Growing older brings a higher risk of serious illnesses such as cancer, heart disease, and dementia. For years, researchers have tackled these conditions individually. Now, many scientists are stepping back to ask a broader question. Instead of treating diseases one by one, could slowing the aging process reduce the risk of several at once? To answer that, they first need to understand what sparks the biological changes that come with age.
A new study published in Science offers an unprecedented look at that process. Researchers at The Rockefeller University built the most detailed atlas so far of how aging affects thousands of cell subtypes across 21 mammalian tissues. By examining nearly 7 million individual cells from mice at three different ages, the team identified which cells are most vulnerable over time and what factors may be driving 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.”
One of the most striking findings was that many age-related shifts happen in sync across multiple organs. The researchers also found that nearly half of these changes differ between males and females.
A Massive Cellular Census Across 21 Organs
To map aging at this scale, Cao’s team, led by graduate student Ziyu Lu, refined a method known as single-cell ATAC-seq. This approach looks at how DNA is packaged inside each cell, revealing which regions of the genome are accessible and active, a key indicator of a cell’s state and function.
The researchers applied this technique to millions of individual cells taken from 21 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.”
In total, the lab identified more than 1,800 distinct cell subtypes, including many rare groups that had never been fully described. The team then tracked how the numbers of these cells changed as the mice moved from young adulthood to middle age and then to old age.
Early and Coordinated Cellular Shifts
For decades, scientists believed aging mainly altered how cells function, not how many of each type exist. This new analysis challenges that view. About one quarter of all cell types showed significant changes in abundance over time. Certain muscle and kidney cell populations declined sharply, while immune cells expanded considerably.
“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.”
Equally surprising was how synchronized these changes were. Similar cellular states rose and fell together across different organs. This pattern suggests that shared signals, possibly factors circulating in the bloodstream, help coordinate aging throughout the body.
The study also revealed pronounced differences between males and females. Roughly 40 percent of aging-associated changes varied significantly by sex. For example, females showed much broader immune activation as they aged.
“It’s possible this could explain the higher prevalence of autoimmune diseases in women,” Cao speculates.
Genetic Hotspots and Future Anti-Aging Therapies
Beyond counting how cell populations shifted, the researchers examined how accessible regions of DNA changed within those cells over time. Out of 1.3 million genomic regions analyzed, about 300,000 displayed significant aging-related alterations. Around 1,000 of those changes appeared across many different cell types, reinforcing the idea that common biological programs drive aging across the body. Many of these shared regions were linked to immune function, 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.”
When the team compared their findings with earlier research, they discovered that immune signaling molecules called cytokines can trigger many of the same cellular changes observed during aging. Cao suggests that drugs designed to adjust these cytokines could potentially slow coordinated aging processes across multiple 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 full aging atlas is available to the public at epiage.net.
