Age-dependent mitochondrial toxicity in renal stem cells: A precise 3D silk matrix model

Aging is a significant risk factor for drug-induced kidney injury, underscoring the need for advanced preclinical models. The impact of age on the susceptibility of human primary kidney stem cells to drug-induced mitochondrial toxicity remains largely uncharacterized. To address this gap, we employed a well-established in vitro 3D model, utilizing a silk fiber matrix, to culture renal stem cells derived from both young and elderly donors. Tenofovir, a commonly prescribed antiretroviral medication linked to renal adverse effects, was used to investigate age-related drug-induced mitochondrial toxicity. Our findings reveal a pronounced age-dependent increase in tenofovir-induced mitochondrial dysfunction in older renal stem cells compared with their younger counterparts. This was characterized by diminished mitochondrial mass and function, ATP production, elevated oxidative stress, senescence gene expression, and compromised renal cell function. These results highlight the critical role of aging in exacerbating drug-induced renal injury. The 3D silk matrix model utilizing elderly donor-derived renal stem cells offers a promising platform for identifying medications with age-specific renal toxicity potential and for developing targeted therapies to safeguard the aging kidney.