Very recommendable! An interesting hypothesis! Will we one day find the triggers of the aging program in humans?
"... Yet the underlying biology of aging remains a matter of uncertainty and debate.
Many lines of research align with the theory that aging is a direct result of decay — the inevitable degradation of molecules (including proteins or DNA), organelles, cells, or whole organs — from external assault or inexorable breakdown. When the body’s repair mechanisms fail to keep pace with these changes ...
Far from a random but linear process of wear and tear ... aging is a stepwise, programmed, orderly affair. “The destruction of the system is programmed at a very early stage,” ... Using technology that offers a systemwide view of the aging process in mice ... has outlined discrete stages of aging, akin to those of embryonic development, that are defined by changes in molecular signals and specific cell populations. In humans, the process likely begins before age 30. ...
In one series of experiments ... processed 21 million cells, sampled from 14 tissues or organs in about 50 male and female mice at five life stages, and built a data set of gene expression for each cell. “It’s extremely large-scale data,” ... “You know which organ it’s from and which age it’s from, and you also know extensive molecular information.” Each stage was marked by a dramatic decline in or expansion of specific cell types. ...
Two of his landmark papers, published in 2025 and 2026 in Science, point to a radical redistribution of the cells that make up the body as mammals age, and describe some of the epigenomic instructions that guide this process. “There are molecular changes and maybe some other changes in aging,” ... “but they all converge in the remodeling of the cell society.” ...
In one set of studies, we extracted more than 20 million cells from various organs from mice of different ages: 3, 6, 12, 16, and 23 months — roughly equivalent to 20, 30, 50, 60, and 75 years in humans. We analyzed the expression of 20,000 genes per cell and used this information to define the cell types. Then we tracked their population dynamics. ...
We found that not every cell type gets changed in aging. We identified 536 main cell types and 1,828 subtypes. Only about one-quarter of these subtypes show a strong shift in aging. Others remain stable across the lifespan.
It is surprising to find that changes in aging are not universal across all the cells, that there are specific cell populations that are more vulnerable. ...
We found that aging can be separated into distinct time windows. In each window, specific groups of cells show coordinated dynamics.
In the early phase, for example, we see that some cell types are rapidly depleted. This is followed by another phase, in which other cells are greatly expanded. ...
researchers have observed a phenomenon called “abrupt aging” in middle-aged humans that is consistent with the cell population dynamics we saw. When researchers analyze protein signatures in human blood, they see a significant change between the mid-40s and late 50s. People also tend to report an abrupt decline in function in middle age ...
What do your findings tell us about the nature of aging?
Previously, people saw aging as a linear accumulation of damage to molecules such as proteins and DNA.
But we found that aging is not a linear process. It’s more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs. Our claim is that aging is not so much molecular damage as a remodeling of the entire cell society. ...
Our technology allows us to examine the genomic program that governs the function of each cell — which regions of the genome are active and which are silent. If it’s random molecular damage, we might see random changes across the genome. But we always see the same regions that are open [active] or closed [silent] at each stage. We identified 280,000 genomic regions that are reproducibly open or closed during the aging process in specific cell types. ...
So the body has a program for aging?
Yes, the abrupt changes in mammalian aging along with the coordinated cellular dynamics at each stage suggest there are upstream signals that control aging. It’s like a tree in autumn: Its leaves fall not in a linear way but in just two weeks during the transition between summer and autumn. ..."
From the editor's summary and abstract (1):
"Editor’s summary
Aging is a complex process that results in functional changes across tissues and cell types. These changes are beginning to be documented across organismal lifespans using single-nuclei RNA sequencing. Zhang et al. generated cell atlases across multiple time points in both a commonly used mouse strain and two immunodeficient strains and their wild-type counterparts, cataloging changes in cell populations and expression changes within cell types over these time points. Investigating the role of a diminished immune complement, the authors found that certain intestinal epithelial populations increased in the absence of these adult lymphocytes. This study provides a resource for researchers studying aging, particularly in the context of immunodeficiency. ...
Structured Abstract
INTRODUCTION
As we age, certain cell types within the diverse cellular landscape of various organs undergo substantial changes. These alterations not only affect the overall function of the organism but also play a critical role in the development of age-related diseases.
Cataloging these vulnerable cell types is essential for understanding the cellular basis of aging-related pathologies and for identifying potential interventions. However, the inherent heterogeneity and varying cell proportions within each organ make it challenging to identify rare but crucial aging-associated cell types. Although single-cell genomics studies have examined the effect of aging on various organs, conventional studies face challenges such as imbalanced sex representation, biased age sampling, and limited cell coverage. These limitations hinder a comprehensive and systematic dissection of the aging process at the cellular level.
RATIONALE
To establish a panoramic cellular characterization of organismal aging in mammals and identify cell types associated with the aging process, we optimized the low-cost, high-throughput EasySci method to establish a unified single-nuclei profiling platform for all major mammalian organs. We collected and profiled tissue and organ samples from mice across their life span using a sex-balanced cohort with multiple replicates, all processed by a single individual to minimize batch effects.
