As we age with each passing year, we become more susceptible to chronic diseases like cancer, heart disease, and dementia. Scientists have long focused on fighting these conditions one at a time. Recently, however, many have begun to wonder whether they can slow aging itself. But to ward off age-related changes to the body, they must first understand what triggers them.
Now, in a study published in Science, researchers at The Rockefeller University have created the most comprehensive atlas yet of how aging affects thousands of cell subtypes across 21 mammalian tissues. By profiling nearly 7 million individual cells from mice at three different ages, the team identified which cells are most vulnerable to aging and what drives their decline.
"Our goal was to understand not just what changes with aging, but why," says Junyue Cao , who heads the Laboratory of Single Cell Genomics and Population Dynamics . "By mapping both cellular and molecular changes, we can identify what drives aging. That opens the door to interventions that target the aging process itself."
Among the most surprising takeaways from the new study was that many age-related changes are synchronized across organs, and that nearly half of all changes are different between males and females.
A cellular census of aging
To achieve the scale needed to map aging across the entire body, Cao's team, led by graduate student Ziyu Lu, optimized a technique called single-cell ATAC-seq. The method studies how DNA is packaged in each cell to reveal which genomic regions are open and readable—a telltale signature of the cell's state and function. The researchers applied this technique to millions of individual cells from 21 different organs in 32 mice at three ages: one month (young adult), five months (middle-aged), and 21 months (elderly).
"What's remarkable is that this entire atlas was generated by a single graduate student," Cao says. "Most large atlases like this require large consortia with dozens of laboratories but our method is far more efficient than other approaches."
Cao's lab pinpointed more than 1,800 subtypes of cells—including many rare subtypes never before characterized. Then, they tracked how the abundance of each cell changed from young adulthood through middle age to old age in mice.
Scientists had long assumed that aging mostly changed how cells work, not how many of each type you have. But the new results showed that about a quarter of all cell types show significant population shifts with age. Some types of muscle and kidney cells showed steep declines with age, while immune cells expanded dramatically.
"The system is far more dynamic than we realized," says Cao. "And some of these changes begin surprisingly early. By five months of age, some cell populations had already begun to decline. This tells us that aging isn't just something that happens late in life; it's a continuation of ongoing developmental processes."
Just as surprising, he says, was the coordination of these changes across distant organs. The same cellular states appeared and declined in parallel across different tissues. This suggests that there are signals, such as factors circulating in the blood, that coordinate these changes throughout the body.
The team also uncovered striking sex differences. About 40 percent of all aging-associated changes were significantly different between males and females. Females showed much broader immune activation during aging, for example.
"It's possible this could explain the higher prevalence of autoimmune diseases in women," Cao speculates.
Toward anti-aging therapeutics
Beyond tracking which cells changed their population numbers with age, the team also mapped how the readable portions of DNA shifted in those cell types over time. Of 1.3 million regions of the genome that Lu and Cao studied, about 300,000 showed significant aging-related changes. 1,000 of those changes were seen across many different cell types, once again pointing toward shared biological programs that drive aging throughout the body. Many shared areas were linked to the immune system, inflammation, or stem cell maintenance.
"This challenges the idea that aging is just random genomic decay," Cao says. "Instead, we see specific regulatory hotspots that are particularly vulnerable, and these are precisely the regions we should be studying if we want to understand what drives the aging process."
By comparing their data with previous studies, Cao's team found that immune signaling molecules called cytokines can trigger many of the same cellular changes seen in aging. Drugs that modulate these cytokines, Cao hypothesizes, could help slow coordinated aging processes across many different organs.
"This is really a starting point," Cao says. "We've identified the vulnerable cell types and molecular hotspots. Now the question is whether we can develop interventions that target these specific aging processes. Our lab is already working on that next step."
The complete atlas is now publicly available at epiage.net .
