Slowing the aging process has become a focal point for scientists looking to reduce the risk of age-related diseases, such as cancer, heart disease, and dementia. To develop effective therapies against aging, researchers must first understand what causes age-related changes to the body in the first place.
By profiling nearly 7 million single cells from mice at three ages, researchers from The Rockefeller University have now created a map of how aging reshapes cells across the body.
This atlas of cellular aging revealed that the populations of almost a quarter of all cell types shift with age. These changes were found to be synchronized across organs, suggesting the body has a coordinated response to aging. Aging also appeared to differ by biological sex; for example, females showed broader immune activation.
The researchers hope this atlas will provide a valuable resource for guiding the development of therapeutic strategies to maintain or restore youthful cell states.
An organism-wide view of cellular aging
Crucial to generating the map of aging were recent advances in genomics. “Over the past decade, single-cell genomics has let us move from ‘averaging’ signals across millions of cells to measuring what’s happening inside individual cells. That matters for aging because tissues are mixtures of many cell types, and they don’t all age in the same way,” Dr. Junyue Cao, associate professor at The Rockefeller University, told Technology Networks.
“Even more importantly, today’s methods are scalable enough to profile many tissues and many animals at one time, which makes it possible to build true ‘atlases’ of organismal aging rather than from a single organ,” he continued.
While alternative aging atlases exist, Cao explains that many focus only on RNA (gene expression). These often fail to capture an important layer of regulation—that is, which parts of the genome are open and available for gene expression. “In addition, many atlases are limited to a small number of organs, which makes it hard to tell whether an observed change is truly ‘systemic’ (shared across the body) or just tissue-specific,” said Cao.
To generate an organism-wide map of aging, Cao’s team optimized a technique called single-cell ATAC-seq. Cao describes single-cell ATAC-seq as a “powerful” technique for studying aging, given that “many age-related changes may start as shifts in regulation before we see large changes in gene expression.” The technique was used to profile chromatin accessibility, a readout of gene regulation, across 21 mouse tissues in 32 mice at three ages (1, 5, and 21 months), and in both sexes.
What is single-cell ATAC-seq?
Single-cell ATAC-seq measures which parts of the genome are open and readable in each cell. These accessible regions often include enhancers and other regulatory elements that control gene activity, providing insights into a cell’s state and function.
Using their optimized single-cell ATAC-seq protocol, Cao and colleagues compiled a catalog of ~1.3 million open regulatory elements across tissues and cells, providing a “regulatory map” of aging.
The dataset revealed that 146 of 536 organ-specific cell types changed significantly with age, challenging previous assumptions that aging only impacts cellular function. Specialized kidney, muscle, and lung cells all declined with age, while there was an expansion of immune cells.
These changes weren’t limited to single organs, with the same cellular states declining across different tissues. “Broadly distributed lineages (especially immune and stromal cells) show synchronized shifts across multiple organs, suggesting systemic signals help drive parts of the aging process,” explained Cao.
“We see evidence that aging changes are not random decay, but a coordinated and programmed process across the body.” — Dr. Junyue Cao
The researchers also observed striking differences between the sexes. Sex differences were observed in ~40% of aging-associated cell types. Females displayed stronger immune activation, which the researchers say may help explain the higher prevalence of autoimmune diseases in women.
The future of anti-aging therapies
The atlas created by Cao and colleagues not only provides new insights into aging but could also be a useful resource for guiding therapeutic strategies aimed at preserving or restoring youthful tissue states.
“Therapeutic development needs two things: (1) a clear picture of what ‘healthy/youthful’ cell states look like across tissues, and (2) a way to identify which cell types and regulatory programs are most vulnerable—and therefore most actionable,” Cao said. “This atlas is intended as that kind of reference, helping prioritize targets and pathways by showing where aging-related changes are strongest and most consistent.”
The atlas could also help evaluate the effectiveness of a drug, gene therapy, or lifestyle intervention aimed at slowing or reversing aspects of aging. As sex was identified as a major axis of aging heterogeneity, Cao highlights that some interventions “may need to be tested and optimized with sex-specific effects in mind.”
The study has several limitations, such as being based on analysis in mice, not humans. In addition, the analysis did not include molecules such as RNA and proteins, which could provide further information on the functional consequences of regulatory changes with aging.
Future studies that integrate aging-associated regions identified in the atlas with loci from human genome-wide association studies could help prioritize cell types and regulatory elements to target with drugs to mediate disease risk.
Reference: Lu Z, Zhang Z, Xu Z, Abdulraouf A, Zhou W, Cao J. Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging. Science. 391(6788):eadw6273. doi: 10.1126/science.adw6273
About the interviewee
Dr. Junyue Cao received his PhD from the University of Washington in 2019. In August 2020, he started his independent lab as an assistant professor and head of the Laboratory for Single Cell Genomics at The Rockefeller University. His lab focuses on investigating how a cell population in our body maintains homeostasis and how it is disrupted in aging through developing novel single-cell and spatial genomic techniques.
Cao has been awarded the NIH Director’s New Innovator Award, William Ackman and Neri Oxman Innovator Award, Sagol Network GerOmic Award for Junior Faculty, MRA Young Investigator Award, Science & SciLifeLab Grand Prize for Young Scientists, the Verne Chapman Young Scientist Award, Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, and Hevolution/AFAR Young Investigator Award.