In the 1600s the Dutch take over Manhattan Island and during a massacre of native people, John Amsterdam (as he becomes known) saves a woman's life and is wounded in the act. She uses her power as a shaman to heal him, and she also bestows on him the power of eternal youth and immortality--at least until he meets his true love and marries her.
At this point he starts to age normally and will definitely die. In modern New York, John is a police detective who has a few people close to him who know his secret (old friends, literally) and tends to run into people who think they remember him from their own pasts.