通过激活利他性干细胞防御反应减轻癌症化疗诱导的加速衰老

Introduction: Accelerated biological aging (ABA) is increasingly recognised as a driver of poor survivorship outcomes in cancer. Conventional aging biomarkers including epigenetic clocks, inflammatory signatures, and frailty scales are descriptive and lack mechanistic specificity. We hypothesized that the Altruistic Stem Cell (ASC) Defense (ASD) response (1) of mesenchymal stem cells (MSCs) represents protective pathway against chemotherapy and tumor-induced ABA at both systemic and tumor-microenvironment (TME) levels. Methods: A cisplatin-induced accelerated aging mouse model (2) was used to evaluate whether activation of the ASD response mitigates ABA. MCF-7 breast cancer-bearing mice received cisplatin with or without squalene supplementation, a nutritional geroprotectant predicted to enhance ASD activity. ABA was quantified in BM-derived MSCs (CD271+/CD45⁻ progenitors) and tumor-derived CD271⁺ MSCs using two canonical aging hallmarks: DNA double-strand breaks (gammaH2AX) and heterochromatin loss (H3K9Me3). The ASC phenotype of MSCs were measured as described (1). 20 PBMC samples from breast, lung, and ovarian cancer patients (N=10) treated with cisplatin (KaviKrishna HealArt cohort) were analyzed. CD45⁻ MSCs were isolated and expanded under naïve MSC conditions (3). The ASD response was measured by quantifying the ASC phenotype of the CD45- MSCs (3). Results: Cisplatin induced a robust accelerated aging phenotype in tumor-bearing mice, characterized by elevated gammaH2AX and reduced H3K9Me3 in BM-derived MSCs. Notably, TME-derived CD271⁺ MSCs also exhibited pronounced aging features, indicating that chemotherapy accelerates aging locally within the tumor niche. This aging TME correlated with increased tumor burden in cisplatin-treated mice. Although the ASD was activated, it was not sustained. Squalene supplementation sustained the ASD response, evidenced by the mobilization of ASCs to the circulation. Activation of ASD reversed aging hallmarks in both BM-MSCs and tumor-derived CD271⁺ MSCs, reducing DNA damage and restoring heterochromatin integrity. Importantly, squalene-treated mice displayed reduced tumor growth, suggesting that preventing aging of the TME suppresses tumor-supportive signals. In the human study, we identified a subset of patients (n=4) with ASD-positive MSCs showed significantly lower gammaH2AX (p < 0.05) and higher H3K9Me3 CTCF values compared to patients (n=6) having ASD-negative MSCs. Conclusion : Chemotherapy accelerates aging in circulating progenitors and in tumor-derived CD271⁺ MSCs, creating an aging TME that may foster tumor progression. Clinically, ASD can be quantified from PBMC-derived MSCs and may serve as a biomarker to stratify patients at highest risk of ABA. References: 1. Pathak L, et al PMID: 33887214.2. Das B, et al. PMID: 18813359.3. Talukdar J et al. https://doi.org/10.1158/1538-7445.AM2016-920.