The maintenance of genomic integrity through the DNA repair processes is essential for proper cellular metabolism, growth, and development. DNA damage plays a key role in mutagenesis and the development of cancer. The cellular DNA damage response activates complex signaling pathways that may promote not only DNA repair and survival but also can trigger cell suicide. Exceptionally long-lived animals may allow explaining the mechanisms of healthy aging without cancer. One of the particular emphases of this review is the link between oxidative stress, DNA repair pathways, and longevity. We specifically focus on the long-lived aquatic organisms, which provide a novel understanding of both healthspan and lifespan despite high oxidative stress caused by environmental factors.