Rejuvenating our cells can make them more prone to cancer
Stanford University researcher Thomas Rando talks about efforts to increase the number of healthy years we live
Life hides a disturbing paradox. The body deteriorates inexorably over time and death is an irreversible event. However, some of our cells, even if we are over thirty, can unite to form a new being with all life ahead of them. For years, scientists have been spying on nature to try to decipher the keys to this trick and to be able to turn back the clock on our cells.
Thomas Rando (Brooklyn, New York, 1957), a researcher at Stanford University, is one of these scientists. In his laboratory they are trying to understand some of the closest processes to rejuvenation that have been achieved so far. The reprogramming of adult tissue cells, for example, allows them to be converted into pluripotent stem cells, something similar to giving them back their youth. However, this way of restarting the cell chronometer has a problem. Cells in organs like the liver need to be specialized to do their job and if they are reprogrammed all the way through they lose that specialization. Reprogramming should be stopped long before that happens.
Rando has visited Madrid this week to participate along with other researchers involved in this anti-aging epic. At the CNIO-"la Caixa" Frontiers Meetings, organized by the National Cancer Research Center, he has shared a forum with researchers such as María Blasco, who in 2008 managed to extend the life of mice by 40%, or Juan Carlos Izpisúa, who in 2016 managed to reverse the aging in these same animals. Achievements such as these make us think, for the first time in the history of humanity, that one day there will be weapons to combat the damage caused by the passage of time.
Question: Is it possible to reverse aging?
Answer: Experiments, on organisms such as mice and worms, indicate that you can take these animals and treat them with a drug or give them some other intervention and make all their cells look and behave as if they were younger. The challenge in humans is to find out if it's safe. In animals, there is nothing wrong in the short term, but we are concerned that there may be a catch. For example, if you take an old animal and make the cells look younger, you may make them more likely to develop cancer.
Question: When you talk to cancer researchers, they tell you how complicated it is to stop the processes that cause these diseases, because they are integrated into our normal biology, and when you talk to Alzheimer's researchers you see that they have had little success in fighting the disease. But then you talk to people who are working on aging and they seem to be able to solve all these problems without dealing with them directly, in another way, by fighting the processes of aging that increase the risk of cancer or Alzheimer's.
Answer: One of the things we don't understand about diseases like Alzheimer's, cardiovascular disease or type 2 diabetes is why they occur so much more often when we get older. There is something about aging that seems different from all of these diseases. If, by studying the biology of aging, we are able to modify the aging process or its effects, we can have an impact on all of these age-related diseases, in that they appear later or their severity is reduced.
We are not talking about treating disease but preventing it. For some reason, when we get older we are more vulnerable to disease, so we want to increase our resistance, which is something we think has to do with the aging process, which is a loss of resistance. If this is achieved, it could delay the onset of many diseases and that is where the notion of healthy life expectancy comes in. It is not so much about making people live longer, but living longer without disease.
Cancer is something else, but it is also a disease related to aging. It presents a particular challenge, because our work on reversing aging suggests that there are two sides to the same coin. On one side is aging and on the other is cancer. If we modify all the cells to be younger, we may be making them more susceptible to this type of hyperproliferation that we see in cancer.
Question: When you talk about increasing healthy life expectancy, how long do you think that is feasible in the medium term? There are people who say that we will live for centuries, millennia or even in fifty years' time we will no longer die of old age, or we will totally reverse aging. Do these statements seem reasonable to you?
Answer: The person we know who has lived the longest has reached 122 years of age. Typically, we talk about the longest living people reaching between 110 and 120. That our understanding of the biology of aging processes makes it possible for people to live 150 or 200 years seems quite unlikely. Throughout human history, regardless of dietary changes, medical treatments, or supplements taken, nothing has changed the fact that we live to this limit at around 120. Some animal studies suggest that you can extend their life expectancy, but the closer you get to humans, the less effect we see. This has not been studied in humans, obviously, but even in primates it is only possible to add a few years, but not double the life expectancy.
Question: In super-centenarians, sometimes it seems that it doesn't matter whether they live a healthy life or not. Do we know anything about that special protection they seem to have?
Answer: We understand very little. When you ask these supercentennials about their lifestyle, there is no magic recipe, special diet, special exercise or supplements. There are people from many parts of the world with very different lifestyles who reach these ages healthy. That said, when you look at populations around the world that have the longest populations, like the Sardinians or Okinawans, they have things in common: Low-carb diets, they eat a lot of vegetables, and they tend to be physically active. There are some clues, but there is no answer on how to live beyond 100 years and stay healthy.
Question: Is it already possible to design drugs to increase healthy longevity in humans?
Answer: The hope is that our studies can help create therapies and drugs that people can take to alter their metabolism and somehow gain resistance to diseases of aging. But what we don't know is if there are people, even though they almost certainly exist, for whom these treatments will cause life-shortening problems.
We do many of our studies on organisms that are identical to each other, such as mice or worms. Although we see that there are treatments that work in mice that are genetically identical, it's possible that that will only work in a very small group of humans. Among people who are genetically very different, some may benefit, but others may suffer.
Question: Is it necessary to fully understand the biological processes that seem to reset the clock of life in order to create anti-aging treatments, or can we try things that we see working even if we don't know why?
Answer: We still don't understand very well what happens during fertilization, when the clock runs out and you start over again, but it seems to have to do with what happens with cell reprogramming. When we reprogram the cells to be stem cells, they also become younger. The expectation is that we will be able to understand what the mechanisms are that explain that process and see if we can use it for some therapies. But we are far from that.
Question: Can a person's cells be reprogrammed while maintaining their qualities?
Answer: That's the key. In my own lab we're studying that now, testing the idea that you can reprogram cells to rejuvenate them without turning them into stem cells. You don't want to turn your liver cells into stem cells, you want them to be what they are, but younger, even temporarily.
Question: There are many people in the computer environment who say they will be able to crack the code of life to offer a solution to the problem of aging other than what biologists can offer. Do you think that is possible?
Answer: I think the solutions will come from the intersection of biology and computing. I don't think the code can be broken in a computer without doing experiments to get the data. I see it as a process where you do experiments to get data that are analyzed computationally and then you generate hypotheses and test them in the lab and then you do more analysis. I think it's a back-and-forth game.
Question: Are there clinical trials planned to test any of these hypotheses in humans?
Answer: There are regulatory challenges. Aging is not now considered an approved indication for specific clinical trials in the US. Also, there's a practical problem, because if you're going to test something for aging, you're going to need giant trials for decades and decades. They will be incredibly expensive. It's unlikely that they're going to be the clinical trials that we see in the near future. Instead, I think we will have trials for diseases of aging rather than for aging itself.
Question: Are there already people trying anti-aging therapies on themselves?
Answer: Yes, of course. There are companies that are selling products that are not drugs, that are supplements and therefore not subject to the regulatory process, that say they are going to help you live longer. But we don't know if they work, because they're not subject to clinical trials. There are also people who are taking approved drugs for diseases that they don't have because they think it's the kind of drug that will help them live longer.
Question: Do you know of any promising cases with this self-medication?
Answer: No, because you never know. You never know how a person who is taking something would have aged without the drug, it's something you can't observe outside of trials. They're anecdotes.
