods with Yamanaka factors or others. They are still laboratory techniques.

Q. The book Dying Young at 140, written by molecular biologist María Blasco and journalist Mónica Salomone, says that the oldest animal in the world is a clam from Iceland that lived 507 years. Is there something biological that prevents us from living 507 years?

A. We do not know why whales live 200 years, a mouse lives three and we live 80. Perhaps by understanding evolutionary biology we can incorporate natural strategies of some species and make them our own to live better. Paraphrasing María Blasco, what we all want is to die young after many years of life. But we are all going to die, because we are mortal.

Q. Do you believe that the 140 years in the title of that book are achievable?

A. We have better hygiene, vaccines, access to education, to healthcare. It will not be very complicated for those already born to live to 100 years, or more than 100 for those born now. But I don’t know if it will be 120, 130, 140. Rejuvenating and turning back the clock is something very revolutionary that is not going to happen tomorrow, but I think that the accumulation of advances is going to generate synergies that will make us go faster than we think now.

Q. Only one person has lived more than 120 years, Frenchwoman Jeanne Calment (1875-1997).

A. Yes, now there is a 116-year-old lady in Catalonia [Maria Branyas]. Before we did not see diseases that are now common, such as Alzheimer’s, because people did not reach the age of 80 or 90. There are diseases that we do not know about today and that will appear when it is normal, if it ever becomes normal, to exceed 100 years of age.

Q. Typical diseases when you are 120 years old.

A. We don’t know those.

Q. You have focused on researching muscle regeneration. The first one that usually comes to mind is the biceps of the arm, but the beating heart or the diaphragm that allows you to breathe are also muscles. Why do our cells stop working?

A. I have dedicated myself to trying to see how to repair skeletal muscle, which is not so different from how to repair other tissues. We have to find out why it malfunctions, try to repair it with stem cells and form new tissue. It’s like repairing a car. The new paradigm is not to change something specific that works poorly, but to go back so that everything works better.

Q. If Izpisua and his Chinese colleagues are successful and rejuvenate monkeys through reprogramming, how could the leap be made to humans?

A. That work is early and has years left and much to be understood before it might be possible to move in to humans.

Q. A promising experimental cancer treatment can be tested on dying patients who have no other alternative, but how could a non-aging treatment be tested on healthy people?

A. Altos’ mission is focused on reversing disease and not on anti-aging per se. In people, the mechanisms of turning back the clock are not going to be a pill in a few years. First you have to know how they work and prevent side effects. Until we know how it happens and what risks it has, it surely cannot be managed.

Q. Do you take rapamycin or metformin?

A. No, I know people who take it amateurishly, but not me.

Q. And do you restrict calories?

A. In my laboratory we have worked with calorie restriction in mice and it works. We see that their muscle aging is better than that of their counterparts who eat ad libitum. We have also studied time-restricted eating: eating the same thing, but in only eight hours. We see that the mice are much better, they have better autophagy and a better circadian rhythm, which we all lose during aging. The rhythm imposed by food — by the timing of the meal, not so much by eating less — makes these functions more defined. Many functions improve by eating in a restricted time, we are seeing beneficial effects. Their muscles are better when they eat for several months at a certain time. We have seen that their muscles look like those of younger mice.

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