The risk of serious illnesses such as cancer, heart disease and dementia increases with age. For years, researchers have studied these diseases individually. Now many scientists are taking a step back and asking a broader question: could slowing down the ageing process reduce the risk of several diseases at once, rather than treating each disease individually? To answer this question, they first need to understand what triggers the biological changes that occur with age. A new study published in Science offers unprecedented insight into this process.
A Comprehensive Cell Count in 21 Organs
Rockefeller University researchers have created the most detailed atlas yet of how aging affects thousands of cell subtypes in 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 might drive their decline.
“Our goal was to understand not only what changes with aging, but also why,” said Junyue Cao, head of the Single Cell Genomics and Population Dynamics Laboratory. “By mapping both cellular and molecular changes, we can find out what drives the aging process. This opens up possibilities for interventions that directly target the ageing process itself.” One of the most striking findings was that many age-related changes occur synchronously in multiple organs. The researchers also found that almost half of these changes differ between men and women.
Early and Coordinated Cellular Changes
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 examines how DNA is packaged in each cell, revealing which regions of the genome are accessible and active – a key indicator of a cell’s health and function. The researchers applied this technique to millions of individual cells taken from 21 organs of 32 mice at three ages: one month (young adults), five months (middle-aged) and 21 months (older animals). “What’s remarkable is that this entire atlas was created by a single graduate student,” Cao said. “Most large atlases like this require large consortia with dozens of labs, but our method is far more efficient than other approaches.” In total, the lab identified more than 1,800 different cell subtypes, including many rare groups that had never been fully described. The team then tracked how the number of these cells changed as the mice progressed from young adulthood to middle age and then old age.
For decades, scientists believed that aging mainly changed the way cells functioned, but not the number of individual cell types. This new analysis challenges this view. About a quarter of all cell types showed significant changes in their frequency over time. Certain muscle and kidney cell populations decreased sharply, while the number of immune cells increased significantly. “The system is much more dynamic than we thought,” says Cao. “And some of these changes start surprisingly early. By the age of five months, some cell populations had already started to decline. This shows us that ageing is not just something that occurs in old age, but a continuation of ongoing developmental processes.”
Equally surprising was how synchronized these changes were. Similar cell states increased and decreased simultaneously in different organs. This pattern suggests that common signals, possibly factors circulating in the bloodstream, help to coordinate the ageing process throughout the body. The study also showed clear differences between men and women. About 40 percent of the age-related changes varied significantly by gender. For example, women showed much greater immune activation with increasing age. This could possibly explain the higher prevalence of autoimmune diseases in women.
Genetic Hotspots and Future Anti-Ageing Therapies
In addition to counting the changes in cell populations, the researchers examined how accessible regions of DNA in these cells changed over time. Out of 1.3 million genomic regions analyzed, about 300,000 showed significant age-related changes. About 1,000 of these changes occurred in many different cell types, supporting the idea that common biological programs control the aging process throughout the body. Many of these common regions were related to immune function, inflammation or stem cell maintenance. “This challenges the notion that aging is just random genomic decay,” Cao explained. “Instead, we see specific regulatory hotspots that are particularly vulnerable, and it is these regions that we should investigate if we want to understand what drives the ageing process.”
When the team compared their findings with previous research, they found that immune signaling molecules called cytokines can trigger many of the same cellular changes observed during the aging process. Cytokines are small protein molecules (proteins) that are used by the immune system as messengers. They are mainly secreted by immune cells such as white blood cells and are used for communication between cells. Cao suspects that drugs that regulate these cytokines could potentially slow down coordinated ageing processes in several organs. This is really just the beginning. The researchers have identified the susceptible cell types and molecular hotspots. Now the question is whether they can develop interventions that target these specific aging processes. Their lab is already working on this next step.
How to Turn Gut Bacteria into Anti-Ageing Factories
Another study examined the role of gut bacteria in longevity. Researchers at the Janelia Research Campus in Virginia have found a way to make bacteria living in the digestive systems of animals act like miniature factories that produce compounds associated with longer life. The findings point to a potential new approach for developing drugs that affect the gut microbes rather than acting directly on the body.
The researchers investigated whether they could stimulate the body’s gut microbiota (a collection of bacteria in the gut that produces many different compounds) to produce substances that promote health and longevity. They focused on colanic acid, a compound that is naturally produced by gut bacteria and has already been shown to extend the lifespan of nematodes and fruit flies. In their latest experiments, the team found that gut bacteria produced much higher levels of colanic acid when exposed to low doses of the antibiotic cephaloridine. Roundworms given cephaloridin lived longer, suggesting a link between the increase in this bacterial compound and improved longevity.
The researchers then tested this approach in mice. Low doses of cephaloridin activated gene expression in gut bacteria involved in the production of colanic acid. This led to noticeable changes in age-related metabolism, including higher levels of good cholesterol and lower levels of bad cholesterol in male mice and reduced insulin levels in female mice. Cephaloridine has an important advantage. When taken orally, it is not absorbed into the bloodstream. This means that it can affect the gut microbiome without affecting the rest of the body, avoiding toxicity and unwanted side effects. According to the researchers, the results show a promising strategy for promoting longevity through the use of drugs that act on bacteria rather than human cells. They anticipate that this work could reshape the development of future drugs by shifting the focus to compounds that stimulate the microbiota to produce health-promoting molecules for their hosts.