Abstract 622: Age-dependent changes in cell cycle dynamics and hematopoietic responses to chemotherapy

Abstract Background: Precision medicine emphasizes individualized cancer treatment, particularly for elderly lung cancer patients facing unique chemotherapy challenges. Age-related changes in cell cycle dynamics significantly influence therapeutic outcomes, yet their role in optimizing personalized therapies remains underexplored. This study investigates these age-related dynamics to inform personalized therapeutic strategies for elderly lung cancer patients. Methods: Single-cell RNA sequencing data from 166 healthy individuals (aged 25-85 years) were analyzed to explore age-associated changes in cell cycle distribution, differentially expressed genes (DEGs), and enriched pathways. Young (9-11 weeks) and aged (17 months) mice received weekly cisplatin for four cycles. Peripheral blood and hematopoietic stem cells (HSCs) were monitored dynamically for cell cycle phases, DNA damage (γ-H2AX), and vascular leakiness using immunofluorescence. RNA sequencing of HSCs identified DEGs and enriched pathways after treatment cycles. Results: Single-cell analysis revealed a linear decrease in S-phase proportions with age (r=−0.681, p=0.0026) and identified 28 DEGs, including PAXB-AS1, BABAM1, and DONSON, enriched in immune regulation and cell cycle pathways. In murine models, aged mice showed impaired immune recovery, with persistently higher neutrophil proportions (post-cycle 1: 14.75% vs. 6.1%, p<0.05) and lower lymphocyte proportions (post-cycle 1: 65.73% vs. 79.98%, post-cycle 4: 60.5% vs. 63.8%) compared to young mice. Moreover, aged mice exhibited delayed neutrophil recovery (Day 4 vs. Day 2), accompanied by persistent G1-phase arrest in HSCs (Day 4: 86% vs. 82%) and reduced G2/M-phase proportions (Day 4: 3% vs. 6%). RNA sequencing of aged HSCs further revealed significant enrichment in the DNA_DAMAGE_TELOMERE_STRESS_INDUCED_SENESCENCE pathway after four treatment cycles (|NSE| = 1.98, p < 0.05), a pattern absent in young mice. Finally, γ-H2AX flow cytometry confirmed increased DNA damage in aged HSCs, while immunofluorescence demonstrated heightened bone marrow vascular leakiness in aged mice. Conclusion: Aging significantly alters cell cycle dynamics, hematopoietic recovery, and chemotherapy responses, highlighting the need to integrate cell cycle-based insights into personalized treatment strategies. These findings provide a foundation for future research on age-specific therapeutic interventions in lung cancer. Citation Format: Jianxing He,Yue Pan,Hao Liu,Ying Huang,Hongsheng Deng,Chao Yang,Qi Cai,Shan Xiong,Huiting Liu,Wenhua Liang. Age-dependent changes in cell cycle dynamics and hematopoietic responses to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 622.