The genetic roots of the diverse paces and shapes of ageing and of the large variations in longevity observed across the tree of life are poorly understood. Indeed, pathways associated with ageing/ longevity are incompletely known, both in terms of their constitutive genes/proteins and of their molecular interactions. Moreover, there is limited overlap between the genes constituting these pathways across mammals. Yet, dedicated comparative analyses might still unravel evolutionarily conserved, important pathways associated with longevity or ageing. Here, we used an original strategy with a double evolutionary and systemic focus to analyse protein interactions associated with ageing or longevity during the evolution of five species of Opisthokonta. We ranked these proteins and interactions based on their evolutionary conservation and centrality in past and present protein-protein interaction (PPI) networks, providing a big systemic picture of the evolution of ageing and longevity pathways that identified which pathways emerged in which Opisthokonta lineages, were conserved, and/or central. We confirmed that longevity/ ageing-associated proteins (LAPs), be they pro-or anti-longevity, are highly central in extant PPI, consistently with the antagonistic pleiotropy theory of ageing, and identified key antagonistic regulators of ageing/longevity, 52 of which with homologues in humans. While some highly central LAPs were evolutionarily conserved for over a billion years, we report a clear transition in the functionally important components of ageing/longevity within bilaterians. We also predicted 487 novel evolutionarily conserved LAPs in humans, 54% of which are more central than mTOR, and 138 of which are druggable, defining new potential targets for anti-ageing treatments in humans.