Scientists identify the enzyme that drives aging in the kidney's irreplaceable filter cells and knock it out in mice
Scientists identify the enzyme that drives aging in the kidney's irreplaceable filter cells and knock it out in mice
On 21 September 2026, a Research Square preprint (not yet peer-reviewed) from a group of biologists at the University of Texas Health Science Center at San Antonio reported that the enzyme CerS6 in podocytes, the cells that filter blood in the kidney, drives their senescence through accumulation of the lipid ceramide C16 and activation of the protein p53. In aged marmosets this pathway was more active than in young animals; in mice with CerS6 knocked out specifically in podocytes, signs of age-related kidney damage were markedly reduced.
The glomerulus is a tuft of capillaries in the kidney where blood is filtered under pressure into urine. Podocytes wrap around these capillaries from the outside, forming the final filtration barrier for proteins and blood cells. They do not divide: a lost cell is not replaced, so their senescence irreversibly weakens the entire filter. About 38% of people over 65 have chronic kidney disease, and podocyte senescence is one of its mechanisms.
The biologists studied common marmosets, small New World primates whose genome was sequenced in 2014. They age faster than larger primates and have long served as a convenient model of aging. In aged animals (approximately 16 years, compared to 3 in young ones) the glomeruli contained more senescent cells, and podocytes showed higher levels of p53 and p21, markers of cellular senescence. These same animals had elevated CerS6 in their podocytes and higher levels of its product, ceramide C16, accumulating in the glomeruli. The higher the CerS6 level, the more severe the glomerular damage, the greater the protein loss in urine, and the lower the level of Klotho, a protein whose decline is associated with kidney aging.
Among related enzymes, CerS6 produces specifically ceramide C16. As early as 2018, a separate laboratory showed that this molecule binds directly to p53 and blocks MDM2, a protein that normally rapidly degrades p53. To establish which of the two events comes first (the rise in ceramide or the activation of p53), the researchers induced senescence in cultured podocytes with doxorubicin, a chemotherapy drug that at laboratory doses triggers cellular senescence. Knocking down CerS6 reduced both ceramide levels and p53 activity, while pharmacological suppression of p53 did not lower ceramide, placing ceramide upstream of p53 in this pathway.
The decisive test was performed in mice with CerS6 knocked out only in podocytes. Normally aged mice (24 months) developed signs of kidney aging: glomerular scarring and fibrosis, accumulation of senescent cells, urinary protein loss, and elevated cystatin C, a marker of declining kidney function. In mice lacking podocyte CerS6 these changes were substantially milder, and the gene deletion did not affect organ weight or blood glucose levels. Single-cell RNA sequencing of kidney tissue confirmed the result: mice without CerS6 showed suppression of both senescence programs and p53-p21 pathway genes.
Ceramide C16 also proved to be a potential biomarker: its urinary levels rose with age alongside increasing protein leakage through the filter, and in CerS6-knockout mice this rise was markedly attenuated. The authors propose developing CerS6 inhibitors or PROTACs (drugs that degrade a protein inside the cell rather than blocking it) as interventions against kidney aging.
"Targeting the CerS6/ceramide C16 axis may offer a new strategy to preserve podocyte health and slow kidney aging..." the authors write.
Before this work, the CerS6/ceramide C16/p53 pathway was recognized as a driver of podocyte injury only in diabetic kidney disease. The new finding extends it to ordinary aging, without diabetes, independently in a primate and in a mouse, and makes CerS6 a drug target for protecting the kidney's filtration barrier.
Earlier this week, MIT identified a shared lipid signature of cellular senescence linked to the marker p21 and proposed testing its causal role by knocking out the enzymes that elongate such lipids. For CerS6, this has already been done: removing the enzyme reduces both ceramide and the p53-p21 program.