The kidney as a window into mammalian aging: Metabolic frailty, mitochondrial resilience, and the continuum from injury to aging

Aging-related decline of kidney function bears major medical and biological implications: chronic kidney disease (CKD) and acute kidney injury (AKI) risk rise sharply with age, and tubular epithelial cells in the kidney are paradoxically long-lived despite engaging in intense oxidative metabolic work. Mitochondrial relation to kidney physiology may unveil new hallmarks of mammalian aging. Our work has identified the central redox cofactor, nicotinamide adenine dinucleotide, as both a measurable and modifiable target to augment energy metabolism within the kidney and confer resistance to acute stressors that otherwise provoke AKI. More recently, we found that aging and transient injuries indefinitely degrade the fidelity of the kidney's mitochondrial DNA (mtDNA). Moreover, mtDNA mutation burden correlates with CKD severity and predicts future AKI events. These findings identify mtDNA mutations as a new, measurable determinant of kidney health and resilience, in turn proposing novel ways to track resilience in related organs.