How aging clocks can help us understand why we age—and if we can reverse it

Be honest: Have you ever looked up someone from your childhood on social media with the sole intention of seeing how they’ve aged? 

One of my colleagues, who shall remain nameless, certainly has. He recently shared a photo of a former classmate. “Can you believe we’re the same age?” he asked, with a hint of glee in his voice. A relative also delights in this pastime. “Wow, she looks like an old woman,” she’ll say when looking at a picture of someone she has known since childhood. The years certainly are kinder to some of us than others.

But wrinkles and gray hairs aside, it can be difficult to know how well—or poorly—someone’s body is truly aging, under the hood. A person who develops age-related diseases earlier in life, or has other biological changes associated with aging (such as elevated cholesterol or markers of inflammation), might be considered “biologically older” than a similar-age person who doesn’t have those changes. Some 80-year-olds will be weak and frail, while others are fit and active. 

Doctors have long used functional tests that measure their patients’ strength or the distance they can walk, for example, or simply “eyeball” them to guess whether they look fit enough to survive some treatment regimen, says Tamir Chandra, who studies aging at the Mayo Clinic. 

But over the past decade, scientists have been uncovering new methods of looking at the hidden ways our bodies are aging. What they’ve found is changing our understanding of aging itself. 

“Aging clocks” are new scientific tools that can measure how our organs are wearing out, giving us insight into our mortality and health. They hint at our biological age. While chronological age is simply how many birthdays we’ve had, biological age is meant to reflect something deeper. It measures how our bodies are handling the passing of time and—perhaps—lets us know how much more of it we have left. And while you can’t change your chronological age, you just might be able to influence your biological age.

It’s not just scientists who are using these clocks. Longevity influencers like Bryan Johnson often use them to make the case that they are aging backwards. “My telomeres say I’m 10 years old,” Johnson posted on X in April. The Kardashians have tried them too (Khloé was told on TV that her biological age was 12 years below her chronological age). Even my local health-food store offers biological age testing. Some are pushing the use of clocks even further, using them to sell unproven “anti-aging” supplements.

The science is still new, and few experts in the field—some of whom affectionately refer to it as “clock world”—would argue that an aging clock can definitively reveal an individual’s biological age. 

But their work is revealing that aging clocks can offer so much more than an insta-brag, a snake-oil pitch—or even just an eye-catching number. In fact, they are helping scientists unravel some of the deepest mysteries in biology: Why do we age? How do we age? When does aging begin? What does it even mean to age?

Ultimately, and most importantly, they might soon tell us whether we can reverse the whole process.

Clocks kick off

The way your genes work can change. Molecules called methyl groups can attach to DNA, controlling the way genes make proteins. This process is called methylation, and it can potentially occur at millions of points along the genome. These epigenetic markers, as they are known, can switch genes on or off, or increase or decrease how much protein they make. They’re not part of our DNA, but they influence how it works.

In 2011, Steve Horvath, then a biostatistician at the University of California, Los Angeles, took part in a study that was looking for links between sexual orientation and these epigenetic markers. Steve is straight; he says his twin brother, Markus, who also volunteered, is gay.

That study didn’t find a link between DNA methyl­ation and sexual orientation. But when Horvath looked at the data, he noticed a different trend—a very strong link between age and methylation at around 88 points on the genome. He once told me he fell off his chair when he saw it. 

Many of the affected genes had already been linked to age-related brain and cardiovascular diseases, but it wasn’t clear how methylation might be related to those diseases. 

If a model could work out what average aging looks like, it could potentially estimate whether someone was aging unusually fast or slowly. It could transform medicine and fast-track the search for an anti-aging drug. It could help us understand what aging is, and why it happens at all.

In 2013, Horvath collected methylation data from 8,000 tissue and cell samples to create what he called the Horvath clock—essentially a mathematical model that could estimate age on the basis of DNA methylation at 353 points on the genome. From a tissue sample, it was able to detect a person’s age within a range of 2.9 years.

That clock changed everything. Its publication in 2013 marked the birth of “clock world.” To some, the possibilities were almost endless. If a model could work out what average aging looks like, it could potentially estimate whether someone was aging unusually fast or slowly. It could transform medicine and fast-track the search for an anti-aging drug. It could help us understand what aging is, and why it happens at all.

The epigenetic clock was a success story in “a field that, frankly, doesn’t have a lot of success stories,” says João Pedro de Magalhães, who researches aging at the University of Birmingham, UK.

It took a few years, but as more aging researchers heard about the clock, they began incorporating it into their research and even developing their own clocks. Horvath became a bit of a celebrity. Scientists started asking for selfies with him at conferences, he says. Some researchers even made T-shirts bearing the front page of his 2013 paper.

Some of the many other aging clocks developed since have become notable in their own right. Examples include the PhenoAge clock, which incorporates health data such as blood cell counts and signs of inflammation along with methyl­ation, and the Dunedin Pace of Aging clock, which tells you how quickly or slowly a person is aging rather than pointing to a specific age. Many of the clocks measure methylation, but some look at other variables, such as proteins in blood or certain carbohydrate molecules that attach to such proteins.

