Physiological stresses, such as pathogen infection, are detected by “cellular Surveillance Activated Detoxification and Defenses” (cSADD) systems that trigger host defense responses. Aging is associated with physiological stress, including impaired mitochondrial function. Here, we investigated whether an endogenous cSADD pathway is activated during aging in C. elegans. We provide evidence that the transcription factor ZIP-2, a well-known immune response effector in C. elegans, is activated in response to age-associated mitochondrial dysfunction. ZIP-2 mitigates multiple aging phenotypes, including mitochondrial disintegration and reduced motility of the pharynx and intestine. Importantly, our data suggest that ZIP-2 is activated during aging independently of bacterial infection and of the transcription factors ATFS-1 and CEBP-2. Thus, ZIP-2 is a key component of an endogenous pathway that delays aging phenotypes in C. elegans. Our data suggest that aging coopted a compensatory strategy for regulation of aging process as a guarded process rather than a simple passive deterioration process.