DJ-1 depletion prevents immunoaging in T-cell compartments

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases. We analyzed CD4 Tconv cells (CD4+CD25- cells) isolated from the spleen of aged DJ-1 knockout (KO) mice vs. age- and gender-matched WT littermates (3 WT, 3 KO) using the Affymetrix Mouse Gene 2.0 ST Array. RNA samples of CD4+CD25- Tconv cells sorted from ~45-weeks old DJ-1-/- mice and age- and gender-matched DJ-1+/+ littermates using BD FACSAria III, were analysed at EMBL Genomics Core Facility (Heidelberg, Germany). Array data was processed by Affymetrix Expression Console v1.4 using Exon-level analysis. No technical replicates were induced.