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After completing the Last Judgment, Michelangelo began work on a Conversion of St. Paul fresco commissioned by the Pope in 1542 for his Cappella Paolina. He finished three years later, and shortly after began his The Crucifixion of St. Peter fresco, which he completed in 1550. In both of these works, which Michelangelo had difficulty executing due to his declining health, he returned to the luminous color of the Sistine ceiling while continuing with the flattened anti-perspective he had explored in the Last Judgment. The Cappella Paolina frescoes were to be Michelangelo's final paintings.

Michelangelo's Last Judgment was less well received by religious figures than it was by artists, and it inspired considerable controversy with the onset of the Catholic Church's Counter-Reformation in the 1540s. One result of this effort was that Neoplatonism was decreed heretical, meaning that nudes in art could no longer be sanctioned by Christian doctrine. The Council of Trent, the official summit meetings that outlined the changes of the Counter- Reformation, decided essentially to prohibit the use of the nude in religious art entirely, save for in a few specifically noted scenes. In 1545 and again in 1550, the poet Pietro Aretino accused the "godless" Michelangelo of desecrating the Sistine Chapel by turning it into a whorehouse with his naked figures. Michelangelo's public response to the criticism of Pope Paul IV was vehement, but his private reaction was more vulnerable.

Michelangelo displayed increasing religious piety over the years, and this change in religious feeling accounts in large part for his switch from art to architecture late in his life. In a 1554 sonnet written after the completion of his last painting, Michelangelo wrote that "Neither painting nor sculpture will be able any longer to calm my soul, now turned toward divine love." In addition to Michelangelo's newfound piety, the deaths of some of his closest friends and his growing physical incapacitation overwhelmed him with a deep sense of shame and melancholy. In an attempt to reconcile his love of art and his religion, Michelangelo turned his attention almost exclusively to architectural projects in the service of the Church. Of these, the most noteworthy was the design and construction of St. Peter's. for which Michelangelo would accept no financial compensation.

Ironically, during this dark period Michelangelo was at the height of his fame–in 1550, Vasari published the first edition of Michelangelo's biography in his Lives of the Artists, and Condivi published his more accurate Life of Michelangelo in 1553. In 1545, Michelangelo's assistants finally completed the tomb of Julius, but only a few figures in the piece are his and he took little pride in the finished project. In 1547, Michelangelo began working on one of his three final sculptures, the so-called Florentine Pieta, which he intended for his tomb. However, after the death of his faithful assistant Francesco Urbino, Michelangelo tried to destroy the sculpture by smashing it with a hammer. Later a student repaired it and continued work on it, but it remains unfinished.

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