Today, there are hundreds or even thousands of clocks out there, says Chiara Herzog, who researches aging at King’s College London and is a member of the Biomarkers of Aging Consortium. Everyone has a favorite. Horvath himself favors his GrimAge clock, which was named after the Grim Reaper because it is designed to predict time to death.

That clock was trained on data collected from people who were monitored for decades, many of whom died in that period. Horvath won’t use it to tell people when they might die of old age, he stresses, saying that it wouldn’t be ethical. Instead, it can be used to deliver a biological age that hints at how long a person might expect to live. Someone who is 50 but has a GrimAge of 60 can assume that, compared with the average 50-year-old, they might be a bit closer to the end.

GrimAge is not perfect. While it can strongly predict time to death given the health trajectory someone is on, no aging clock can predict if someone will start smoking or get a divorce (which generally speeds aging) or suddenly take up running (which can generally slow it). “People are complicated,” Horvath tells MIT Technology Review. “There’s a huge error bar.”

On the whole, the clocks are pretty good at making predictions about health and lifespan. They’ve been able to predict that people over the age of 105 have lower biological ages, which tracks given how rare it is for people to make it past that age. A higher epigenetic age has been linked to declining cognitive function and signs of Alzheimer’s disease, while better physical and cognitive fitness has been linked to a lower epigenetic age.

Black-box clocks

But accuracy is a challenge for all aging clocks. Part of the problem lies in how they were designed. Most of the clocks were trained to link age with methylation. The best clocks will deliver an estimate that reflects how far a person’s biology deviates from the average. Aging clocks are still judged on how well they can predict a person’s chronological age, but you don’t want them to be too close, says Lucas Paulo de Lima Camillo, head of machine learning at Shift Bioscience, who was awarded $10,000 by the Biomarkers of Aging Consortium for developing a clock that could estimate age within a range of 2.55 years.

LEON EDLER

“There’s this paradox,” says Camillo. If a clock is really good at predicting chronological age, that’s all it will tell you—and it probably won’t reveal much about your biological age. No one needs an aging clock to tell them how many birthdays they’ve had. Camillo says he’s noticed that when the clocks get too close to “perfect” age prediction, they actually become less accurate at predicting mortality.

Therein lies the other central issue for scientists who develop and use aging clocks: What is the thing they are really measuring? It is a difficult question for a field whose members notoriously fail to agree on the basics. (Everything from the definition of aging to how it occurs and why is up for debate among the experts.)

They do agree that aging is incredibly complex. A methylation-based aging clock might tell you about how that collection of chemical markers compares across individuals, but at best, it’s only giving you an idea of their “epigenetic age,” says Chandra. There are probably plenty of other biological markers that might reveal other aspects of aging, he says: “None of the clocks measure everything.” 

We don’t know why some methyl groups appear or disappear with age, either. Are these changes causing damage? Or are they a by-product of it? Are the epigenetic patterns seen in a 90-year-old a sign of deterioration? Or have they been responsible for keeping that person alive into very old age?

To make matters even more complicated, two different clocks can give similar answers by measuring methylation at entirely different regions of the genome. No one knows why, or which regions might be the best ones to focus on.

“The biomarkers have this black-box quality,” says Jesse Poganik at Brigham and Women’s Hospital in Boston. “Some of them are probably causal, some of them may be adaptive … and some of them may just be neutral”: either “there’s no reason for them not to happen” or “they just happen by random chance.”

What we know is that, as things stand, none of the clocks are precise enough to predict the biological age of a single person (sorry, Khloé). Putting the same biological sample through five different clocks will give you five wildly different results.

Even the same clock can give you different answers if you put a sample through it more than once. “They’re not yet individually predictive,” says Herzog. “We don’t know what [a clock result] means for a person, [or if] they’re more or less likely to develop disease.”

And it’s why plenty of aging researchers—even those who regularly use the clocks in their work—haven’t bothered to measure their own epigenetic age. “Let’s say I do a clock and it says that my biological age … is five years older than it should be,” says Magalhães. “So what?” He shrugs. “I don’t see much point in it.”

You might think this lack of clarity would make aging clocks pretty useless in a clinical setting. But plenty of clinics are offering them anyway. Some longevity clinics are more careful, and will regularly test their patients with a range of clocks, noting their results and tracking them over time. Others will simply offer an estimate of biological age as part of a longevity treatment package.

And then there are the people who use aging clocks to sell supplements. While no drug or supplement has been definitively shown to make people live longer, that hasn’t stopped the lightly regulated wellness industry from pushing a range of “treatments” that range from lotions to herbal pills all the way through to stem-cell injections.

Some of these people come to aging meetings. I was in the audience at an event when one CEO took to the stage to claim he had reversed his own biological age by 18 years—thanks to the supplement he was selling. Tom Weldon of Ponce de Leon Health told us his gray hair was turning brown. His biological age was supposedly reversing so rapidly that he had reached “longevity escape velocity.”

But if the people who buy his supplements expect some kind of Benjamin Button effect, they might be disappointed. His company hasn’t yet conducted a randomized controlled trial to demonstrate any anti-aging effects of that supplement, called Rejuvant. Weldon says that such a trial would take years and cost millions of dollars, and that he’d “have to increase the price of our product more than four times” to pay for one. (The company has so far tested the active ingredient in mice and carried out a provisional trial in people.)

