"Here, we identify a critical role for lysosomal phospholipid metabolism in senescent TECs."
BUFFALO, NY — October 13, 2026 — A new research paper was published in Volume 18 of Aging on September 16, 2026, titled " Targeting phospholipase Pla2g15 reduces long-chain BMP phospholipids abundance and senescence in kidney cells ."
The study found that disrupting the gene Pla2g15 reduced stress-induced cellular senescence in mouse kidney cells while altering the composition of phospholipids involved in lysosomal function. The findings identify a possible connection between lipid metabolism, mitochondrial pathways and kidney aging, suggesting that PLA2G15 could become a potential therapeutic target for age-related kidney disease.
The research was led by first author Sanne van der Rijt, affiliated with Amsterdam UMC . Corresponding authors Georges E. Janssens and Riekelt H. Houtkooper are also affiliated with Amsterdam UMC , while corresponding author Alessandra Tammaro is affiliated with Amsterdam UMC and Leiden University Medical Center .
Chronic kidney disease (CKD) becomes increasingly common with age and is associated with progressive loss of kidney function. One contributing factor is the accumulation of senescent cells, particularly proximal tubular epithelial cells (TECs), which play an important role in reabsorbing filtered substances and maintaining kidney function. Although cellular senescence can initially protect against damage, persistent senescent cells can release inflammatory and profibrotic factors that contribute to tissue injury, scarring and functional decline.
The researchers focused on the role of lysosomes, cellular compartments responsible for breaking down and recycling biological materials. Lysosomal function depends partly on specialized phospholipids, including bis(monoacylglycerol)phosphate (BMP), which helps maintain the organization and activity of the lysosomal system. Previous research has linked increased BMP abundance to aging and kidney disease, but its contribution to cellular senescence remains incompletely understood.
The study examined PLA2G15, a lysosomal enzyme involved in BMP breakdown and lipid metabolism. To investigate its role, the researchers first compared kidneys from young and aged male mice. Older kidneys showed greater accumulation of BMP lipids and increased Pla2g15 expression, alongside changes associated with cellular senescence. These findings suggested a relationship between altered lysosomal lipid metabolism and kidney aging.
To explore this relationship more directly, the researchers used CRISPR/Cas9 gene editing to disrupt Pla2g15 in immortalized mouse proximal tubular epithelial cells. Two independently generated knockout cell lines showed markedly reduced PLA2G15 protein expression and enzyme activity, allowing the team to examine how loss of the enzyme affected lipid composition and senescence-related responses.
Lipidomic analysis revealed widespread changes in phospholipid metabolism. Loss of Pla2g15 increased the overall abundance of BMP and its precursor, lysophosphatidylglycerol (LPG). However, the composition of BMP changed substantially. Despite the increase in total BMP, several long-chain unsaturated BMP species were reduced, demonstrating that PLA2G15 influences specific lipid species rather than simply controlling total phospholipid abundance.
The researchers then investigated whether these changes affected cellular senescence. They exposed normal and Pla2g15-deficient kidney cells to doxorubicin, a chemotherapy drug used experimentally to induce DNA damage and senescence. In normal cells, doxorubicin increased the senescence-associated protein P21 and caused pronounced cell-cycle arrest at the G2/M phase. In contrast, cells lacking Pla2g15 showed significantly lower P21 expression and reduced G2/M arrest, indicating attenuation of the senescence response.
Further lipidomic analysis revealed an important difference between the two cell types. Doxorubicin-treated normal cells accumulated several long-chain polyunsaturated BMP species, including BMP42:6, BMP42:8 and BMP44:8. Cells lacking Pla2g15, however, displayed a shift toward shorter BMP species and reduced abundance of long-chain unsaturated BMPs. This suggests that changes in the composition of lysosomal phospholipids are linked to the development of stress-induced senescence.
To investigate the underlying mechanisms, the researchers also performed proteomic analysis, identifying more than 3,400 proteins. Cells lacking Pla2g15 showed increased abundance of proteins associated with mitochondrial metabolic pathways, including NAD+ metabolism and fatty acid oxidation. Among these were NAMPT and NMNAT3, which participate in NAD+ metabolism, and CPT2, an enzyme involved in mitochondrial fatty acid oxidation.
The proteomic findings also showed reduced abundance of proteins involved in cell-cycle progression and ribosomal processes, together with increased expression of LAMP1, a lysosomal membrane protein. These results suggest that loss of PLA2G15 may influence both mitochondrial and lysosomal biology. However, direct measurements of mitochondrial metabolic function and lysosomal activity were not performed, so the proposed functional benefits remain to be confirmed.
"Our findings point to PLA2G15 as a critical regulator of senescence through its role in lysosomal lipid remodelling and mitochondrial metabolism."
The findings could have implications for understanding chronic kidney disease, where impaired lipid metabolism, mitochondrial dysfunction and persistent senescence contribute to kidney damage. By identifying PLA2G15 as a regulator of BMP composition and senescence-related changes, the study offers a possible molecular target for future research into strategies aimed at preserving kidney-cell health during aging.
However, the research remains preclinical. The observations in aged mouse kidneys were associative, while the protective effects of Pla2g15 disruption were demonstrated in cultured mouse kidney cells exposed to doxorubicin. This experimental model does not fully reproduce natural kidney aging or chronic kidney disease in living organisms. The researchers also note that pharmacological inhibition of PLA2G15 has not been tested, and it remains unknown whether such an approach would produce the same effects as genetic disruption.
Additional studies using genetically modified animals, other senescence models and direct measurements of mitochondrial and lysosomal function will be needed to establish the biological mechanisms and therapeutic relevance. Because the mouse experiments involved only males, future investigations should also examine whether similar relationships occur in females.
Overall, the study identifies a connection between PLA2G15 activity, lysosomal phospholipid composition and cellular senescence in kidney cells. The findings suggest that selectively modifying BMP metabolism could influence age-related cellular changes and provide a foundation for investigating PLA2G15 as a potential therapeutic target in kidney aging and chronic kidney disease.
Paper DOI: https://doi.org/10.18632/aging.206415
