T cell immunity is crucial for human survival, coordinating responses to new pathogens and establishing immune memory in early life, and, in later life, maintaining immune homeostasis through immune and tumor surveillance. A lifetime of exposure to diverse antigens through infections and vaccination generate memory T cells that can persist for decades in the absence of antigenic re-exposure and comprise the predominant T cell subset throughout adult life. These memory T cells are susceptible to repeated stimulation over time due to chronic infections, and with age, T cells undergo dynamic alterations that are associated with immunodeficiency. Studies of memory T cell persistence and aging mostly sample peripheral blood while the majority of T cells, particularly tissue-resident memory T cells (TRM), are maintained in diverse tissues, including lymphoid and mucosal sites, where they mediate frontline protection. The longevity, maintenance, and age-associated changes of T cells across these key sites remain unknown and are important for developing age-targeted strategies for immune modulation. Utilizing our human tissue resource through a collaboration with LiveOnNY, a local organ procurement organization, we presented a comprehensive analysis of human T cell subset dynamics and aging in blood and tissue samples obtained from 88 organ donors over 10 decades of life. We revealed that T cell tissue localization and subset are factors that influence the phenotypic, functional, and epigenetic changes observed over age. Using retrospective radiocarbon (14C) birth dating and assessment of cellular turnover, we showed that T cells across blood and tissues are maintained through continuous turnover. However, within tissues, histological and flow cytometric analyses demonstrated age-associated structural changes, regression, and senescence in lymphoid but not in mucosal organs. We observed differential expression of proliferation marker Ki67 and senescence markers between T cell subsets, with CD8+ TRM having the lowest expression of these markers compared to circulating TEM and TEMRA, suggesting that TRM may undergo less turnover for their maintenance. Epigenetic analysis revealed comparable age-associated loss in global DNA methylation for CD8+ TEM and TRM cells but increased epigenetic regulation of gene expression over age for TRM cells. Paired with transcriptomic analysis, we observed inverse correlation between promoter DNA methylation and gene expression at genes related to T cell differentiation, homing, survival, regulation, and effector function, predominantly in TRM. Our results provide compelling evidence for continuous turnover for T cells across the body but different aging phenotypes depending on tissue localization and/or T cell subset, with tissue residency potentially protecting T cells from senescent changes over age, and these findings may have implications in the design of effective age-targeted treatment and prevention strategies.

The aging of the hematopoietic system is driven in part by defects occurring in hematopoietic stem cells (HSC). Given that HSCs provide the organism with blood and immune cells lifelong, understanding the mechanisms underlying HSC aging is vital to develop interventions that address the deterioration of the hematopoietic system at its root. Past work has indicated roles for both intrinsic and extrinsic processes in driving HSC decline during aging. Still, their roles are not fully understood, especially the relationship between different drivers, and the mechanisms by which HSCs maintain functionality in the face of age-related insults. To better understand cell-intrinsic regulation of HSC aging, we investigated nucleolar DNA damage marks stemming from replication stress in old HSCs, and connected it with nucleolar stress induction which impairs protein translation and cell cycling. Although nucleolar stress dampens old HSC activity, we reveal the cytoprotective effect of the p53-mediated nucleolar stress response to be essential for preserving the residual potential of old HSCs. Additionally, though inflammation from the niche contributes to HSC aging, the exact role of microenvironmental alterations often remains unclear. Here, we uncover an important role for IL-1 derived from endosteal stromal cells in driving both HSC and niche cell aging, and demonstrate inhibition of IL-1 signaling as a tractable strategy that counters niche deterioration to improve HSC function. These findings unveil new mechanisms of HSC aging, raise the possibility that nucleolar stress signaling could be harnessed to improve the output of old HSCs in clinical settings, and demonstrate the therapeutic viability of IL-1 blockade in improving old HSC function.

University of Macau / Institute of Chinese Medical Sciences

The signaling mechanisms involved in UVB-induced skin cancer are complex and although the scope of this work is inherently limited in focus, the findings may provide insight into how estrogen receptor signaling impacts cell growth, senescence, and apoptosis to protect keratinocytes. Additional signaling due to E2-activation of the estrogen receptor may provide back-up or redundant pathways in response to UVB.

Indiana University-Purdue University Indianapolis (IUPUI) / Literature has demonstrated the ability of human adipose tissue to generate large amounts of lactate. However, it is not understood why adipose tissue produces lactate, how the production of lactate is regulated, and what potential benefit this has to the adipocyte or the organism. We first characterized a human model of adipogenic differentiation with minimal donor to donor variability to assess metabolic changes associated with mature adipocytes compared to their precursors. Indeed, similar to what was observed in human clinical studies, the differentiated adipocytes demonstrated increased lactate production. However, the differentiated adipocytes compared to their precursors (preadipocytes or ASCs) demonstrate an aerobic glycolysis-like (also called Warburg effect-like) increase in glycolysis characterized by a 5.2 fold increase in lactate production in normoxic conditions (atmospheric oxygen tension). Remarkably, this increase in lactate occurred even though the differentiated adipocytes simultaneously demonstrate an increase in oxidative capacity. This low fraction of oxidative capacity coupled with increased lactate production indicated regulation of oxidative rates most likely at the point of pyruvate conversion to either acetyl-CoA (oxidative metabolism) or lactate (glycolytic metabolism). To investigate the potential regulation of this metabolic phenotype, PDK isoform expression was assessed and we found PDK 1 and 4 transcript and protein elevated in the differentiated cells. Non-selective pharmacologic inhibition of the PDKs resulted in decreased lactate production, supporting a regulatory role for PDK in modulation of the observed Warburg effect. PDK inhibition also resulted in increased ROS production in the adipocytes after several hours of treatment and a decrease in cell viability when PDK inhibition was carried out over 36 hours. The resulting loss in viability could be rescued by antioxidant (Tempol) treatment, indicating the decrease in viability was ROS mediated. Similar to what is seen in cancer cells, our data demonstrate that differentiation of human adipocytes is accompanied by a PDK-dependent increase in glycolytic metabolism (Warburg effect) that not only leads to lactate production, but also seems to protect the cells from increased and detrimental generation of ROS.