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As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.

Sinclair et al. combine quantitative proteomics and an autophagy flux reporter to map autophagy substrates and triggers during CD8 T cell differentiation. Proteins degraded and fueled by autophagy in naïve and effector T cells are identified and it is revealed that the regulation of amino acid transport allows antigen receptors and inflammatory cytokines to repress autophagy flux to shape T cell differentiation.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase, and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis. Here the authors report that pharmacological inhibition of ABHD11 modulates T-cell effector function via increased 24,25-epoxycholesterol biosynthesis and subsequent liver X receptor activation.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

This study shows that animal-based high-fat diets accelerate tumour growth and impair anti-tumour response to melanoma in obese mice, whereas plant-based high-fat diets do not.

Iron has been shown to be necessary for the activation and differentiation of CD8⁺ T cells. Here the authors investigate changes in CD8⁺ T cell metabolism in iron limiting conditions and find that aspartate is increased yet downstream nucleotide synthesis is suppressed and addition of exogenous aspartate partially rescues T cell function.

Nprl3 controls erythroblast metabolism and is upregulated by α -globin enhancers sited within its introns. This arrangement couples metabolic and developmental control during erythropoiesis and may explain the ancient synteny of α -globin with Nprl3.

The leaf epidermis is sealed by a lipid-rich cuticle to prevent water loss and interspersed with stomatal pores to allow gas exchange. Here the authors provide evidence that two barley proteins, HvYDA1 and HvBRX-Solo, regulate both processes linking epidermal patterning with cuticular properties in a cereal crop.

Kynurenine is an immunomodulatory aryl hydrocarbon receptor (AHR) ligand. Here the authors show, using a new flow cytometry based method, that kynurenine needs to be transported across the plasma membrane of activated T cells by the transporter protein SLC7A5 to activate the AHR.

Glutamine can feed into the TCA cycle as a fuel for oxidative phosphorylation and thereby can affect metabolic pathways in lymphocytes. Yet here the authors show that glutamine serves predominantly as a signalling molecule that sustains cMyc expression to control NK cell metabolism and effector function.

Pallett et al. report that myeloid derived suppressor cells expand, home to the liver, and inhibit T cell-mediated liver damage in chronic hepatitis B virus infection.

Glucose is an important nutrient that feeds into glycolytic control of T cell function and differentiation. Here the authors show that T cells are superior to dendritic cells (DC) at glucose uptake, and by depriving DCs of this nutrient in their microenvironment T cells activate DC proinflammatory functions, which in turn enhance T cell effector functions in DC-T cell cocultures.

T cell activation triggers proliferation and effector-cell differentiation. Cantrell and colleagues show that TCR signaling induces upregulation of amino-acid transporters necessary for metabolic reprogramming via the kinase complex mTORC1 and transcription factor c-Myc.

Intracellular proteins are regulated by multiple post-translation modifications. Cantrell and colleagues show that nutrient flux regulates intracellular protein modification by O-GlcNAcylation, which drives thymocyte development and T cell proliferation.

An exciting genome-wide association study in the British population for seven common diseases. This analysis confirms previously identified loci and provides strong evidence for many novel disease susceptibility loci.

Cantrell and colleagues perform a comparative quantitative mass spectrometric analysis of the proteomes of naïve and activated CD4⁺ and CD8⁺ T cells. Proteomes are dynamically regulated and mTORC1 inhibition leads to differential consequences depending on cell state.

Proteomic profiling can provide new insight into the cellular regulation of effector functions. Cantrell and colleagues report discordant mRNA profiles and protein profiles in activated CD8⁺ T cells and reveal new roles for mTORC1 in regulating the function of cytotoxic T lymphocytes.

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for more than 5,000 genes, including 2,850 novel null, 2,987 novel conditional-ready and 4,433 novel reporter alleles.