Developing a novel aging assessment model to uncover heterogeneity in organ aging and screening of aging-related drugs
Abstract Background The decline in organ function due to aging significantly impacts the health and quality of life of the elderly. Assessing and delaying aging has become a major societal concern. Previous studies have largely focused on differences between young and old individuals, often overlook...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-025-01501-0 |
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| Summary: | Abstract Background The decline in organ function due to aging significantly impacts the health and quality of life of the elderly. Assessing and delaying aging has become a major societal concern. Previous studies have largely focused on differences between young and old individuals, often overlooking the complexity and gradual nature of aging. Methods In this study, we constructed a comprehensive multi-organ aging atlas in mice and systematically analyzed the aging trajectories of 16 organs to elucidate their functional specificity and identify organ-specific aging trend genes. Cross-organ association analysis was employed to identify global aging regulatory genes, leading to the development of a multi-organ aging assessment model, hereafter referred to as the 2A model. The model’s validity was confirmed using single-cell RNA sequencing data from aging mouse lungs, cross-species gene expression profiles, and pharmacogenomic data. Furthermore, a random walk algorithm and a weighted integration approach combining gene set enrichment analysis were implemented to systematically screen potential drugs for mitigating multi-organ aging. Results The 2A model effectively assessed aging states in both human and mouse tissues and demonstrated predictive capability for senescent cell clearance rates. Compared to the sc-ImmuAging and SCALE clocks, the 2A model exhibited superior predictive accuracy at the single-cell level. Organ-specific analyses identified the lungs and kidneys as particularly susceptible to aging, with immune dysfunction and programmed cell death emerging as key contributors. Notably, single-cell data confirmed that plasma cell accumulation and naive-like cell reduction showed linear changes during organ aging. Aging trend genes identified in each organ were significantly enriched in aging-related functional pathways, enabling precise assessment of the aging process and determination of organ-specific aging milestones. Additionally, drug screening identified Fostamatinib, Ranolazine, and Metformin as potential modulators of multi-organ aging, with mechanisms involving key pathways such as longevity regulation and circadian rhythm. Conclusions The 2A model represents a significant advancement in aging assessment by integrating multi-dimensional validation strategies, enhancing its accuracy and applicability. The identification of organ-specific aging pathways and candidate pharmacological interventions provides a theoretical foundation and translational framework for precision anti-aging therapies. |
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| ISSN: | 1756-994X |