Unveiling the Impact of Senescent Cells on Aging at the Single-Cell Level

A groundbreaking study led by researchers from Kyoto University has introduced an innovative in vivo system to explore how senescent cells influence aging through complex mechanisms within living tissues. Published in Nature Aging, this research provides detailed insights into the behavior of senescent cells and their effects on cellular and tissue functions.

Cellular senescence is a process where cells permanently stop dividing in response to stressors such as DNA damage, oxidative stress, or oncogene activation. While this mechanism plays a crucial role in preventing tumor development and aiding in tissue repair, the accumulation of senescent cells over time has been linked to various age-related diseases and tissue decline.

One of the major challenges in aging research has been understanding the precise roles of senescent cells in vivo due to difficulties in identifying and studying these cells within complex tissue environments. To overcome this, the research team developed two genetically engineered mouse models that can induce senescence by activating key pathways—ERK and p38 MAPK—via inducible expression of constitutively active MEK1 (caMEK1) or MKK6 (caMKK6). These models, combined with a dual-color labeling system, allow scientists to distinguish primary senescent cells from secondary ones based on fluorescence markers, enabling gene expression analysis at the single-cell level.

Using this system, the team observed that inducing senescence in liver and colon tissues resulted in hallmark features such as increased p21 expression, DNA damage response activation, and secretion of SASP factors. Transcriptomic profiling demonstrated that senescent cells exhibit highly diverse gene expression patterns, influenced by tissue type, the method of induction, and spatial arrangement within tissues.

A key discovery was that SASP factors like IL-1β, especially secreted by macrophages, could induce secondary senescence in neighboring cells, emphasizing the importance of intercellular signaling. Additionally, the study found that senescent cells disrupt normal tissue organization, such as liver zonation—an essential aspect for metabolic function—which was notably seen in caMEK1-induced models. This disruption led to decreased expression of metabolic genes, mirroring changes observed in aged tissues.

Importantly, the transcriptomic profiles of the senescent cells closely resembled those found in naturally aged mice and humans, providing evidence for a causal role of senescence in tissue dysfunction associated with aging. By capturing the dynamics of primary and secondary senescence in vivo, this research offers valuable insights into how senescent cells influence tissue health and aging.

The study's findings not only deepen our understanding of aging processes but also establish new avenues for therapeutic interventions targeting senescence. The generated mouse models serve as powerful tools for future research aimed at mitigating age-related decline and developing anti-aging strategies.

For more details, see the publication: Yuko Sogabe et al., "Characterizing primary and secondary senescence in vivo," Nature Aging (2025).