mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole blood samples from the Leiden Longevity Study (LLS). This is an unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle-age. By comparing mRNA levels of nonagenarians and middle-aged controls, the mTOR signalling gene set was found to associate with old age (p=4.6 x 10(-7) ). Single gene analysis showed that seven out of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared to their spouses, indicating association with familial longevity in middle-age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.