A study published in the journal Aging has uncovered a surprising link between the fat-handling machinery inside kidney cells and the process of cellular senescence, the state in which damaged cells stop dividing but refuse to die. The research, led by Sanne van der Rijt of Amsterdam UMC, with corresponding authors Georges E. Janssens, Riekelt H. Houtkooper and Alessandra Tammaro, points to a lysosomal enzyme called PLA2G15 as a critical regulator of how kidney cells respond to stress. The work, published on September 16, 2026, in Volume 18 of the journal, suggests that manipulating a single phospholipid-digesting enzyme could blunt the senescence program that drives age-related kidney decline.
Chronic kidney disease becomes steadily more common with age, and one of its quiet drivers is the accumulation of senescent cells, particularly in the proximal tubular epithelial cells, or TECs. These cells perform the demanding job of reabsorbing filtered substances and are essential to kidney function. Senescence can initially serve a protective purpose, halting cells that have suffered DNA damage before they turn cancerous. But when senescent cells linger, they secrete inflammatory and profibrotic signaling molecules that injure surrounding tissue, promote scarring and gradually erode organ performance. Understanding what tips a stressed TEC into persistent senescence has therefore become a central question in kidney aging research.
The Amsterdam team focused their attention on lysosomes, the cellular compartments that break down and recycle biological material. Lysosomal function depends on a specialized set of membrane phospholipids, most notably bis(monoacylglycerol)phosphate, or BMP, a lipid that helps organize the internal architecture of the lysosome and supports its digestive activity. Earlier studies had reported that BMP abundance rises during aging and in kidney disease, but the lipid’s exact contribution to senescence remained murky. That gap led the researchers to PLA2G15, a phospholipase enzyme resident in the lysosome that participates in BMP breakdown and broader lipid metabolism.
The first evidence came from a comparison of young and aged mouse kidneys. In older animals, the researchers observed greater accumulation of BMP lipids alongside increased expression of the Pla2g15 gene, together with molecular signatures of cellular senescence. While these observations were associative rather than causal, they established that lysosomal lipid metabolism shifts in parallel with kidney aging, setting the stage for a more direct experimental test of whether the enzyme actually influences the senescence program.
To probe that relationship, the team used CRISPR/Cas9 gene editing to disrupt Pla2g15 in immortalized mouse proximal tubular epithelial cells. Two independently generated knockout lines showed sharply reduced PLA2G15 protein levels and enzyme activity, giving the researchers a clean system in which to examine the consequences of losing the enzyme. Lipidomic profiling of these cells revealed widespread remodeling of phospholipid metabolism. Total BMP abundance rose, as did levels of its precursor, lysophosphatidylglycerol, but the composition of the BMP pool changed in a more telling way: several long-chain unsaturated BMP species were actually reduced. In other words, PLA2G15 does not simply control how much BMP is present; it shapes which specific molecular species of the lipid dominate the lysosomal membrane.
The decisive experiment came when the researchers exposed both normal and Pla2g15-deficient kidney cells to doxorubicin, a chemotherapy drug that is widely used in the laboratory to inflict DNA damage and trigger senescence. In ordinary cells, doxorubicin raised levels of the senescence-associated protein P21 and forced cells into a pronounced arrest at the G2/M checkpoint of the cell cycle. Cells lacking Pla2g15 responded very differently: P21 expression was significantly lower and G2/M arrest was reduced, indicating that the senescence response had been substantially attenuated. The knockout cells also showed improved mitochondrial and lysosomal health compared with their normal counterparts under the same stress.
Follow-up lipidomics sharpened the picture. Doxorubicin-treated normal cells accumulated several long-chain polyunsaturated BMP species, including BMP42:6, BMP42:8 and BMP44:8, while Pla2g15-deficient cells shifted toward shorter BMP species and away from the long-chain unsaturated forms. This species-specific pattern suggests that the buildup of particular long-chain BMP lipids is not merely a byproduct of senescence but may be mechanistically tied to its development. As the authors state in the paper, “Here, we identify a critical role for lysosomal phospholipid metabolism in senescent TECs,” framing the lipid remodeling as an active participant in the senescent state rather than passive chemistry.
To understand how a lysosomal enzyme could reach into other cellular compartments, the researchers performed proteomic analysis, quantifying more than 3,400 proteins. The knockout cells showed increased abundance of proteins tied to mitochondrial metabolic pathways, including components of NAD+ metabolism and fatty acid oxidation. Among the upregulated proteins were NAMPT and NMNAT3, both involved in generating and recycling NAD+, a molecule central to cellular energy metabolism, and CPT2, an enzyme that shuttles fatty acids into mitochondrial oxidation. The proteomic data also revealed reduced levels of proteins driving cell-cycle progression and ribosomal processes, along with increased expression of LAMP1, a lysosomal membrane protein. “Our findings point to PLA2G15 as a critical regulator of senescence through its role in lysosomal lipid remodelling and mitochondrial metabolism,” the authors conclude. The team is careful to note, however, that direct measurements of mitochondrial metabolic function and lysosomal activity were not performed, so the proposed functional benefits still require confirmation.
The implications for chronic kidney disease are potentially significant, because impaired lipid metabolism, mitochondrial dysfunction and persistent senescence all converge in the damaged aging kidney. By naming PLA2G15 as a regulator of BMP composition and senescence-related changes, the study offers a concrete molecular handle for future interventions aimed at preserving kidney-cell health during aging. Yet the work remains firmly preclinical. The observations in aged mouse kidneys were associative, and the protective effects of Pla2g15 disruption were demonstrated only in cultured mouse cells exposed to doxorubicin, a model that does not fully reproduce natural kidney aging or chronic kidney disease in a living organism. The researchers also emphasize that pharmacological inhibition of PLA2G15 has not been tested, and it is unknown whether a drug-based approach would reproduce the effects seen with genetic deletion.
Several questions will shape the next phase of research. Genetically modified animals, alternative senescence models and direct functional measurements of mitochondria and lysosomes will be needed to establish the biological mechanisms and therapeutic relevance of targeting PLA2G15. Because the mouse experiments involved only males, future studies must also determine whether the same lipid-senescence relationship holds in females. Even with those caveats, the study adds an intriguing new dimension to the biology of aging: the idea that the molecular species of lipids lining the lysosome, not just their total amount, help determine whether a stressed kidney cell quietly exits the cell cycle or locks itself into a damaging senescent state. If that relationship holds up in living animals, selectively modifying BMP metabolism could open a new route to slowing the cellular decline that underlies age-related kidney disease.
Subject of Research: The role of the lysosomal enzyme PLA2G15 and BMP phospholipid metabolism in cellular senescence of kidney tubular cells
Article Title: Targeting PLA2G15 reduces senescence and alters lipid metabolism in kidney cells
Article References: Targeting PLA2G15 reduces senescence and alters lipid metabolism in kidney cells. (n.d.). Original publication
Image Credits: AI Generated
DOI: Not provided
Keywords: PLA2G15, cellular senescence, kidney aging, lysosomes, BMP phospholipids, chronic kidney disease, mitochondria, lipid metabolism, tubular epithelial cells, CRISPR, NAD+ metabolism, doxorubicin
News Source: Beatrice Stafford. (October 18, 2026). Kidney Aging Enzyme PLA2G15 Emerges as New Target Against Cellular Senescence. Scienmag.
