Telomere dysfunction leads to metabolic and mitochondrial compromise. The study shows that telomere dysfunction activates p53, which represses PGC-1α and PGC-1β, leading to impaired mitochondrial biogenesis, reduced gluconeogenesis, cardiomyopathy, and increased reactive oxygen species (ROS). This dysfunction is associated with organ failure and reduced organismal fitness. Telomere dysfunction was shown to decrease mitochondrial DNA content and impair mitochondrial function in mice. The study also demonstrates that p53 deficiency can restore PGC network expression, mitochondrial respiration, and cardiac function. Telomere dysfunction represses PGC-1α and PGC-1β, which are critical for mitochondrial biology and cellular metabolism. The study further shows that p53 directly represses PGC-1α and PGC-1β promoters, linking telomere dysfunction to mitochondrial and metabolic compromise. The findings suggest that telomere dysfunction contributes to age-related pathologies by impairing mitochondrial function and PGC activity. The study also highlights the importance of PGC-1α and PGC-1β in maintaining mitochondrial function and metabolic homeostasis. Overall, the study provides evidence that telomere dysfunction leads to mitochondrial and metabolic compromise, contributing to organ failure and aging.Telomere dysfunction leads to metabolic and mitochondrial compromise. The study shows that telomere dysfunction activates p53, which represses PGC-1α and PGC-1β, leading to impaired mitochondrial biogenesis, reduced gluconeogenesis, cardiomyopathy, and increased reactive oxygen species (ROS). This dysfunction is associated with organ failure and reduced organismal fitness. Telomere dysfunction was shown to decrease mitochondrial DNA content and impair mitochondrial function in mice. The study also demonstrates that p53 deficiency can restore PGC network expression, mitochondrial respiration, and cardiac function. Telomere dysfunction represses PGC-1α and PGC-1β, which are critical for mitochondrial biology and cellular metabolism. The study further shows that p53 directly represses PGC-1α and PGC-1β promoters, linking telomere dysfunction to mitochondrial and metabolic compromise. The findings suggest that telomere dysfunction contributes to age-related pathologies by impairing mitochondrial function and PGC activity. The study also highlights the importance of PGC-1α and PGC-1β in maintaining mitochondrial function and metabolic homeostasis. Overall, the study provides evidence that telomere dysfunction leads to mitochondrial and metabolic compromise, contributing to organ failure and aging.