Aging of the Immune System. Mechanisms and Therapeutic Targets

Abstract

Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease. Immune system aging functions as an accelerator for other age-related pathologies. It occurs prematurely in some clinical conditions, most prominently in patients with the autoimmune syndrome rheumatoid arthritis (RA); and such patients serve as an informative model system to study molecular mechanisms of immune aging. T cells from patients with RA are prone to differentiate into proinflammatory effector cells, sustaining chronic-persistent inflammatory lesions in the joints and many other organ systems. RA T cells have several hallmarks of cellular aging; most importantly, they accumulate damaged DNA. Because of deficiency of the DNA repair kinase ataxia telangiectasia mutated, RA T cells carry a higher burden of DNA double-strand breaks, triggering cell-indigenous stress signals that shift the cell's survival potential and differentiation pattern. Immune aging in RA T cells is also associated with metabolic reprogramming; specifically, with reduced glycolytic flux and diminished ATP production. Chronic energy stress affects the longevity and the functional differentiation of older T cells. Altered metabolic patterns provide opportunities to therapeutically target the immune aging process through metabolic interference.

Keywords: DNA damage; T cells; glycolysis; immune aging; inflammation.

Figure 1.

DNA damage in rheumatoid arthritis (RA) T cells. Deficiency of the cell cycle regulator and DNA repair kinase ataxia telangiectasia mutated (ATM) changes the fate of T cells in patients with RA. ATM^lo T cells bypass the G₂/M cell cycle checkpoint and insufficiently repair DNA double-strand breaks. One of the major consequences is excessive death of the T cells, possibly leading to lymphopenia, proliferative pressure to compensate for the loss, and thus premature aging. DNA-PKcs = DNA-dependent protein kinase, catalytic subunit.

Figure 2.

Metabolic reprogramming of prematurely aged T cells in rheumatoid arthritis (RA). Glucose imported into the cell can either be broken down to generate ATP or be shunted into the pentose phosphate pathway (PPP) to generate reductive elements (NADPH). In RA T cells high activity of glucose-6-phosphate dehydrogenase (G6PD) and low activity of phosphofructokinase (PFK) result in excessive shunting of glucose, leaving the cell under reductive stress and impairing redox signaling. As a consequence, such cells insufficiently activate the cell cycle regulator ataxia telangiectasia mutated (ATM), which results in bypassing of the G₂/M phase, hyperproliferation, and a bias toward proinflammatory effector functions. ROS = reactive oxygen species.