To dissect intercellular regulatory networks, we used a cell-knockdown strategy to selectively deplete mature lymphocytes in vivo in adult and aged mice, allowing us to investigate their role in regulating the population dynamics of other cell types during aging.
RESULTS
We generated PanSci, an atlas comprising single-nucleus transcriptome profiles of 21,786,931 cells from >600 samples, covering 14 different tissues or organs across five life stages in both male and female mice.
This extensive dataset enabled us to construct a unified cellular map of organismal aging, identifying >300 distinct cell types and >3000 cellular states. Using this dataset, we characterized sex-dimorphic gene expression patterns shared across organs and cell types as well as cell types with sex-specific molecular programs. Additionally, by clustering >200 cell subtypes undergoing marked aging-associated population changes, we uncovered nonlinear temporal dynamics of aging at the cellular level.
Moreover, we mapped the cross-organ immune landscape of aging, revealing both widespread and organ-specific alterations in immune cells. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent.
CONCLUSION
PanSci provides a comprehensive catalog of aging-related cell population changes, featuring a balanced representation of replicates across sexes, a broader age range, and substantially larger cell numbers compared with existing studies. Our data suggest that aging, at the cellular level, progresses through dynamic changes rather than a simple linear trajectory.
By identifying >200 distinct cellular states with marked aging-related changes, we demonstrate the potential of scalable single-cell genomic techniques to uncover key cellular targets for therapeutic innovations aimed at restoring cellular functions and rejuvenating systemic biological processes in aging and diseases. ..."
From the editor's summary and abstract (2):
"Editor’s summary
Aging atlases have been generated for multiple organisms, but they are often restricted to capturing the transcriptional landscape across cells.
Lu et al. created a single-cell chromatin accessibility atlas in mice for 21 tissues over three age time points ... They combined this atlas with a previous gene expression atlas of aging and found many changes in cellular composition and chromatin accessibility with aging.
Changes occurred across cell types, but immune cells in particular showed diverging patterns with aging, and the authors were able to trace these patterns to particular transcription factor motifs within the peaks. Many of these changes were sex specific, reinforcing the importance of using diverse samples in such endeavors. ...
Structured Abstract
INTRODUCTION
Aging is the leading risk factor for many diseases. This association underscores the potential of therapies targeting the aging process itself to delay or prevent age-related diseases. Substantial advances in single-cell genomics have enabled the profiling of alterations in aging. However, these analyses typically focus on transcriptomics and overlook the impact of chromatin landscapes.
RATIONALE
Single-cell assay for transposase-accessible chromatin using sequencing (ATAC-seq), which analyzes genome-wide chromatin accessibility at the single-cell level, has enabled the mapping of the cell type–specific chromatin landscape in a range of mammalian tissues.
With a further optimized version of single-cell ATAC-seq by combinatorial indexing (EasySci-ATAC), we investigated aging-associated changes in cell populations and chromatin changes across the entire organism, aiming to identify aging-associated noncoding regions and their corresponding cell types.
RESULTS
In this study, we applied EasySci-ATAC to profile chromatin accessibility in more than 10 million nuclei across 21 tissue types from mice spanning three age groups (1 month, 5 months, and 21 months). We detected a total of 1.3 million cis-regulatory elements and identified cell type–specific usages of them.
We reported aging-associated population dynamics of 536 tissue-level main cell types and 1828 finer-grained subtypes. In broadly distributed cell types, we observed coordinated expansion or depletion of the same subtype in multiple organs.
At the molecular level, we identified extensive chromatin reprogramming with aging, including changes in the accessibility of individual peaks and certain transcription factor motifs, and linked them to expression changes of putative target genes.
Moreover, we detected extensive sexual dimorphism, including age-conserved, sex-specific chromatin states for the same cell types and age-sex interaction effects at both proportional and molecular levels.
CONCLUSION
Our organism-level single-cell chromatin accessibility atlas illuminates how aging remodels cellular composition and regulatory regions of multiple tissues.
In addition to many highly tissue-specific changes, we uncovered coordinated cellular and molecular dynamics that are shared across different organs, including immune remodeling, broad depletion of functional cell types, the emergence of inflammation-related states, and sex-dependent trajectories.
By cataloging these changes, we offer a resource for understanding the molecular logic of aging and for guiding therapeutic strategies aimed at preserving or restoring youthful tissue states. ..."
Why Aging May Be a Program, Not a Breakdown | Quanta Magazine "By deciphering the molecular signatures of millions of mouse cells, Junyue Cao has found that aging is not haphazard wear and tear but rather a “remodeling of the cell society.”"
Cellular architecture of organismal aging.
An organism-wide single-cell atlas of chromatin accessibility reveals cellular dynamics and epigenomic remodeling during aging.
