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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.

Gonzalez-Hurtado, Leveau and colleagues characterize adipose resident tissue macrophages across lifespan in mice, finding that nerve-associated macrophages, which mitigate inflammation and control lipolysis and catecholamine resistance, are lost during aging.

To gain insights into the early immune dynamics of transcriptional changes during SARS-CoV-2 infection, Singh et al. provide longitudinal scRNA-Seq of the broncho-alveolar compartment of SARS-CoV-2 infected rhesus macaques. They observe an accumulation of a distinct macrophage population that possesses an interferon-driven innate anti-viral gene signature early during infection that correlates with viral clearance.

The authors describe how reduced dietary availability and systemic loss of cysteine leads to adipose tissue browning and rapid weight loss in mice and humans.

Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.

Studying ageing at the single-cell level has provided insight into the changes that occur systemically and in tissues as we age. For example, we now have a greater appreciation of the heterogeneity and dynamic nature of immune cell ageing and of the impact of age-associated tissue remodelling on the immune system, together contributing to increased vulnerability to some diseases.

Multi-omic analysis of the developing mouse kidney shows strong sex-dependent differences in gene expression during development and aging. These differences are likely mediated by sex hormones.

Variants of the 3′−5′ exonuclease TREX1 can cause retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Here, the authors show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and render cells more vulnerable to DNA damage inducing agents.

ATG5 expression in neutrophils counters type I interferon signalling and downstream activation of neutrophil swarming and NET release to limit disease severity during Mycobacterium tuberculosis infection.

Type 1 regulatory T cells (Tr1) represent a major obstacle that compromises naturally occurring and therapeutically induced tumour-specific immunity.

Central nervous system (CNS)-derived regulatory self-peptides are essential for maintaining a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity.

Multiomics profiling of circulating monocytes from young and older healthy males reveals key determinants of healthy aging, including regions of age-associated DNA hypo- and hypermethylation, cellular chromatin landscape and effect on gene expression.

Autophagy in CD11c⁺ phagocytes prevents myeloid-derived suppressor cell recruitment and promotes protective T cell responses during high-dose Mycobacterium tuberculosis infection in mice.

Crohn’s disease results from transmural inflammation in the gut, but analyses of local immune populations are still lacking. Here, the authors show, by combining multiple single-cell approaches, that intraepithelial and lamina propria T cells are heterogenous, show unique phenotypes, and exhibit altered subsets upon inflammation.

Macrophages are revealed to adopt a polymerase II pause/release process to effectively deal with ingested apoptotic corpses and for continuous efferocytosis.

A study finds T cells in areas of tau, not amyloid, pathology in Alzheimer’s disease brain and mouse models, with their presence correlating with neuronal loss and their depletion, or that of microglia, preventing neurodegeneration and cognitive decline.

Zika virus infections can cause devastating congenital birth defects but the underlying interactions with the host immune system are not well understood. Here, the authors examine the immune basis of vaginal protection and susceptibility to Zika viral infection, and identify a hormonal dependent role for interferon-lambda-mediated protection against disease.

Merlin et al. find that non-canonical glutamine transamination is required for macrophage efferocytosis in atherosclerotic plaques by sustaining redox buffering and fueling energy production for cytoskeletal rearrangements.

Khader and colleagues show Mycobacterium tuberculosis (Mtb)-specific B cells are needed to recruit T_FH cells into follicular-like structures within lung granulomas to control the Mtb bacilli; however, specific antibodies and many conventional properties of B cells are dispensable.

Edelson and colleagues show that the transcription factor Bhlhe40 is required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages, but not that of other tissue-resident macrophages.

The ketogenic diet is a low-carbohydrate, high-fat diet that forces a metabolic switch towards fatty acid oxidation. Here, Goldberg et al. show that a ketogenic diet initially improves metabolic health and expands adipose tissue γδ T cells that are important for glycaemic control during obesity.

Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.

Complete gene expression deconvolution remains a challenging problem. Here, the authors provide a solution based on the recognition that expression levels of cell type specific genes are mutually linear across mixtures and mutually linear gene clusters correspond to cell type-specific signatures.

Williams and colleagues investigate the origin, dynamics and transcriptional profiles of aortic intima macrophages during atherosclerosis disease progression.