More generally, Horvath says he “gets a bad taste in [his] mouth” when people use the clocks to sell products and “make a quick buck.” But he thinks that most of those sellers have genuine faith in both the clocks and their products. “People truly believe their own nonsense,” he says. “They are so passionate about what they discovered, they fall into this trap of believing [their] own prejudices.” 

The accuracy of the clocks is at a level that makes them useful for research, but not for individual predictions. Even if a clock did tell someone they were five years younger than their chronological age, that wouldn’t necessarily mean the person could expect to live five years longer, says Magalhães. “The field of aging has long been a rich ground for snake-oil salesmen and hype,” he says. “It comes with the territory.” (Weldon, for his part, says Rejuvant is the only product that has “clinically meaningful” claims.) 

In any case, Magalhães adds that he thinks any publicity is better than no publicity.

And there’s the rub. Most people in the longevity field seem to have mixed feelings about the trendiness of aging clocks and how they are being used. They’ll agree that the clocks aren’t ready for consumer prime time, but they tend to appreciate the attention. Longevity research is expensive, after all. With a surge in funding and an explosion in the number of biotech companies working on longevity, aging scientists are hopeful that innovation and progress will follow. 

So they want to be sure that the reputation of aging clocks doesn’t end up being tarnished by association. Because while influencers and supplement sellers are using their “biological ages” to garner attention, scientists are now using these clocks to make some remarkable discoveries. Discoveries that are changing the way we think about aging.

How to be young again

Two little mice lie side by side, anesthetized and unconscious, as Jim White prepares his scalpel. The animals are of the same breed but look decidedly different. One is a youthful three-month-old, its fur thick, black, and glossy. By comparison, the second mouse, a 20-month-old, looks a little the worse for wear. Its fur is graying and patchy. Its whiskers are short, and it generally looks kind of frail.

But the two mice are about to have a lot more in common. White, with some help from a colleague, makes incisions along the side of each mouse’s body and into the upper part of an arm and leg on the same side. He then carefully stitches the two animals together—membranes, fascia, and skin. 

The procedure takes around an hour, and the mice are then roused from their anesthesia. At first, the two still-groggy animals pull away from each other. But within a few days, they seem to have accepted that they now share their bodies. Soon their circulatory systems will fuse, and the animals will share a blood flow too.

LEON EDLER

White, who studies aging at Duke University, has been stitching mice together for years; he has performed this strange procedure, known as heterochronic parabiosis, more than a hundred times. And he’s seen a curious phenomenon occur. The older mice appear to benefit from the arrangement. They seem to get younger.

Experiments with heterochronic parabiosis have been performed for decades, but typically scientists keep the mice attached to each other for only a few weeks, says White. In their experiment, he and his colleagues left the mice attached for three months—equivalent to around 10 human years. The team then carefully separated the animals to assess how each of them had fared. “You’d think that they’d want to separate immediately,” says White. “But when you detach them … they kind of follow each other around.”

The most striking result of that experiment was that the older mice who had been attached to a younger mouse ended up living longer than other mice of a similar age. “[They lived] around 10% longer, but [they] also maintained a lot of [their] function,” says White. They were more active and maintained their strength for longer, he adds.

When his colleagues, including Poganik, applied aging clocks to the mice, they found that their epigenetic ages were lower than expected. “The young circulation slowed aging in the old mice,” says White. The effect seemed to last, too—at least for a little while. “It preserved that youthful state for longer than we expected,” he says.

The young mice went the other way and appeared biologically older, both while they were attached to the old mice and shortly after they were detached. But in their case, the effect seemed to be short-lived, says White: “The young mice went back to being young again.” 

To White, this suggests that something about the “youthful state” might be programmed in some way. That perhaps it is written into our DNA. Maybe we don’t have to go through the biological process of aging. 

This gets at a central debate in the aging field: What is aging, and why does it happen? Some believe it’s simply a result of accumulated damage. Some believe that the aging process is programmed; just as we grow limbs, develop a brain, reach puberty, and experience menopause, we are destined to deteriorate. Others think programs that play an important role in our early development just turn out to be harmful later in life by chance. And there are some scientists who agree with all of the above.

White’s theory is that being old is just “a loss of youth,” he says. If that’s the case, there’s a silver lining: Knowing how youth is lost might point toward a way to somehow regain it, perhaps by restoring those youthful programs in some way. 

Dogs and dolphins

Horvath’s eponymous clock was developed by measuring methylation in DNA samples taken from tissues around the body. It seems to represent aging in all these tissues, which is why Horvath calls it a pan-tissue clock. Given that our organs are thought to age differently, it was remarkable that a single clock could measure aging in so many of them.

But Horvath had ambitious plans for an even more universal clock: a pan-species model that could measure aging in all mammals. He started out, in 2017, with an email campaign that involved asking hundreds of scientists around the world to share samples of tissues from animals they had worked with. He tried zoos, too.   

The pan-mammalian clock suggests that there is something universal about aging—not just that all mammals experience it in a similar way, but that a similar set of genetic or epigenetic factors might be responsible for it.

