Garza-Martinez, L. | Search bioRxiv

bioRxiv2026

A transitional senescence program drives inflammatory monocyte state expansion in aging humans

Dysfunctional monocyte states contribute to age-related pathologies and systemic inflammation. However, the gene regulatory networks governing the transition to these states remain unknown. Here we used bulk and single-cell multidimensional integrative profiling to reveal previously uncharacterized monocyte state transitions during human aging. We show that a transient senescent-like population arising from classical CD14++ CD16- monocytes drives the accumulation of an inflammatory monocyte state in aging humans. This senescence-associated transition is orchestrated by the master senescence regulator AP-1, which acts on a pre-established chromatin landscape to rewire the monocyte transcription factor (TF) network and activate both senescence- and age-associated inflammatory transcriptional programs. Through integration with clinical transcriptomic datasets, we demonstrate that senescent-like and aged monocytes are transcriptionally primed toward sepsis-associated states. Overall, our study provides the core gene-regulatory principles underlying a senescent-like transitional state in monocytes and identifies AP-1 as an attractive target to modulate systemic inflammation in age and disease.

systems biology↗

bioRxiv2025

Senescent CD8+ T Effector Memory Cells are Functionally Impaired, Enriched in Aging and Disease, and a Barrier to Immunotherapy

Senescent cells play important roles in various biological processes that promote fitness and health, however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells progressively accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. Supporting this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we further characterized the senescence state of human SA-{beta}Gal-expressing CD8 T effector cells, their functional capabilities, and their involvement in aging and disease. Single-cell RNA sequencing revealed that SA-{beta}Gal-expressing CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in effector memory (EM) T cells. SA-{beta}Gal-expressing CD8 TEM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells, compared to CD8 TEM cells with low SA-{beta}Gal activity. Gene signatures of senescent SA-{beta}Gal-expressing CD8 TEM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and smokers. Furthermore, our results demonstrate that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 TEM cells to immunotherapy. Collectively, our study demonstrates that the senescence state impairs the functions of CD8 TEM cells and reveals the involvement of senescent and dysfunctional CD8 TEM cells in aging, disease, exposure to toxins, and responses to immunotherapy.

cell biology↗