Abstract: TH-OR017
Multimodal Spatial Imaging Reveals Endogenous Adenine as a Metabolic Inducer of Senescence in Aging Kidneys
Session Information
- CKD: Exploring Intertwined Mechanisms of Disease Progression
November 06, 2025 | Location: Room 362A, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Maity, Soumya, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Saliba, Afaf, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Tamayo, Ian M., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Shaji, Alan, The University of Texas at Austin, Austin, Texas, United States
- Zhang, Guanshi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Salmon, Adam, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Group or Team Name
- For the Kidney Precision Medicine Project (KPMP).
Background
Cellular senescence is a key contributor to age-related kidney dysfunction, yet its underlying mechanisms remain poorly understood. Senescent cells are characterized by p53 activation, accumulation of cyclin-dependent kinase inhibitors (p21 and p16), elevated β-galactosidase (β-gal) activity, and senescence-associated secretory phenotype (SASP). Given their distinct metabolic profile, we aimed to characterize the metabolomic signatures of senescent cells in aged kidneys to identify novel metabolic drivers of chronic kidney disease (CKD) in aging.
Methods
We used p16-tdTomato reporter mice, in which p16-expressing cells fluoresce red, enabling precise localization of senescent cells in situ. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was performed on kidney tissues from these mice, marmosets, and KPMP participants. By integrating spatial metabolomics with optical imaging, we generated high-resolution multimodal maps of tissue architecture and metabolite distribution to profile the metabolic landscape of senescent regions in the kidneys.
Results
Untargeted spatial metabolomics identified adenine as one of the top four altered small-molecule metabolites in senescent regions of kidneys from 15-month-old p16-tdTomato mice. Multimodal imaging revealed adenine accumulation in β-gal-positive senescent regions. Elevated adenine levels were also observed in kidney cortex samples from older (>60 years) vs. younger (<40 years) human donors, 15-month-old vs. 3-month-old reporter mice, and 16-year-old vs. 3-year-old marmosets. Adenine administration to young mice induced mTORC1-mediated expression of p21, p16, and SASP markers. In p16-reporter mice, kidneys subjected to unilateral ischemia-reperfusion injury (IRI) exhibited increased senescence with colocalized adenine accumulation compared to contralateral kidneys one year post-injury. Notably, pharmacologic inhibition of endogenous adenine synthesis conferred renal protection and suppressed SASP in bilateral IRI and cisplatin-induced AKI mouse models.
Conclusion
These findings identify endogenous adenine as a metabolic driver of cellular senescence in aging and injured kidneys. Inhibiting its production may provide a novel therapeutic strategy to mitigate CKD progression associated with normal or accelerated aging.
Funding
- Other NIH Support