In a mouse tumour model, immunotherapy-induced rejection of tumour cells requires presentation of both MHC class I and MHC class II antigens, which activate CD4⁺ and CD8⁺ T cells, respectively.

Colonna and colleagues show that human innate lymphoid cells undergo conversion from ILC3s into ILC1-like cells in tissues in vivo.

Matthew Meyerson, Ramaswamy Govindan and colleagues examine the exome sequences and copy number profiles of 660 lung adenocarcinoma and 484 lung squamous cell carcinoma tumors. They identify novel significantly mutated genes and amplification peaks and find that around half of the tumors have at least five predicted neoepitopes.

A delay in T cell responses is postulated as a possible explanation for the limited efficacy of vaccines against tuberculosis. Here the authors demonstrate this T-cell block and remove it by activating endogenous dendritic cells or delivering activated dendritic cells to the lungs, enhancing immunity of mice toMycobacterium tuberculosis.

Koenig et al. present integrated single-cell and single-nucleus RNA-sequencing data of cardiac samples obtained from 27 healthy donors and 18 individuals with dilated cardiomyopathy. This extensive resource provides insights on cell composition and gene expression changes driven by the disease status, sex or age of the patients.

This study reports the structure of hRSV NS1, identifying unique regions that modulate host gene expression and contribute to inhibition of the IFN-I pathway and of dendritic cell maturation, pointing to new avenues of hRSV attenuation.

The transcriptional repressor Zbtb46 is expressed by DCs and endothelial cells. In this study, Choi and colleagues find downregulation of Zbtb46 confers a pro-tumor program in the vasculature and hematopoietic system, by promoting angiogenesis and the development of immunosuppressive myeloid cells.

Alternatively activated (M2) macrophages use fatty acid oxidation for their metabolic needs. Pearce and colleagues show that triacylglycerols metabolized by lysosomal acid lipase are required for the M2 activation of and function of macrophages.

Colonna and colleagues report dysregulated gene expression in microglia harboring homozygous mutations of DAP12 from individuals with Nasu–Hakola disease, a form of early-onset dementia.

A new method allows selection of matched controls from an external pool of samples without genotype sharing. This method has been implemented in an online repository containing 39,472 exome sequencing controls that can be used for association analyses.

A prevalent rifampicin resistance mutation in Mycobacterium tuberculosis alters bacterial virulence lipid expression and enables bypasses of a host immune axis that is critical for the control of drug-susceptible infections.

Itaconate production is a hallmark of inflammatory activated macrophages. Swain et al. compare the biological effects of itaconate and its common derivatives, identifying a new regulatory mode of inhibiting IL-1β secretion and enhancing IFN-β signalling.

Activation of dendritic cells induces a metabolic switch from oxidative phosphorylation to glycolysis. Pearce and colleagues show TLR signaling rapidly induces glycolysis by activating a TBK1–IKKε–Akt–HK-II kinase cascade to support the fatty acid synthesis required for the activation of dendritic cells.

Arthur et al. report the biochemical and proteomic (SomaLogic) profiling of plasma and CyTOF immunophenotyping of peripheral blood mononuclear cells from 71 individuals with COVID-19 or other inflammatory pulmonary diseases, and 148 healthy donors aged 25–80 years old. The Resource reveals unique determinants of COVID-19 disease relative to healthy aging and other pulmonary disorders.

The autophagy proteins Beclin 1 and FIP200, but not other essential autophagy components, such as ATG5, ATG16L1 or ATG7, regulate quiescence of tissue-resident macrophages, thereby modulating immune activation and resistance to Listeria monocytogenes infection.

The immunoregulatory metabolite itaconate and its dimethyl derivative induce electrophilic stress and react with glutathione to induce both Nrf2-dependent and Nrf2-independent responses, resulting in AF3-mediated inhibition of the inflammation-related protein IκBζ.

A carcinogen-induced mouse tumour model is used here to show that mutant tumour-specific antigens are targets for CD8⁺ T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy, and that these antigens can be used effectively in therapeutic vaccines; this advance potentially opens the door to personalized cancer vaccines.

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. Here, the monoclonal antibodies produced in two infected subjects in response to human immunodeficiency virus (HIV) glycoprotein have been analysed. The results provide evidence for polyreactivity, which may be required when the density of glycoprotein spikes is so low that bivalent binding is unlikely.