China and the world are facing severe population aging and an increasing burden of age-related diseases. Aging of the brain causes major age-related brain diseases, such as neurodegenerative diseases and stroke. Identifying biomarkers for the effective assessment of brain aging and establishing a brain aging assessment system could facilitate the development of brain aging intervention strategies and the effective prevention and treatment of aging-related brain diseases. Thus, experts from the Aging Biomarker Consortium (ABC) have combined the latest research results and practical experience to recommend brain aging biomarkers and form an expert consensus, aiming to provide a basis for assessing the degree of brain aging and conducting brain-aging-related research with the ultimate goal of improving the brain health of elderly individuals in both China and the world.

Immune checkpoint inhibitors (ICIs) use antibodies that block cell surface immune checkpoint proteins with great efficacy in treating immunogenic or “immune hot” tumors such as melanoma, kidney, and lung adenocarcinoma. ICIs have limited response rates to other non-immunogenic cancers. The tumor microenvironment (TME) consists of many cell types that collectively promote tumor progression. Cancer therapeutics are commonly designed to target one molecule in one defined cell type. There is growing evidence that long-term therapeutic responses require the targeting of cancer cells and tumor-promoting populations within the TME. The question remains whether we can identify targetable molecules/pathways that are critical for multiple cell types. Here, we will discuss several molecular targets that may fit a “two or multiple birds, one stone” model, including the B-cell lymphoma-2 (BCL-2) family pro-survival factors, transcriptional factors including signal transducer and activator of transcription 3, the nuclear receptor 4A family (NR4A1, NR4A2, and NR4A3), as well as epigenetic regulators such as bromodomain and extra-terminal (BET) family proteins, histone deacetylase family, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), and lysine-specific demethylase 1 (LSD1/KDM1A). We will focus on the rationale of these targets in immune modulation, as well as the strategies for targeting these important proteins for cancer therapy.

DNA accumulation is associated with the development of autoimmune inflammatory diseases. However, the pathological role and underlying mechanism of cytoplasmic DNA accumulation in CD4⁺ T cells have not been well established. Here, we show that Trex1 deficiency-induced endogenous DNA accumulation in CD4⁺ T cells greatly promoted their induction of autoimmune inflammation in a lupus-like mouse model. Mechanistically, the accumulated DNA in CD4⁺ T cells was sensed by the KU complex, then triggered the activation of DNA-PKcs and ZAK and further facilitated the activation of AKT, which exacerbated glycolysis, thereby promoting the inflammatory responses. Accordingly, blocking the DNA sensing pathway in CD4⁺ T cells by genetic knockout of Zak or using our newly developed ZAK inhibitor iZAK2 attenuated all pathogenic characteristics in a lupus-like inflammation mouse model induced with Trex1-deficient CD4⁺ T cells. Overall, our study demonstrated a causal link between DNA-sensing and metabolic reprogramming in CD4⁺ T cells for inflammatory induction and suggested inhibition of the DNA sensing pathway may be a potential therapy for the treatment of inflammatory diseases.