Gene variants as determinants of longevity: focus on the inflammatory factors

Human longevity is an extremely complex trait with various genetic, epigenetic and environmental factors acting upon the longevity phenotype. It is now becoming evident that whilst the genetic differences contribute only modestly to life expectancy before the age of 60 years, their impact on survival becomes more prominent at the extreme ages. Several longevity gene candidates have emerged during the past decade; the majority of them are related either to inflammatory functions, stress response or to lipid and glucose metabolism. The variants of inflammatory and immune response genes are of special interest since advancing ages is accompanied by a decline in several immune functions--a phenomenon called immunosenescence. Paradoxically, ageing is also characterised by chronic low-grade inflammation termed "inflammaging", which manifests as a two- to fourfold increase in the production of proinflammatory cytokines and acute phase proteins. These contrasting phenomena provide a functional rationale of how the genetic differences in inflammatory mediators may modify the life span of the elderly. Besides describing the pre-existing inflammatory and immune-related longevity gene variants, in this review, we also explain some of the theoretical and practical challenges that genetic longevity studies often encounter.