Inside your body, aging unfolds at remarkably different rates

Recently, scientists at Stanford University began to wonder why identical lab mice, bred with the same DNA and brought up in identical conditions, wound up so different in their old age.

Some mice could ace cognitive tests and race around on their running wheels. Others would forget simple tasks and hobble from place to place. Genetically, they remained indistinguishable, but their twilight years could hardly have been more distinct.

The scientists’ attempts to untangle what was going on inside these mice is redefining how we think about aging. It has opened up a new area of research into what scientists are calling “organ aging,” which looks at how different parts of our bodies seem to start aging earlier than others, affecting what diseases we develop and how long we live.

The research suggests aging isn’t strictly temporal, not solely about minutes and years passing. Once considered a steady, predictable decline, affecting everything in our bodies, everywhere, all at once, aging is much more haphazard than we once thought, starting in different parts of our bodies at different times, possibly long before we’re even thinking about aging.

It’s also personal, occurring at a unique molecular level inside each of us, and the process may be partially within our control. Once we know how our own organs are aging, we may be able to brake or speed that process by how we live.

By using advanced molecular biology, genetics and big data to analyze blood samples from people, scientists can tell that some of us are “heart agers,” meaning our hearts appear much older than the rest of our bodies, or we’re “brain agers,” with a relatively old brain in our skulls, or if we’re fortunate, we might be “brain youthers,” with a brain relatively younger than any other organ we possess. Or we could be “muscle agers” or “liver youthers.” Almost any organ can be the first to show signs of extreme aging.

The consequences for our health are considerable. In one of the largest human studies to date of organ aging, Stanford scientists found that heart agers are far more likely to develop heart failure than other people, while brain youthers are about 80 percent less likely to develop dementia in later years than people with average or old brains.

The results underscore “just how complicated aging is,” said Hamilton Se-Hwee Oh, a postdoctoral researcher who led the study while at Stanford.

They also represent one of the first and potentially most practical takeaways from the broader and often wildly hyped science of human aging.

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The newest way to think about biological age

Aging is far more erratic than many of us might expect.

“You can take animals that are genetically identical, that are raised in the same cages with the same food and same handling, everything about them is exactly the same, but they show different molecular changes with age and different functional decline and diseases at different times,” said Tony Wyss-Coray, the director of the Phil and Penny Knight Initiative for Brain Resilience at Stanford University and senior author of the recent Stanford study of organ aging.

What separates the animals seems to be their biological age, a concept at the heart of the organ-aging research. We all have, of course, a chronological age, according to our birth date. And scientists for years have been refining the definition of a separate biological age, which marks how well our bodies are functioning. Our biological age can be older or younger than our birth age.

“We all know 50-year-olds who don’t look that age, for better or worse,” said Thomas Rando, a molecular biologist and the director of the Broad Stem Cell Research Center at the University of California at Los Angeles, who studies aging and longevity. Those people’s biological age are likely to differ from their calendar years.

In the past decade, scientists have begun harnessing the power of machine learning and complex new biotechnology to create “clocks” designed to estimate biological age. These clocks rely on the analysis of blood and other tissue samples from thousands of people and animals of all ages.

By analyzing these samples, scientists have zeroed in on similarities by age, focusing on specific patterns of gene activity or molecular levels commonly seen at certain ages. These patterns can then be used as biomarkers of biological age.

If a 40-year-old’s gene activity matches that seen in most other 40-year-olds, for instance, that person would be biologically 40. But if his gene patterns more closely resemble those of a typical 30- or 50-year-old, he’d be considered biologically out of alignment with his birth age.

Dozens of at-home tests now promise to estimate biological age from a cheek swab or other sample. None have been approved by the Food and Drug Administration. Prices are as high as $500. And many scientists worry they rely on vastly oversimplified and unreliable interpretations of the aging-clock algorithms scientists originally developed.

“I’ve taken quite a few” of the over-the-counter tests, said Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York. “They showed me being anywhere from 20 years younger to three years older” than his actual age of 68.

But a deeper, more-intractable concern is that the DIY biological age tests offer a single estimate of how an entire body is aging. It’s increasingly clear aging doesn’t work that way.

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Aging fast or slow

One of the first major studies of organ aging appeared in 2020 in the journal Nature, with Wyss-Coray and other researchers tracking gene activity and other cellular changes in 17 organs from lab mice of all ages. The results showed that some of the rodents’ organs were growing old faster or slower, from mouse to mouse, organ to organ, and even from one cell to another within the same organ.

That finding reinforced the growing sense among scientists that “aging isn’t linear,” Wyss-Coray said.

That mouse study and others also hinted that the sequence of organ aging could affect lifelong health, with fast-aging organs influencing later disease risk, and also that aging might, in some fashion, be “contagious,” with whichever organs aged earliest releasing biochemicals that jump-started aging elsewhere in the body.

But, of course, mice aren’t us, so the next obvious step was to repeat the mouse study in people and see if the results would be similar. There were, however, hurdles.

It’s not possible to obtain tissue samples from certain organs, such as the brain, in living people. So Wyss-Coray and his colleagues needed to come up with a different approach than they’d used with mice.

