Colo died in her sleep overnight, less than a month after her birthday, the zoo announced. She surpassed the usual life expectancy of captive gorillas by two decades.
"Colo touched the hearts of generations of people who came to see her and those that cared for her over her long lifetime," zoo president Tom Stalf said in a statement. "She was an ambassador for gorillas and inspired people to learn more about the critically endangered species and motivated them to protect gorillas in their native habitat."
The zoo said the gorilla's body will be cremated and the ashes will be buried at an undisclosed location at the zoo.
Colo was born at the zoo on December 22, 1956. She eventually became a mother of three, grandmother of 16, great-grandmother of 12 and great-great-grandmother of three.
Zoo officials said a post-mortem examination was planned to determine Colo's cause of death. The median life expectancy for female gorillas in human care is 37.5 years.
Veterinarians recently removed a malignant tumour from Colo, but the zoo had said she was doing well. The necropsy could help show whether the cancer contributed to her death, but the results aren't anticipated for several weeks.
Colo is the second zoo gorilla to die in Ohio this month. Cleveland Metroparks Zoo said one of its two male western lowland gorillas, a 32-year-old named Bebac, died on January 6.
Zoo experts say animals in human care are living longer than ever as early diagnosis and improvements in medical care extend their lives. The oldest known living male gorilla, Ozzie, is 55 years old and lives at the Atlanta Zoo, which has a geriatric gorilla specialty.
Nikko, a 33-year-old snow monkey at the Minnesota Zoo, is the oldest male snow monkey in North America. Zulie, a 30-year-old Black Howler monkey at the Beardsley Zoo in Bridgeport, Connecticut, is the oldest living female Howler monkey in captivity.
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