On 28 February 1548 Pope Paul III celebrated his eightieth birthday. He had been considered old when he assumed the papacy at age sixty-six. By now his age was a constant backdrop to the affairs of his pontificate. Thus, in 1544, in preparation for the Council, Paul had renewed his binding instructions on what was to happen regarding a papal election if he should die while the Council was in progress. Around 1546, he wrote his Ricordi for his grandson, Alessandro, acknowledging that his time was near and giving advice about promoting the family interests under the next papacy. On the family side, news of even minor ailments prompted requests for reassurance from Farnese relatives, his grandchildren in particular. In fact, Paul's health was fairly stable and he remained as engaged and attentive as ever to the issues of the day. Of these, the Council and the Farnese patrimony received his particular attention. Both these hinged on his relationship with the emperor.

Over the course of 1547 Paul's relationship with Charles fell into an abyss. Added to their conflict over the Council's transfer to Bologna and Charles’ toleration of Protestant doctrine and practice in Germany came a shocking imperial attack on the Farnese family. On 10 September 1547, agents of the Imperial Viceroy of Milan, Ferrante Gonzaga, murdered Paul's son, Pierluigi, and Gonzaga quickly took possession of the Farnese territory of Piacenza.