“I learned that people had spent careers collecting [animal] tissues,” he says. “They had freezers full of [them].” Amenable scientists would ship those frozen tissues, or just DNA, to Horvath’s lab in California, where he would use them to train a new model.

Horvath says he initially set out to profile 30 different species. But he ended up receiving around 15,000 samples from 200 scientists, representing 348 species—including everything from dogs to dolphins. Could a single clock really predict age in all of them?

“I truly felt it would fail,” says Horvath. “But it turned out that I was completely wrong.” He and his colleagues developed a clock that assessed methylation at 36,000 locations on the genome. The result, which was published in 2023 as the pan-mammalian clock, can estimate the age of any mammal and even the maximum lifespan of the species. The data set is open to anyone who wants to download it, he adds: “I hope people will mine the data to find the secret of how to extend a healthy lifespan.”

The pan-mammalian clock suggests that there is something universal about aging—not just that all mammals experience it in a similar way, but that a similar set of genetic or epigenetic factors might be responsible for it.

Comparisons between mammals also support the idea that the slower methylation changes occur, the longer the lifespan of the animal, says Nelly Olova, an epigeneticist who researches aging at the University of Edinburgh in the UK. “DNA methylation slowly erodes with age,” she says. “We still have the instructions in place, but they become a little messier.” The research in different mammals suggests that cells can take only so much change before they stop functioning.

“There’s a finite amount of change that the cell can tolerate,” she says. “If the instructions become too messy and noisy … it cannot support life.”

Olova has been investigating exactly when aging clocks first begin to tick—in other words, the point at which aging starts. Clocks can be trained on data from volunteers, and by matching the patterns of methylation on their DNA to their chronological age. The trained clocks are then typically used to estimate the biological age of adults. But they can also be used on samples from children. Or babies. They can be used to work out the biological age of cells that make up embryos. 

In her research, Olova used adult skin cells, which—thanks to Nobel Prize–winning research in the 2000s—can be “reprogrammed” back to a state resembling that of the pluripotent stem cells found in embryos. When Olova and her colleagues used a “partial reprogramming” approach to take cells close to that state, they found that the closer they got to the entirely reprogrammed state, the “younger” the cells were. 

It was around 20 days after the cells had been reprogrammed into stem cells that they reached the biological age of zero according to the clock used, says Olova. “It was a bit surreal,” she says. “The pluripotent cells measure as minus 0.5; they’re slightly below zero.”

Vadim Gladyshev, a prominent aging researcher at Harvard University, has since proposed that the same negative level of aging might apply to embryos. After all, some kind of rejuvenation happens during the early stages of embryo formation—an aged egg cell and an aged sperm cell somehow create a brand-new cell. The slate is wiped clean.

Gladyshev calls this point “ground zero.” He posits that it’s reached sometime during the “mid-embryonic state.” At this point, aging begins. And so does “organismal life,” he argues. “It’s interesting how this coincides with philosophical questions about when life starts,” says Olova. 

Some have argued that life begins when sperm meets egg, while others have suggested that the point when embryonic cells start to form some kind of unified structure is what counts. The ground zero point is when the body plan is set out and cells begin to organize accordingly, she says. “Before that, it’s just a bunch of cells.”

This doesn’t mean that life begins at the embryonic state, but it does suggest that this is when aging begins—perhaps as the result of “a generational clearance of damage,” says Poganik.

It is early days—no pun intended—for this research, and the science is far from settled. But knowing when aging begins could help inform attempts to rewind the clock. If scientists can pinpoint an ideal biological age for cells, perhaps they can find ways to get old cells back to that state. There might be a way to slow aging once cells reach a certain biological age, too. 

“Presumably, there may be opportunities for targeting aging before … you’re full of gray hair,” says Poganik. “It could mean that there is an ideal window for intervention which is much earlier than our current geriatrics-based approach.”

When young meets old

When White first started stitching mice together, he would sit and watch them for hours. “I was like, look at them go! They’re together, and they don’t even care!” he says. Since then, he’s learned a few tricks. He tends to work with female mice, for instance—the males tend to bicker and nip at each other, he says. The females, on the other hand, seem to get on well. 

The effect their partnership appears to have on their biological ages, if only temporarily, is among the ways aging clocks are helping us understand that biological age is plastic to some degree. White and his colleagues have also found, for instance, that stress seems to increase biological age, but that the effect can be reversed once the stress stops. Both pregnancy and covid-19 infections have a similar reversible effect.

Poganik wonders if this finding might have applications for human organ transplants. Perhaps there’s a way to measure the biological age of an organ before it is transplanted and somehow rejuvenate organs before surgery. 

But new data from aging clocks suggests that this might be more complicated than it sounds. Poganik and his colleagues have been using methylation clocks to measure the biological age of samples taken from recently transplanted hearts in living people. 

If being old is simply a case of losing our youthfulness, then that might give us a clue to how we can somehow regain it.

Young hearts do well in older bodies, but the biological age of these organs eventually creeps up to match that of their recipient. The same is true for older hearts in younger bodies, says Poganik, who has not yet published his findings. “After a few months, the tissue may assimilate the biological age of the organism,” he says. 

