“Cellular senescence is a fundamental biological process that underlies organismal aging and age-related diseases; however, the temporal dynamics of gene expression during senescence remain unclear.”

Click here to listen to this press release.

BUFFALO, NY — April 29, 2026 — A new research paper was published in Volume 18 of Aging-US on April 10, 2026, titled “Stage-dependent transcriptomic changes in human dermal fibroblast senescence model.”

The study was led by first author Michiko Kudo from the University of Tokyo and DHC Corporation Laboratories and corresponding author Shuichi Asakawa from the University of Tokyo. In this work, the researchers took a closer look at how gene expression changes as cells age, focusing on human dermal fibroblasts—a widely used model for studying aging in skin and connective tissues. While cellular senescence is known to play a central role in aging, the timing and progression of molecular changes during this process have remained difficult to define.

To explore this, the team developed a stepwise model of replicative senescence, categorizing cells into three stages—young, middle, and old—based on their cumulative number of divisions. This approach allowed them to capture the gradual nature of aging, rather than relying on acute stress models that may overlook early-stage transitions.

One of the more interesting findings was that the “middle” stage—often overlooked—is not just a simple midpoint, but a biologically active transition phase. Although gene expression profiles in young and middle cells appeared similar at first glance, a closer look showed that important molecular changes had already begun during this phase.

In particular, genes involved in immune and inflammatory responses were activated early, even before cells reached full senescence. This suggests that aging-related inflammation may begin much earlier than previously appreciated, gradually intensifying as cells progress toward the late stage.

At the same time, genes responsible for maintaining basic cellular functions—such as protein synthesis, cell structure, and adhesion—showed a progressive decline as aging advanced. Together, these changes suggest a shift in cellular priorities, where stress and inflammatory signals increase while maintenance and repair functions gradually decline.

To better understand these patterns, the researchers combined transcriptomic analysis with network and matrix factorization approaches. These methods revealed distinct gene expression programs associated with different stages of aging, including early immune activation, mid-stage extracellular remodeling, and late-stage functional decline.

“These findings suggest that immune–inflammatory responses are engaged from early senescence, whereas cell adhesion and maintenance pathways decline progressively.”

Importantly, the results point to the middle stage of senescence as a potential window for intervention. Unlike fully senescent cells, which exhibit more stable and potentially irreversible changes, cells in this transitional phase may retain some degree of plasticity, making them more responsive to therapeutic strategies.

Overall, this study offers a clearer picture of how aging unfolds at the molecular level. By identifying stage-specific changes in gene expression, the authors provide new insight into the early drivers of cellular senescence and highlight potential targets for delaying or modifying age-related decline.

Paper DOI: https://doi.org/10.18632/aging.206371         

Corresponding author: Shuichi Asakawa – [email protected]

Keywords: cellular senescence, aging, dermal fibroblasts, transcriptome analysis, immune–inflammatory signaling, aging biomarkers

Click here to sign up for free Altmetric alerts about this article.