The global population is aging rapidly due to advances in technology and improvements in public health. Furthering knowledge about the aging process will allow discoveries of interventions and treatment to promote healthy aging that will hopefully, in turn, grant individuals access to a better quality of life during their later years. Several longevity modulators have been identified in various model organisms, and many of them seem to be conserved. One example of such a longevity modulator is the mitochondrial electron transport chain (ETC) function. Mitochondrial ETC function has long been associated with aging and lifespan determination, where moderately reduced mitochondrial ETC function extends the lifespan of various organisms, suggesting that the pro-longevity effects of ETC function are well-conserved. The detailed mechanism of how mitochondrial function affects organismal lifespan remains unknown. Several transcription factors have been shown to promote lifespan when mitochondrial ETC function is impaired, suggesting that ETC dysfunction may induce a transcriptional network reprogramming response. Whether these transcription factors collaborate to modulate lifespan has not been fully explored. My thesis work shows that transcription factors CEH-23 and     p53/CEP-1 likely collaborate to modulate lifespan under ETC stress as these transcription factors shows an epistatic relationship in their longevity effects. Consistently, microarray analyses revealed that CEH-23 and CEP-1 share a significant overlap in their transcriptional outputs, which are enriched in kinases and phosphatases. Intriguingly, the majority of CEH-23 and CEP-1 common targets are also regulated by AMP-activated protein kinase, suggesting that these two transcription factors engage AMPK signaling to modulate the lifespan of animals with impaired ETC. This study links the transcriptional response to the cell signaling response in organisms with impaired mitochondrial ETC, which provides important insights into how mitochondria function to modulate organismal lifespan.