Stress-induced biological aging: A review and guide for research priorities.

Exposure to chronic adverse conditions, and the resultant activation of the neurobiological response cascade, has been associated with an increased risk of early onset of age-related disease and, recently, with an older biological age. This body of research has led to the hypothesis that exposure to stressful life experiences, when occurring repeatedly or over a prolonged period, may accelerate the rate at which the body ages. The mechanisms through which chronic psychosocial stress influences distinct biological aging pathways to alter rates of aging likely involve multiple layers in the physiological-molecular network. In this review, we integrate research using animal, human, and in vitro models to begin to delineate the distinct pathways through which chronic psychosocial stress may impact biological aging, as well as the neuroendocrine mediators (i.e., norepinephrine, epinephrine, and glucocorticoids) that may drive these effects. Findings highlight key connections between stress and aging, namely cellular metabolic activity, DNA damage, telomere length, cellular senescence, and inflammatory response patterns. We conclude with a guiding framework and conceptual model that outlines the most promising biological pathways by which chronic adverse conditions could accelerate aging and point to key missing gaps in knowledge where future research could best answer these pressing questions.

Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes.

Research with animals and humans has demonstrated that chronic stress exposure can impact key biological aging pathways such as inflammation and DNA damage, suggesting a mechanism through which stress may increase risk for age-related disease. However, it is less clear whether these effects extend to other hallmarks of the aging process, such as cellular senescence. Male SCID mice were exposed to 14 days of restraint stress, with (n â€‹= â€‹6) or without (n â€‹= â€‹10) propranolol administration, or a non-stress control condition (n â€‹= â€‹10). Normal femoral bone marrow leukocytes were isolated from engrafted leukemia cells that had been injected prior to the stressor, as the mice were also under a cancer challenge. We performed whole genome transcriptional profiling to assess indicators of biological aging: cell stress, DNA damage repair, cellular senescence markers p16INK4a and p21, and the pro-inflammatory senescence-associated secretory phenotype (SASP). ANCOVAs that adjusted for tumor load and Fisher's pairwise comparisons revealed that stressed mice had enhanced p16INK4a (p â€‹= â€‹.02) and p21 (p â€‹= â€‹.004), lower DNA damage repair (p â€‹< â€‹.001), and higher SASP (p â€‹= â€‹.03) gene expression than control mice. Stressed mice also showed up-regulated beta-adrenergic (CREB) and inflammatory (NF-кB, AP-1) and down-regulated cell stress (Nrf2) transcription factor activity relative to control mice (ps â€‹< â€‹.01). Propranolol reversed CREB and Nrf2 activity (ps â€‹< â€‹.03). Findings suggest that chronic stress exposure can impact several key biological aging pathways within bone marrow leukocytes and these effects may be partially mediated by sympathetic beta-adrenergic receptor activation.

Evaluation of clonal hematopoiesis in pediatric ADA-SCID gene therapy participants.

Autologous stem cell transplant with gene therapy (ASCT-GT) provides curative therapy while reducing pretransplant immune-suppressive conditioning and eliminating posttransplant immune suppression. Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase and telomere lengths (TLs) shorten with natural aging and DNA damaging processes. It is possible that, if CHIP is present before ASCT-GT or mutagenesis occurs after busulfan exposure, the hematopoietic stem cells carrying these somatic variants may survive the conditioning chemotherapy and have a selective reconstitution advantage, increasing the risk of hematologic malignancy and overall mortality. Seventy-four peripheral blood samples (ranging from baseline to 120 months after ASCT-GT) from 10 pediatric participants who underwent ASCT-GT for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) after reduced-intensity conditioning with busulfan and 16 healthy controls were analyzed for TL and CHIP. One participant had a significant decrease in TL. There were no CHIP-associated mutations identified by the next-generation sequencing in any of the ADA-SCID participants. This suggests that further studies are needed to determine the utility of germline analyses in revealing the underlying genetic risk of malignancy in participants who undergo gene therapy. Although these results are promising, larger scale studies are needed to corroborate the effect of ASCT-GT on TL and CHIP. This trial was registered at www.clinicaltrials.gov as #NCT00794508.