The northern white rhino is a subspecies of white rhino.
Forty-one years is at the upper end of a white rhino's life expectancy.
Zoo officials said Nola was under veterinary care for a bacterial infection, as well as age-related health issues, but Nola's condition worsened and they made the hard decision to euthanize her.
A popular white rhinoceros has been euthanized at San Diego Zoo Safari Park after a series of illnesses - leaving just three members of the critically endangered species alive in the world.
Nola had previously undergone multiple procedures and diagnostic tests over the past few months to find the source of an infection near her right hip.
With Nola's death, there are only three northern white rhinos left in the world. She originally came from a zoo in what is is now the Czech Republic. All three - a male and two females - live on the Ol Pejeta Conservency in Kenya. Many people expressed their condolences to the zoo and shared memories of Nola through Facebook. They are constantly under a 24-hour armed guard.
The project is being run out of the zoo's Institute for Conservation Research, along with scientists from the Center for Regenerative Medicine at the Scripps Research Institute in La Jolla.
Genetic material from a dozen northern white rhinos has been preserved at the San Diego Zoo Institute for Conservation Research, for future reproductive opportunities, zoo officials said. To date, a total of 94 southern white rhinos, 68 greater one-horned rhinos and 14 black rhinos have been born at the San Diego Zoo Safari Park.
Nearly a year ago, the world sadly lost the only other male northern white rhino due to cancer.
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