The risk for the major morbidities, including cancer, cardiovascular disease and osteoporosis, is strongly age-related, identifying the aging process as a principal contributor to disease. Diseases of older individuals are often inflammatory, implicating the immune system and the immune aging process as critical pathogenic drivers.

Cells of the adaptive immune system, specifically T cells, are known to live for many decades and thus are particularly susceptible to aging. In successfully aging individuals, T cells adjust to the pressures imposed by aging. Individuals that develop the inflammatory condition rheumatoid arthritis (RA) typically have maladaptive T-cell aging and accumulate aged, pro-inflammatory effector T cells. Rheumatoid arthritis has therefore emerged as an informative model system to study the molecular pathways of T-cell aging and to explore the reversibility and treatability of the T-cell aging process  

Prematurely aged T-cells in RA patients have two major molecular deficits: (1) Cellular bioenergetics are shifted such that the T-cells diverge to synthetic and proliferative functions; rendering them tissue-invasive and inflammatory. (2) The telomeric repair machinery is defective, leaving the cells with damaged telomeres and insufficient cell cycle checkpoint control. The underlying molecular defects have been identified, providing potential therapeutic targets to slow and revert the immune aging process. The metabolic reprogramming of pre-aged T-cells results from the repression of the glycolytic enzyme PFK, leading to low pyruvate production, and dampened mitochondrial respiration. With reduced glycolytic flux, pre-aged T-cells shunt glucose into the pentose phosphate pathway and produce excess amounts of NADPH. As a result, cellular reactive oxygen species are consumed and redox signaling is impaired, such as the activation of the redox-sensitive kinase ATM. ATM^low T-cells bypass the G2/M checkpoint, hyperproliferate and differentiate into IFN-g and IL-17-producing effectors. The telomere repair defect is connected to the repression of the repair nuclease MRE11A. MRE11A localizes to chromosomal ends, where its nucleolytic activity provides telomeric protection. Uncapped telomeres in MRE11A^low T-cells are associated with induction of a premature aging program, including upregulation of p16, p21 and CD57. MRE11A^low T cells are tissue-invasive and induce aggressive inflammation in joint tissues.

Young T-cells subjected to PFK or MRE11A loss acquire a premature aging phenotype and turn into inflammatory effector cells. Conversely, restoring PFK and MRE11A in pre-aged T-cells corrects their abnormal behavior. We conclude that T-cell aging is reversible and potentially treatable and should be explored as a novel strategy to manage age-related tissue inflammation.