For a study featured on the cover of Nature in 2023, they settled on proteins, “the building blocks of life,” Wyss-Coray said.

Created in cells during gene expression and released constantly into the bloodstream, tens of thousands of proteins course through our bodies all the time. But some are unique to specific organs. Certain genes in liver cells, for instance, produce proteins that can only have come from the liver. Ditto for genes in neurons and lung cells and so on. Prior research had categorized these organ-specific proteins, some of which already are used to check people’s health during standard blood tests.

With that data, the scientists gathered records from existing health databases that included blood samples from about 5,700 men and women of various ages. Using the data, elaborate machine-learning models created molecular, age-related signatures for each of 11 organs: the heart, lungs, arteries, brain, fat, immune system, intestines, kidneys, liver, muscles and pancreas.

At that point, the scientists could identify a prototypical 40-year-old’s liver from a 50-year-old’s by the patterns of proteins in their bloodstreams. They could also identify gaps between the age signatures of people’s organs and their actual, chronological ages.

And many people’s organs, it turned out, were relatively elderly. About 20 percent of the almost 5,700 men and women harbored at least one organ that was significantly older than their birth age, according to their plasma proteins. These affected organs differed from person to person, creating what the scientists called an “ageotype.” People whose hearts were extremely old, compared to their other organs, were heart agers, while those with elderly fat tissue were fat agers.

Perhaps most significant, each aged organ was associated with substantially elevated risks for related diseases.

Heart agers, whether middle aged or older, were as much as 250 percent more likely to develop heart failure in subsequent years as other people, with muscle agers at heightened risk for gait problems, and, well, you get the idea.

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The benefits of a youthful brain

But a pool of about 5,700 study participants, while larger than in many biological studies, was too small for the researchers to delve into the existence or effects of youthful organs.

So, for the newest study, published in June, most of the same scientists turned to the immense trove of data in the UK Biobank, gathering blood and health records from about 44,530 men and women ages 40 to 70 when they joined the biobank. The researchers analyzed blood for organ-aging proteins, compared the same 11 organs’ biological ages to people’s actual ages and also checked for diseases or deaths among people during the next decade or so. (The study is in the preprint stage, meaning it hasn’t been fully peer-reviewed, but the authors expect peer review and publication to be completed soon.)

The associations proved even stronger in this larger group. About 33 percent of the men and women harbored at least one organ that was “extremely” aged, compared with their actual ages. Another 26 percent had two or more extremely aged organs and some as many as eight.

The researchers also again found links between organs’ ages and disease and also lifespan. Heart agers risked heart failure and atrial fibrillation; lung agers developed chronic obstructive pulmonary disease; and for liver agers, it was chronic liver disease.

But the effects of brain aging were the most striking. People with extremely old brains were 3.4 times more likely to develop Alzheimer’s disease than everyone else, while, on the flip side, those with relatively youthful brains had 81 percent less risk of Alzheimer’s than people with brains the same age as them.

The benefits of a youthful brain also extended to longevity, with brain youthers generally outliving brain agers. In fact, an old brain was, of all organs, “most strongly predictive of mortality,” the study authors wrote, “suggesting that the brain may be a central regulator of lifespan in people.”

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Changing our organ age

Perhaps the most important finding in the new study, though, was that organ age “appears to be malleable,” Oh said.

When he and the other scientists compared people’s organ ages to their lifestyles in the new study, they found that those who often smoked, drank or ate processed meats were prone to accelerated organ aging, while anyone who regularly exercised or ate oily fish was far more likely to have youthful organs.

Interestingly, taking estrogen also noticeably affected organ aging in menopausal women, the researchers found. Women who’d used supplemental estrogen wound up with relatively youthful immune systems, livers and arteries, compared to those who hadn’t.

Why and how diet, exercise, hormones or other lifestyle and medical options affect organ aging isn’t clear, Oh said. It’s still impossible, in fact, to pinpoint precisely why our organs age at different rates at all. It might be genetics, lifestyle, luck or all or none of those.

Still, knowing our ageotype could help guide some of our health decisions, Oh said. Someone who knows he or she is a heart ager, for instance, even with no current symptoms, should probably consider more-frequent cardiac testing and diet and exercise changes, such as cutting back on ultra-processed foods and walking for at least 30 minutes a day, while a muscle ager could be advised to take up weight training, which is known to build muscular health at a cellular level.

The organ-aging research “is really interesting, because it does suggest it might be possible to give more granularity into how someone is aging across different systems,” said Morgan Levine, a principal investigator at Altos Lab in San Diego who is widely considered one of the world’s experts on clocks for biological aging. She had no part in the new research.

Blood tests to diagnose ageotype could be on the horizon, although it may still be years before they’re validated by the FDA and available as part of standard health testing, Oh said. “We always need more studies.” (Unvalidated consumer tests could arrive much earlier, he said, but might not be reliable.)

The hope is that these tests will show which of our body parts - our heart, brain, kidneys, skin, fat, intestines or something else - is aging fastest and what, if anything, we can do about it.

The idea that we might be able to change how we age “is what’s really exciting” about this research, Oh said.