BOSTON (Reuters) – U.S. Senator Edward Kennedy, a towering figure in the Democratic Party who took the helm of one of America’s most fabled political families after two older brothers were assassinated, has died at age 77, his family said on Wednesday.

“Edward M. Kennedy, the husband, father, grandfather, brother and uncle we loved so deeply, died late Tuesday night at home in Hyannis Port (Massachusetts),” the Kennedy family said in a statement.

One of the most influential and longest-serving senators in U.S. history — a liberal standard-bearer who was also known as a consummate congressional dealmaker — Kennedy had been battling brain cancer, which was diagnosed in May 2008.

“We’ve lost the irreplaceable center of our family and joyous light in our lives, but the inspiration of his faith, optimism, and perseverance will live on in our hearts forever,” the family statement added.

His death marked the twilight of a political dynasty, and dealt a blow to Democrats as they seek to answer President Barack Obama’s call for an overhaul of the healthcare system. Kennedy had made healthcare reform his signature cause.

Known as “Teddy,” he was the brother of President John Kennedy, assassinated in 1963, Senator Robert Kennedy, fatally shot while campaigning for the 1968 Democratic presidential nomination, and Joe Kennedy, a pilot killed in World War Two.

When he first took the Senate seat previously held by John Kennedy in 1962, he was seen as something of a political lightweight who owed his ascent to his famous name.

Yet during his nearly half century in the chamber, Kennedy became known as one of Washington’s most effective senators, crafting legislation by working with lawmakers and presidents of both parties, and finding unlikely allies.

At the same time, he held fast to liberal causes deemed anachronistic by the centrist “New Democrats,” and was a lightning rod for conservative ire.

He helped enact measures to protect civil and labor rights, expand healthcare, upgrade schools, increase student aid and contain the spread of nuclear weapons.

“There’s a lot to do,” Kennedy told Reuters in 2006. “I think most of all it’s the injustice that I continue to see and the opportunity to have some impact on it.”

After Robert Kennedy’s death, Edward was expected to waste little time in vying for the presidency. But in 1969, a young woman drowned after a car Kennedy was driving plunged off a bridge on the Massachusetts resort island of Chappaquiddick after a night of partying.

Kennedy’s image took a major hit after it emerged he had failed to report the accident to authorities. He pleaded guilty to leaving the scene and received a suspended sentence.

Kennedy eventually ran for his party’s presidential nomination in 1980 but lost to then-President Jimmy Carter.

His presidential ambitions thwarted, Kennedy devoted himself to his Senate career.