If that’s the case, the benefits of young organs might be short-lived. It also suggests that scientists working on ways to rejuvenate individual organs may need to focus their anti-aging efforts on more systemic means of rejuvenation—for example, stem cells that repopulate the blood. Reprogramming these cells to a youthful state, perhaps one a little closer to “ground zero,” might be the way to go.

Whole-body rejuvenation might be some way off, but scientists are still hopeful that aging clocks might help them find a way to reverse aging in people.

“We have the machinery to reset our epigenetic clock to a more youthful state,” says White. “That means we have the ability to turn the clock backwards.” 

How healthy am I? My immunome knows the score.  

The story is a collaboration between MIT Technology Review and Aventine, a non-profit research foundation that creates and supports content about how technology and science are changing the way we live.

It’s not often you get a text about the robustness of your immune system, but that’s what popped up on my phone last spring. Sent by John Tsang, an immunologist at Yale, the text came after his lab had put my blood through a mind-boggling array of newfangled tests. The result—think of it as a full-body, high-resolution CT scan of my immune system—would reveal more about the state of my health than any test I had ever taken. And it could potentially tell me far more than I wanted to know.

“David,” the text read, “you are the red dot.”

Tsang was referring to an image he had attached to the text that showed a graph with a scattering of black dots representing other people whose immune systems had been evaluated—and a lone red one. There also was a score: 0.35.

I had no idea what any of this meant.

The red dot was the culmination of an immuno-quest I had begun on an autumn afternoon a few months earlier, when a postdoc in Tsang’s lab drew several vials of my blood. It was also a significant milestone in a decades-long journey I’ve taken as a journalist covering life sciences and medicine. Over the years, I’ve offered myself up as a human guinea pig for hundreds of tests promising new insights into my health and mortality. In 2001, I was one of the first humans to have my DNA sequenced. Soon after, in the early 2000s, researchers tapped into my proteome—proteins circulating in my blood. Then came assessments of my microbiome, metabolome, and much more. I have continued to test-drive the latest protocols and devices, amassing tens of terabytes of data on myself, and I’ve reported on the results in dozens of articles and a book called Experimental Man. Over time, the tests have gotten better and more informative, but no test I had previously taken promised to deliver results more comprehensive or closer to revealing the truth about my underlying state of health than what John Tsang was offering.

Over the years, I’ve offered myself up as a human guinea pig for hundreds of tests promising new insights into my health and mortality. But no test I had previously taken promised to deliver results more comprehensive or closer to revealing the truth about my underlying state of health.

It also was not lost on me that I’m now 20-plus years older than I was when I took those first tests. Back in my 40s, I was ridiculously healthy. Since then, I’ve been battered by various pathogens, stresses, and injuries, including two bouts of covid and long covid—and, well, life.

But I’d kept my apprehensions to myself as Tsang, a slim, perpetually smiling man who directs the Yale Center for Systems and Engineering Immunology, invited me into his office in New Haven to introduce me to something called the human immunome.

JULIE BIDWELL

Made up of 1.8 trillion cells and trillions more proteins, metabolites, mRNA, and other biomolecules, every person’s immunome is different, and it is constantly changing. It’s shaped by our DNA, past illnesses, the air we have breathed, the food we have eaten, our age, and the traumas and stresses we have experienced—in short, everything we have ever been exposed to physically and emotionally. Right now, your immune system is hard at work identifying and fending off viruses and rogue cells that threaten to turn cancerous—or maybe already have. And it is doing an excellent job of it all, or not, depending on how healthy it happens to be at this particular moment.

Yet as critical as the immunome is to each of us, this universe of cells and molecules has remained largely beyond the reach of modern medicine—a vast yet inaccessible operating system that powerfully influences everything from our vulnerability to viruses and cancer to how well we age to whether we tolerate certain foods better than others.

Now, thanks to a slew of new technologies and to scientists like Tsang, who is on the Steering Committee of the Chan Zuckerberg Biohub New York, understanding this vital and mysterious system is within our grasp, paving the way for powerful new tools and tests to help us better assess, diagnose and treat diseases.

Already, new research is revealing patterns in the ways our bodies respond to stress and disease. Scientists are creating contrasting portraits of weak and robust immunomes—portraits that someday, it’s hoped, could offer new insights into patient care and perhaps detect illnesses before symptoms appear. There are plans afoot to deploy this knowledge and technology on a global scale, which would enable scientists to observe the effects of climate, geography, and countless other factors on the immunome. The results could transform what it means to be healthy and how we identify and treat disease.

It all begins with a test that can tell you whether your immune system is healthy or not.

Reading the immunome

Sitting in his office last fall, Tsang—a systems immunologist whose expertise combines computer science and immunology— began my tutorial in immunomics by introducing me to a study that he and his team wrote up in a 2024 paper published in Nature Medicine. It described the results of measurements made on blood samples taken from 270 subjects—tests similar to the ones Tsang’s team would be running on me. In the study, Tsang and his colleagues looked at the immune systems of 228 patients diagnosed with a variety of genetic disorders and a control group of 42 healthy people.

