A year ago, the world was presented with a disturbing project: a multinational corporation with four Nobel Prize winners on board, a huge budget of $3 billion and a very ambitious goal – extending the life expectancy of people in good health. For months, the company called Altos Labs secretly signed dozens of the world's top scientists, offering them salaries of more than $1 million a year. In March, Altos Labs – backed in the shadow of Russian-Israeli billionaire Yuri Milner – recruited Spanish biologist Pura Muñoz Cánoves, winner of the Spanish National Research Prize, who was by then a professor at Pompeu Fabra University in Barcelona.
Muñoz Cánoves, 61, revealed the mechanisms of aging and muscle regeneration. Her Spanish laboratory developed strategies to repair the muscle tissue of old mice, increase the self-cleaning of their cells and eliminate damaged cells. At Altos Labs' headquarters in San Diego, Muñoz Cánoves and his colleagues are now relying on a new paradigm: the goal is no longer to repair damage, but to literally rejuvenate the human body.
One of Altos Labs' advisors is Japanese doctor Shinya Yamanaka, who won the Nobel Prize in Medicine in 2012 for discovering that an adult cell – from the skin of a finger, for example – can be reprogrammed and revert to an embryonic state capable of doing so capable of transforming into another type of cell, for example into a neuron in the brain. The necessary chemical cocktail – made up of four molecules known as Yamanaka factors – has already shown its effectiveness in mice, which lived 30% longer and experienced seemingly rejuvenating effects on their tissues, according to the results of groundbreaking experiments by Spanish scientist Juan Carlos Izpisua, Manuel Serrano and Maria Abad. Altos Labs also added these three researchers to the team. Muñoz Cánoves explains the objectives of her research after participating in the “Trends 2023” event organized by EL PAÍS.
Ask. A mouse lives to be three years old, a squirrel can live to be 25 years old, and the shaved mouse even lives to be over 40 years old, as they are quite similar animals. Can we dream of increasing human life expectancy tenfold?
Answer. And whales live 200 years. We don't know why some species have such a long lifespan and others such a short one. I don't know the causes, but I think we have to try to live better. If we assume that there is a higher risk of disease as we age, a new branch of biomedicine focuses on keeping the body young for as long as possible to prevent disease or make it appear as late as possible. This is also the premise of Altos: to keep cells and organisms young and healthy for as long as possible. It is a new paradigm that aims to prevent the occurrence of diseases in general and not individually. Altos' strategy is to rejuvenate itself through reprogramming: try to turn back the clock a little to delay the entire outbreak of disease. It is still in its infancy and is still far from being put into practice.
Q American experts Matt Kaeberlein and Brian Kennedy explained in the journal Nature in 2009 that a life-extension pill was science fiction. Is it still like that?
TO. I don't think so much anymore, it's been almost 15 years. 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 emerge so quickly. But it's still early.
Q Do you think a pill can completely stop cancer, Alzheimer's and cardiovascular disease?
TO. No, not a pill. They need to be dealt with on various fronts. In Altos we are trying to make the cells stronger. Over time, cells lose their ability to stop stress and become more vulnerable. When they regenerate using reprogramming methods, they can better deal with stress and prevent disease. That's still early. We need to see how we can safely reprogram cells.
Q An injection?
TO. We're not there yet. We are beginning to understand how we can turn back the clock. Matt Kaeberlein and Brian K. Kennedy said in 2009 that there might be a pill that would keep us young longer, but that was still science fiction. You were probably referring to rapamycin or metformin pills, which prevent aging. What is still a long way off, however, is the actual reversal of age-related diseases – i.e. turning back the clock.
Q Reverse aging?
TO. Yes, reverse, but we already know that this was possible in experiments with mice and in human cells. Shinya Yamanaka received the Nobel Prize for this. The proof of concept with its risks is there: aging can be reversed. A cell can become younger. Yamanaka managed to return it to 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 live longer and improve tissue function and regeneration in normally aging mice. This has already happened, Altos is working on ways to translate these approaches to humans, but this will take some time.
Q It is conceptually possible to travel back in time in a human's cells.
TO. I'm not talking about humans, I'm talking about mice, but yes, it is possible in humans, Altos and others have shown this in human cells.
Q So with animals.
TO. In animals. This has already happened in a mouse model of progeria and normal aging mice. The proof of concept is there: it is possible to travel back in time a little. And this proof of concept gives you hope in figuring out how to do it safely. But that is still a thing of the future. Altos, like other companies, wants to start rejuvenating cells so that they become healthier, younger and more resilient to better withstand diseases that come with time. It's actually quite simple, but it won't happen tomorrow.
