Loneliness is a stressful experience that appears to interfere with health and social integration (SI). Recently, researchers proposed that both antecedents and consequences of loneliness may change across the life span. To fully understand the processes related to loneliness it may thus be crucial to adopt an age-differentiated perspective. This study contributes to the literature by investigating how the interrelationship between loneliness and SI and that between loneliness and physical health changes as people move from middle adulthood into old age. We also investigate the extent to which a person’s level of negative affect (NA) may serve as age-differentiated mediator on the pathway that leads from loneliness to impaired physical health. The data for our study were gathered over up to 15 years of study from 11,010 participants in the German Ageing Survey (DEAS [Deutscher Alterssurvey]). We examined all interrelations of interest over a broad age range of 40 to 84 years by using an accelerated longitudinal data design. Autoregressive structural equation models were applied for statistical analyses. The results suggest a reciprocal relationship between loneliness and SI that appears to strengthen as people get older. The reciprocal relationship between loneliness and NA, in contrast, appears to grow weaker with increasing age. As a consequence, the NA-mediated effect that loneliness exerts on physical health may actually decrease as people grow older. We conclude that the processes related to loneliness are best understood using a developmental perspective that takes age-specific resources, roles, and living conditions into account.