To help me visualize what my results might look like, Tsang opened his laptop to reveal several colorful charts from the study, punctuated by black dots representing each person evaluated. The results reminded me vaguely of abstract paintings by Joan Miró. But in place of colorful splotches, whirls, and circles were an assortment of scatter plots, Gantt charts, and heat maps tinted in greens, blues, oranges, and purples.

It all looked like gibberish to me.

Luckily, Tsang was willing to serve as my guide. Flashing his perpetually patient smile, he explained that these colorful jumbles depicted what his team had uncovered about each subject after taking blood samples and assessing the details of how well their immune cells, proteins, mRNA, and other immune system components were doing their job.

IBRAHIM RAYINTAKATH

The results placed people—represented by the individual dots—on a left-to-right continuum, ranging from those with unhealthy immunomes on the left to those with healthy immunomes on the right. Background colors, meanwhile, were used to identify people with different medical conditions affecting their immune systems. For example, olive-green indicated those with auto-immune disorders; orange backgrounds were designated for individuals with no known disease history. Tsang said he and his team would be placing me on a similar graph after they finished analyzing my blood.

Tsang’s measurements go significantly beyond what can be discerned from the handful of immune biomarkers that people routinely get tested for today. “The main immune cell panel typically ordered by a physician is called a CBC differential,” he told me. CBC, which stands for “complete blood count,” is a decades-old type of analysis that counts levels of red blood cells, hemoglobin, and basic immune cell types (neutrophils, lymphocytes, monocytes, basophils, and eosinophils). Changes in these levels can indicate whether a person’s immune system might be reacting to a virus or other infection, cancer, or something else. Other blood tests—like one that looks for elevated levels of C-reactive protein, which can indicate inflammation associated with heart disease—are more specific than the CBC. But they still rely on blunt counting—in this case of certain proteins.

Tsang’s assessment, by contrast, tests up to a million cells, proteins, mRNA and immune biomolecules—significantly more than the CBC and others. His protocol is designed to paint a more holistic portrait of a person’s immune system by not only counting cells and molecules but also by assessing their interactions. The CBC “doesn’t tell me as a physician what the cells being counted are doing,” says Rachel Sparks, a clinical immunologist who was the lead author of the Nature Medicine study and is now a translational medicine physician with the drug giant AstraZeneca. “I just know that there are more neutrophils than normal, which may or may not indicate that they’re behaving badly. We now have technology that allows us to see at a granular level what a cell is actually doing when a virus appears—how it’s changing and reacting.”

Tsang’s measurements go significantly beyond what can be discerned from the handful of immune biomarkers that people routinely get tested for today. His assessment tests up to a million cells, proteins, mRNA and immune biomolecules.

Such breakthroughs have been made possible thanks to a raft of new and improved technologies that have evolved over the past decade, allowing scientists like Tsang and Sparks to explore the intricacies of the immunome with newfound precision. These include devices that can count myriad different types of cells and biomolecules, as well as advanced sequencers that identify and characterize DNA, RNA, proteins, and other molecules. There are now instruments that also can measure thousands of changes and reactions that occur inside a single immune cell as it reacts to a virus or other threat.

Tsang and Spark’s’ team used data generated by such measurements to identify and characterize a series of signals distinctive to unhealthy immune systems. Then they used the presence or absence of these signals to create a numerical assessment of the health of a person’s immunome—a score they call an “immune health metric,” or IHM.

JARED SOARES

To make sense of the crush of data being collected, Tsang’s team used machine-learning algorithms that correlated the results of the many measurements with a patient’s known health status and age. They also used AI to compare their findings with immune system data collected elsewhere. All this allowed them to determine and validate an IHM score for each person, and to place it on their spectrum, identifying that person as healthy or not.

It all came together for the first time with the publication of the Nature Medicine paper, in which Tsang and his colleagues reported the results from testing multiple immune variables in the 270 subjects. They also announced a remarkable discovery: Patients with different kinds of diseases reacted with similar disruptions to their immunomes. For instance, many showed a lower level of the aptly named natural killer immune cells, regardless of what they were suffering from. Critically, the immune profiles of those with diagnosed diseases tended to look very different from those belonging to the outwardly healthy people in the study. And, as expected, immune health declined in the older patients.

But then the results got really interesting. In a few cases, the immune systems of  unhealthy and healthy people looked similar, with some people appearing near the “healthy” area of the chart even though they were known to have diseases. Most likely this was because their symptoms were in remission and not causing an immune reaction at the moment when their blood was drawn, Tsang told me. 

In other cases, people without a known disease showed up on the chart closer to those who were known to be sick. “Some of these people who appear to be in good health are overlapping with pathology that traditional metrics can’t spot,” says Tsang, whose Nature Medicine paper reported that roughly half the healthy individuals in the study had IHM scores that overlapped with those of people known to be sick. Either these seemingly healthy people had normal immune systems that were busy fending off, say, a passing virus, or  their immune systems had been impacted by aging and the vicissitudes of life. Potentially more worrisome, they were harboring an illness or stress that was not yet making them ill but might do so eventually.