The biologist Pura Muñoz Cánoves was photographed in Madrid on November 21.JUAN BARBOSA
Q Izpisua announced in March 2022 in EL PAÍS his intention to rejuvenate monkeys by reprogramming their cells. It is the necessary step to go from mouse to human.
TO. Yes, but we also need to understand how it happens. Now we only have proof of concept in mice and human cells. We don't know how these factors cause cells to go back in time, but Altos is focused on understanding this.
Q The Yamanaka experiments date back almost two decades.
TO. But that went back to day zero, in vitro. It returned to the embryonic state. Manuel Serrano's team did it with mice [in 2013], return to day zero, but there were tumors. Izpisua's thing is to go back in time a little without causing any damage. Nobody wants to go back to the embryonic stage. Why would you? In this condition the tissues are not functional.
Q Israeli doctor Nir Barzilai has been seeking funding for years for a large clinical trial involving thousands of people to test whether metformin – a drug often used to control blood sugar levels in patients with type 2 diabetes – reduces age-related diseases overall delayed: cancer, Alzheimer's, cardiovascular diseases.
TO. Metformin and rapamycin are compounds that increase life expectancy in some species. And all in all: if the state of health is prolonged, it almost inevitably leads to a longer life expectancy. These are connections that extend functionality. Altos is focused on turning back the clock: reprogramming cells to return to a previous state and restore function. It is a proof of concept that has already been demonstrated but is still far from being used. Rapamycin and metformin can be taken, but there are no cocktails that can be given to people to try to reverse the clock using cell reprogramming methods using Yamanaka factors or others. These are still laboratory techniques.
Q The book Dying Young at 140, written by molecular biologist María Blasco and journalist Mónica Salomone, states that the world's oldest animal is said to have come from Iceland and was 507 years old. Is there something biological that prevents us from living 507 years?
TO. We don't know why whales live to be 200 years old, a mouse to three, and us to 80 years old. Perhaps by understanding evolutionary biology we can integrate the natural strategies of some species and make them our own to live better. To paraphrase María Blasco: What we all want is to die young after many years of life. But we will all die because we are mortal.
Q Do you think the 140 years in the title of this book is achievable?
TO. We have better hygiene, vaccines, access to education and healthcare. For those who have already been born, it will not be very complicated to live 100 years, and for those who are born now, more than 100 years. But I don't know if it will be 120, 130, 140. Innovating and turning back time is something very revolutionary that will not happen tomorrow, but I think that the accumulation of advances will create synergies that will make it possible for us to move forward faster now than we think.
Q Only one person lived more than 120 years, the Frenchwoman Jeanne Calment (1875-1997).
TO. Yes, there is now a 116-year-old woman in Catalonia [Maria Branyas]. In the past, there were no diseases that are widespread today, such as Alzheimer's, because people were not yet 80 or 90 years old. There are diseases that we don't know about today that appear when it is normal, if it ever was normal, over 100 years old.
Q Typical illnesses at the age of 120.
TO. We don't know them.
Q They have focused on researching muscle regeneration. The first thing that usually comes to mind is the biceps of the arm, but the beating heart or the diaphragm that enables breathing are also muscles. Why do our cells stop working?
TO. I dedicated myself to trying to figure out how to repair skeletal muscle, which is not that different from repairing other tissues. We need to figure out why it isn't working properly, try to repair it with stem cells, and create new tissue. It's like repairing a car. The new paradigm is not about changing something specific that is working poorly, but about going back to make everything work better.
Q If Izpisua and his Chinese colleagues succeed in rejuvenating monkeys through reprogramming, how could the leap to humans succeed?
TO. This work is still in its early stages, with years to go and much still to be understood before it can potentially be translated to humans.
Q A promising experimental cancer treatment can be tested on dying patients who have no other alternative, but how could an anti-aging treatment be tested on healthy people?
TO. Altos' mission is focused on reversing disease, not anti-aging per se. In humans, the mechanisms for turning back the clock will no longer be a pill in a few years. First you need to know how they work and prevent side effects. Until we know how it happens and what risks it poses, we certainly cannot manage it.
Q Are you taking rapamycin or metformin?
TO. No, I know people who approach it amateurishly, but not me.
Q And do you restrict calorie intake?
TO. In my lab we worked with calorie restriction in mice and it worked. We see that their muscle aging is better than that of their counterparts who eat ad libitum. We also examined time-restricted eating: eating the same thing, but in just eight hours. We see that the mice are doing much better, they have better autophagy and a better circadian rhythm, which we all lose as we age. The rhythm set by food – by the timing of the meal, not so much by eating less – defines these functions more strongly. Many functions improve through eating in a limited time, we see positive effects. Your muscles will be better if you eat at a specific time for several months. We saw that their muscles resemble those of younger mice.
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