Aging is characterized by a general decline in the functions of all tissues and an increased incidence of chronic disease. A large body of evidence has correlated age-associated diseases with chronic inflammation leading to an aging theory known as inflammaging (Bonafe et al., 2012). Alzheimer disease, cancer, sarcopenia, atherosclerosis, and diabetes are common diagnoses in the aging population associated to chronic inflammation (Cesari et al., 2003; Bonafe et al., 2012).
It has been proposed that the process of cellular senescence represents a general response to various forms of damage that may accumulate with age. Senescence is a permanent cell cycle arrest triggered by a variety of stressors, including short telomeres, oncogenes, DNA damage, and reactive oxygen species (Coppe et al., 2010). The evidence correlating cellular senescence with aging and age-related diseases is abundant (Coppe et al., 2010). Remarkably, elimination of senescent cells attenuates signs of accelerated aging in mice (Baker et al., 2011). The mechanisms by which senescent cells accelerate organismal aging are not known but senescent cells secrete a large variety of inflammatory cytokines that can impair tissue homeostasis and promote chronic inflammation (Coppe et al., 2010).
Cellular senescence is also a tumor suppressor mechanism and inhibiting key mediators of senescence such as p53, and the retinoblastoma protein leads to accelerated tumor formation (Serrano et al., 1997). It has been proposed that cellular senescence was selected during evolution for tumor suppression and that its pro-aging effect was not eliminated by natural selection because it mainly acts after reproduction (Ferbeyre & Lowe, 2002). High cytokine gene expression by senescent cells is associated with persistent DNA damage signals (Rodier et al., 2009), and in some situations, it can promote tumorigenesis in neighboring cells (Krtolica et al., 2001; Gilbert & Hemann, 2010). Retrospective studies have suggested that the antidiabetic drug metformin has unanticipated cancer prevention activity in patients (Pollak, 2010; Formentini et al., 2012) and inhibits the generation of reactive oxygen species and DNA damage in normal cells expressing oncogenic ras or treated with paraquat (Algire et al., 2012). However, metformin did not prevent RAS-induced growth arrest (Algire et al., 2012). We thus decided to investigate whether metformin could suppress the production of inflammatory cytokines by senescent cells.