These findings have obvious implications for medicine. Spotting a low immune score in a seemingly healthy person could make it possible to identify and start treating an illness before symptoms appear, diseases worsen, or tumors grow and metastasize. IHM-style evaluations could also provide clues as to why some people respond differently to viruses like the one that causes covid, and why vaccines—which are designed to activate a healthy immune system—might not work as well in people whose immune systems are compromised.

Spotting a low immune score in a seemingly healthy person could make it possible to identify and start treating an illness before symptoms appear, diseases worsen, or tumors grow and metastasize.

“One of the more surprising things about the last pandemic was that all sorts of random younger people who seemed very healthy got sick and then they were gone,” says Mark Davis, a Stanford immunologist who helped pioneer the science being developed in labs like Tsang’s. “Some had underlying conditions like obesity and diabetes, but some did not. So the question is, could we have pointed out that something was off with these folks’ immune systems? Could we have diagnosed that and warned people to take extra precautions?”

Tsang’s IHM test is designed to answer a simple question: What is the relative health of your immune system? But there are other assessments being developed to provide more detailed information on how the body is doing. Tsang’s own team is working on a panel of additional scores aimed at getting finer detail on specific immune conditions. These include a test that measures the health of a person’s bone marrow, which makes immune cells. “If you have a bone marrow stress or inflammatory condition in the bone marrow, you could have lower capacity to produce cells, which will be reflected by this score,” he says. Another detailed metric will measure protein levels to predict how a person will respond to a virus.

Tsang hopes that an IHM-style test will one day be part of a standard physical exam—a snapshot of a patient’s immune system that could inform care. For instance, has a period of intense stress compromised the immune system, making it less able to fend off this season’s flu? Will someone’s score predict a better or worse response to a vaccine or a cancer drug? How does a person’s immune system change with age?

Or, as I anxiously wondered while waiting to learn my own score, will the results reveal an underlying disorder or disease, silently ticking away until it shows itself?

Toward a human immunome project  

The quest to create advanced tests like the IHM for the immune system began more than 15 years ago, when scientists like Mark Davis became frustrated with a field in which research—primarily in mice—was focused mostly on individual immune cells and proteins. In 2007 he launched the Stanford Human Immune Monitoring Center, one of the first efforts to conceptualize the human immunome as a holistic, body-wide network in human beings. Speaking by Zoom from his office in Palo Alto, California, Davis told me that the effort had spawned other projects, including a landmark twin study showing that a lot of immune variation is not genetic, which was then the prevailing theory, but is heavily influenced by environmental factors—a major shift in scientists’ understanding.

COURTESY OF SHAI SHEN-ORR

Davis and others also laid the groundwork for tests like John Tsang’s by discovering how a T cell—among the most common and important immune players—can recognize pathogens, cancerous cells, and other threats, triggering defensive measures that can include destroying the threat. This and other discoveries have revealed many of the basic mechanics of how immune cells work, says Davis, “but there’s still a lot we have to learn.”

One researcher working with Davis in those early days was Shai Shen-Orr, who is now director of the Zimin Institute for AI Solutions in Healthcare at the Technion-Israel Institute of Technology, based in Haifa, Israel. (He’s also a frequent collaborator with Tsang.) Shen-Orr, like Tsang, is a systems immunologist. He recalls that in 2007, when he was a postdoc in Davis’s lab, immunologists had identified around 100 cell types and a similar number of cytokines—proteins that act as messengers in the immune system. But they weren’t able to measure them simultaneously, which limited visibility into how the immune system works as a whole. Today, Shen-Orr says, immunologists can measure hundreds of cell types and thousands of proteins and watch them interact.

Shen-Orr’s current lab has developed its own version of an immunome test that he calls IMM-AGE (short for “immune age”), the basics of which were published in a 2019 paper in Nature Medicine. IMM-AGE looks at the composition of people’s immune systems—how many of each type of immune cell they have and how these numbers change as they age. His team has used this information primarily to ascertain a person’s risk of heart disease.

Shen-Orr also has been a vociferous advocate for expanding the pool of test samples, which now come mostly from Americans and Europeans. “We need to understand why different people in different environments react differently and how that works,” he says. “We also need to test a lot more people—maybe millions.”

Tsang has seen why a limited sample size can pose problems. In 2013, he says, researchers at the National Institutes of Health came up with a malaria vaccine that was effective for almost everyone who got it during clinical trials conducted in Maryland. “But in Africa,” he says, “it only worked for about 25% of the people.” He attributes this to the significant differences in genetics, diet, climate, and other environmental factors that cause people’s immunomes to develop differently. “Why?” he asks. “What exactly was different about the immune systems in Maryland and Tanzania? That’s what we need to understand so we can design personalized vaccines and treatments.”

For several years, Tsang and Shen-Orr have advocated going global with testing, “but there has been resistance,” Shen-Orr says. “Look, medicine is conservative and moves slowly, and the technology is expensive and labor intensive.” They finally got the audience they needed at a 2022 conference in La Jolla, California, convened by the Human Immunome Project, or HIP. (The organization was originally founded in 2016 to create more effective vaccines but had recently changed its name to emphasize a pivot from just vaccines to the wider field of immunome science.) It was in La Jolla that they met HIP’s then-new chairperson, Jane Metcalfe, a cofounder of Wired magazine, who saw what was at stake.

