A paper published in Nature Aging earlier this month concluded that it’s unlikely that we will see significant leaps in human life expectancy this century. William Mair, professor of molecular metabolism at Harvard T.H. Chan School of Public Health, shares what researchers know about the biology of aging, the importance of improving health span, and the need to take moonshots.

Q: What did the study find and what conclusions can we draw from it?

A: The study looks back at advances in human life expectancy made between 1990 and 2019 in a number of countries where people typically live longer lives and shows that, while average life expectancy has gone up, maximum lifespan has not changed. Moreover, the pace of increase in average life expectancy has slowed of late. The paper concludes that during that period, medical and public health advances have not slowed human aging and have not done anything to radically prolong lifespan. Certainly, I would agree with that, but I would also add that no strategies have been implemented in that time with that goal in mind.

What we have been doing remarkably successfully is reducing deaths earlier in life and allowing more of us than ever before to reach old age. That incredible success has come at a cost however—revealed by this paper—that our bodies have not evolved the capacity to maintain themselves much beyond our current maximum lifespan. So, our success in allowing more of us to live longer has also given us a much greater burden of age-onset non-communicable diseases, which are causing terrible suffering.

However, as the paper states, historical data show us a ‘glass mortality floor’ of the maximum lifespan a human body can achieve with current medical technologies. What retrospective data simply cannot tell us is if that glass floor can be broken. In fact, the authors themselves conclude that ‘these limits are not brick walls for longevity,’ and on that I’d certainly agree with them.

Q: A key line from the study concludes that “unless the process of biological aging can be slowed, radical human life extension is implausible in this century.” You point out on your website that many organisms, from yeast to primates, can slow the process of aging when nutritional resources are limited. And when they do that, they’re far less susceptible to age-related diseases. Can you walk us through that evidence?

A: Evolution doesn’t care about how long an animal lives. It cares about its ability to pass its genes onto the next generation. We say survival of the fittest, not survival of the oldest. And that’s because for most organisms, death doesn’t come from old age—it comes from infection, accident, or predation. The best strategy then is to eat as much as you can, grow fast and strong, and reproduce, even if that makes your body age faster.

What happens, however, if food becomes scarce? Some organisms have adapted to such stressors by focusing less on growth and reproduction—which require energy—and more on maintaining their body. From an evolutionary standpoint, this allows them to live longer and wait out the famine, at which point they can reproduce.

In the lab, we see this all the time. If you take an animal like a nematode worm, or a fruit fly, or a mouse, and you give it all the food it can eat, it will live fast and die young. It’s programmed to do so. But if you restrict its diet and give it 20% or 30% fewer calories, it will live longer. Interestingly, they will also delay the onset of age-related diseases, such as cancer or cardiovascular diseases.

Q: Could humans slow their aging by limiting their food intake, too?

A: To be able to answer that question definitively would require a human lifespan study with hundreds of people. We can’t do that. However, we are at the point now where we can measure the biological age of an individual and test whether they are aging faster or slower than their chronological age would predict.

Researchers are also starting to do clinical trials on restricted feeding and intermittent fasting in human populations, but we don’t have definitive data yet.

So, the boring answer is, it’s too soon to know. But the exciting answer is that geroscience, the field of aging biology—which didn’t even exist 30 years ago—is trying to work it out.

Q: Your research focuses on understanding the molecular pathways that drive aging. What have you learned so far?

A: My lab thinks that many of the chronic conditions we see in old age—Alzheimer’s disease, cancer, cardiovascular disease, or diabetes—are caused by metabolic dysfunction. These diseases have different etiologies but have one thing in common: Age is their biggest risk factor. My thesis is that they are all linked to dysregulation in metabolism.

When we are young, we can metabolize our nutrients efficiently. We can move between burning sugar during the day and fats at night. As we get old, we become less able to do that. We start to store lipids where we shouldn’t, for example in our organs, which makes us more prone to disease.

I’m interested in understanding what causes this inflexibility and why certain individuals can remain metabolically flexible for longer. Our lab is focused on how a cell senses fuel and controls what we do with it, and how those sensors become less accurate with time.

There are different ways to maintain metabolic flexibility. In the lab, we can do it with diet, drugs, or genetics. But there are also behaviors that could help, and I would love to integrate those two approaches.

Q: Could geroscience lead to interventions that might extend the human lifespan? What breakthroughs would be needed to get there?

A: There are two approaches in the field. One approach is to look at the biological and social factors that help certain people age exceptionally well. There’s something about those people—probably a combination of factors, including genetics, their metabolism, diet, behavior, social integration—which gives them that ability.

This approach will not increase the maximum upper limit of human lifespan. What it can do is gradually increase the median lifespan so that more and more people can reach that upper limit. It’s the type of work that is critical to the mission of our School.

The other approach is to look at whether we can we change the actual biology of human aging. We are looking at cell and tissue rejuvenation, for example. The field is still in its infancy, so it is impossible to know if we’ll be successful or not. That’s the beauty of science.

There is no intellectual reason why we can’t break this upper limit of human lifespan of about 90 years. Public health hasn’t broken it yet, because that’s not what the goal of public health is. Could it be broken through targeting the biology of aging? Quite possibly.

Q: Where do you think the science of longevity should focus? What questions do we most need answers to?

A: We should focus both on what we can do now to improve health span and on a few moonshots.

There is a lot of research being done on aging. My department looks at it from a biological perspective, but there are people in epidemiology, nutrition, and social and behavioral sciences who are looking at it, too. We need to integrate these disciplines to better understand how we can help people age better. We need to test different interventions and quantify what happens to our cells and tissues when those interventions work. Working across disciplines is by far the most promising thing we can do in the field in the short term.

I am in the early stages of building a healthy aging initiative across our School to bring together researchers working on this—I believe we may be the only institution in the world that’s looking at aging from all these angles, but we need to do a better job integrating and funding our work.

We also need to invest in the so-called moonshots, or all those things we’ve successfully tried in a lab in a simple organism, but don’t yet know if they can work in humans. For example, looking at strategies that could turn adult cells back into stem cells. These rejuvenation techniques may one day be used to slow cell and tissue aging and even revert cells to more youthful states. These are high-risk, high-reward projects. My concern with [the Nature Aging] paper is that it will lead people to believe these moonshots are impossible, so we should not invest in them. That would be a critical mistake.

Q: You’ve expressed concern about the way some researchers and doctors talk about longevity. What misinformation is out there and how can it be harmful?

A: There are an increasing number of health influencers who have almost an evangelical following and make bold statements about how to live longer, for example, ice therapy, heat shock, and so on. What they are doing is extrapolating data—from simpler organisms, small sample studies, and non-causal correlative studies—and telling people it’s the truth. That’s not how the scientific process works.

I worry that in a world where people have limited attention spans, the people who speak with confidence and say they have already cured aging will get the microphone. And they either give people false hope or they give a bad name to a field where a lot of great research is being done slowly and carefully.

We all age and we all know someone who is suffering from an age-related condition. We all wish we had something that could help us live longer and age better. But science cannot speak in absolutisms.

When someone asks me if humans will be able to live to 300 one day, the only responsible answer I can give is, “I don’t know, yet!” But that’s not going to get me a lot of hits on TikTok, is it?

 

 

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