“We’ve got all of these advanced molecular immunological profiles being developed,” she said, “but we can’t begin to predict the breadth of immune system variability if we’re  only testing small numbers of people in Palo Alto or Tel Aviv. And that’s when the big aha moment struck us that we need sites everywhere to collect that information so we can build proper computer models and a predictive understanding of the human immune system.”

IBRAHIM RAYINTAKATH

Following that meeting, HIP created a new scientific plan, with Tsang and Shen-Orr as chief science officers. The group set an ambitious goal of raising around $3 billion over the next 10 years—a goal Tsang and Metcalfe say will be met by working in conjunction with a broad network of public and private supporters. Cutbacks in federal funding for biomedical research in the US may limit funds from this traditional source, but HIP plans to work with government agencies outside the US too, with the goal of creating a comprehensive global immunological database.

HIP’s plan is to first develop a pilot version based on Tsang’s test, which it will call the Immune Monitoring Kit, to test a few thousand people in Africa, Australia, East Asia, Europe, the US, and Israel. The initial effort, according to Metcalfe, is expected to begin by the end of the year.  

After that, HIP would like to expand to some 150 sites around the world, eventually assessing about 250,000 people and collecting a vast cache of data and insights that Tsang believes will profoundly affect—even revolutionize—clinical medicine, public health, and drug development.

My immune health metric score is …

As HIP develops its pilot study to take on the world, John Tsang, for better or worse, has added one more North American Caucasian male to the small number of people who have received an IHM score to date. That would be me.

It took a long time to get my score, but Tsang didn’t leave me hanging once he pinged me the red dot. “We plotted you with other participants who are clinically quite healthy,” he texted, referring to a cluster of black dots on the grid he had sent, although he cautioned that the group I’m being compared with includes only a few dozen people. “Higher IHM means better immune health,” he wrote, referring to my 0.35 score, which he described as a number on an arbitrary scale. “As you can see, your IHM is right in the middle of a bunch of people 20 years younger.”

This was a relief, given that our immune system, like so many other bodily functions, declines with age—though obviously at different rates. Yet I also felt a certain disappointment. To be honest, I had expected more granular detail after having a million or so cells and markers tested—like perhaps some insights on why I got long covid (twice) and others didn’t. Tsang and other scientists are working on ways to extract more specific information from the tests. Still, he insists that the single score itself is a powerful tool to understand the general state of our immunomes, indicating the absence or presence of underlying health issues that might not be revealed in traditional testing.

To be honest, I had expected more granular detail after having a million or so cells and markers tested—like perhaps some insights on why I got long covid (twice) and others didn’t.

I asked Tsang what my score meant for my future. “Your score is always changing depending on what you’re exposed to and due to age,” he said, adding that the IHM is still so new that it’s hard to know exactly what the score means until researchers do more work—and until HIP can evaluate and compare thousands or hundreds of thousands of people. They also need to keep testing me over time to see how my immune system changes as it’s exposed to new perturbations and stresses.

For now, I’m left with a simple number. Though it tells me little about the detailed workings of my immune system, the good news is that it raises no red flags. My immune system, it turns out, is pretty healthy.

A few days after receiving my score from Tsang, I heard from Shen-Orr about more results. Tsang had shared my data with his lab so that he could run his IMM-AGE protocol on my immunome and provide me with another score to worry about. Shen-Orr’s result put the age of my immune system at around 57—still 10 years younger than my true age.

The coming age of the immunome

Shai Shen-Orr imagines a day when people will be able to check their advanced IHM and IMM-AGE scores—or their HIP Immune Monitoring Kit score—on an app after a blood draw, the way they now check health data such as heart rate and blood pressure. Jane Metcalfe talks about linking IHM-type measurements and analyses with rising global temperatures and steamier days and nights to study how global warming might affect the immune system of, say, a newborn or a pregnant woman. “This could be plugged into other people’s models and really help us understand the effects of pollution, nutrition, or climate change on human health,” she says.

Other clues could also be on the horizon. “At some point we’ll have IHM scores that can provide data on who will be most affected by a virus during a pandemic,” Tsang says. Maybe that will help researchers engineer an immune system response that shuts down the virus before it spreads. He says it’s possible to run a test like that now, but it remains experimental and will take years to fully develop, test for safety and accuracy, and establish standards and protocols for use as a tool of global public health. “These things take a long time,” he says. 

The same goes for bringing IHM-style tests into the exam room, so doctors like Rachel Sparks can use the results to help treat their patients. “I think in 10 years, with some effort, we really could have something useful,” says Stanford’s Mark Davis. Sparks agrees. “I think by then I’ll be able to use this much more granular understanding of what the immune system is doing at the cellular level in my patients,” she says. “And hopefully we could target our therapies more directly to those cells or pathways that are contributing to disease.”

Personally, I’ll wait for more details with a mix of impatience, curiosity, and at least a hint of concern. I wonder what more the immune circuitry deep inside me might reveal about whether I’m healthy at this very moment, or will be tomorrow, or next month, or years from now. 

David Ewing Duncan is an award-winning science writer. For more information on this story check out his Futures Column on Substack.