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Homeostasis of memory T cells is modulated by each antigen encounter, thereby creating a heterogeneous population preventing precise tracking. Here, the authors use barcode-assisted tracing of Epstein-Barr virus-specific CD8⁺ memory T cells of young and older individuals to find antigen-guided, clonally divergent aging trajectories.

Senescent cells accumulate with age and contribute to the functional decline of many tissues; however, their role in skeletal muscle is not well understood. Here the authors comprehensively assess cellular senescence in skeletal muscle of young and old mice and detail senescence features in subpopulations of p16⁺ fibroadipogenic progenitors and p21⁺ myofibers.

Identification of senescent cells in vivo remains a challenging task. Here the authors present and validate a senescence gene set called SenMayo enriched in human and murine aged tissues.

The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.

This Review explores the translation of senotherapeutics into clinical practice for metabolic disorders. The authors discuss the relationship between metabolic disorders and cellular senescence, current and emerging therapies, and the challenges of translating senotherapeutics into clinical practice for metabolic disorders.

Using mouse and human plasma, Carver et al. identify factors that are altered with age and test which are reverted by a panel of genetic and pharmacological senolytic interventions in aged mice. They identify IL-23R as a senescence-associated, age-increased circulating biomarker.

Organ transplantation involving aged donors is often confounded by reduced post-transplantation organ survival. By studying both human organs and mouse transplantation models, here the authors show that pretreating the donors with senolytics to reduce mitochondria DNA and pro-inflammatory dendritic cells may help promote survival of aged organs.

Technical challenges have previously hindered the detailed study of in vivo senescent cells. Here, the authors deeply characterize senescent skeletal cells across murine aging, establishing CD24 as a marker of osteolineage cells cleared by senolytics.

CD8⁺ T cell–macrophage interactions have a central role in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia in a mouse model of long COVID.

Chini et al. demonstrate that CD38⁺ expression in immune cells increases during aging, owing to the senescence-associated secretory phenotype of senescent cells, and the ecto-enzymatic activity of CD38⁺ affects intracellular NAD⁺ levels in vivo by hydrolyzing the NAD⁺ intermediate nicotinamide mononucleotide extracellularly.

The transfer of nuclear chromatin to the cytoplasm drives the pro-aging inflammatory phenotype of senescent cells. Here, Miller et al. show that this process is suppressed by p53 and that activation of p53 reverses some features of aging in vivo.

In this study, the authors describe SANA, a nitroalkene derivative of salicylate, as a potential activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue. Preclinical and clinical data from this paper also suggest that SANA improves glucose homeostasis and promotes weight loss in mice and humans.

Here, the authors show that different formulations of medical ketogenic diets, and dietary fiber content in particular, differentially impact seizure outcome in mice, via modifying the gut microbiome and microbial pathways associated with fiber-mediated seizure protection.

In a phase 2 randomized control trial, intermittent senolytic therapy administered to postmenopausal women did not result in a reduction in the bone resorption marker, serum CTx, compared to control at 20 weeks.

Antibodies plays critical roles in the adaptive immune response to infectious agents including malaria. Here the authors defined antibody interactions with -Fcγ-receptors expressed on immune cells with sporozoites of Plasmodium falciparum, and identified specific target epitopes of antibodies.

An assessment of blue carbon strategies in Belize shows how quantifying fisheries, tourism and coastal risk co-benefits alongside carbon benefits can inform spatial and temporal target setting for nationally determined climate contributions that simultaneously provide societal benefits.

Transfer of senescent cells into naive, young mice can induce physical dysfunction, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.

Aging increases vulnerability to respiratory viral infections, including by SARS-CoV-2. Delval et al. established a causal role for age-related pre-existing senescent cells in the severity of COVID-19 symptoms in an aging hamster model. Selective depletion of senescent cells using senolytic agents mitigated the risk of severe COVID-19 symptoms linked to aging.

An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

The analysis of metabolites offers promises in biomarker discovery. Here the authors demonstrate the metabolomics analysis of sub-nanoliter samples using triboelectric nanogenerator inductive nanoelectrospray ionization, which they apply to exhaled breath condensate from cystic fibrosis patients and mesenchymal stromal cells.

Regulatory T cells normally maintain high expression of the phosphatase PTEN. Turka and colleagues use conditional deletion of PTEN in regulatory T cells to show that it is critical for their function and stability.

Exhaustion is an acquired state of T cell dysfunction. Sharpe and colleagues demonstrate that the phosphatase PTPN2 supports a T cell-intrinsic exhaustion program in both chronic infection and cancer models.

Wang et al. report a mouse model for targeting of cells with high p21 expression. Using this model, they are able to monitor, sort, image, eliminate or modulate these cells in vivo, which could be a valuable tool to study senescent cells.

During senescence, minority mitochondrial outer membrane permeabilization leads to the release of mtDNA into the cytosol through BAX and BAK macropores, in turn activating the cGAS–STING pathway, a major regulator of the senescence-associated secretory phenotype.

Perivascular and leptomeningeal macrophages, collectively termed here parenchymal border macrophages, are shown to regulate flow dynamics of cerebrospinal fluid, implicating this cell population as new therapeutic targets in neurological diseases such as Alzheimer’s.

Genetic or pharmacological depletion of senescent cells or inhibition of their function reduces bone loss in aged mice.

Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.

A series of techniques (echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure) are used to assess the health of mice.

Raychaudhuri and colleagues identify TCR-intrinsic features that govern development of regulatory T cells.

In this Roadmap, Stellos and colleagues discuss the mechanisms of cardiovascular system ageing and how the ageing of blood, vessels and heart relates to the decline in organ function, and highlight potential therapeutic interventions, challenges in ageing research and future directions for preclinical and clinical studies.

The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.

The polyphenol procyanidin C1, a compound found in grape seeds, possesses senomorphic or senolytic activity and is shown to extend the healthspan and survival of old mice and in various models of senescence-associated disability.

Non-alcoholic fatty liver disease is more common among older individuals. Here, the authors show that senescent cells in the liver promote fat accumulation and steatosis in the liver, and that clearance of senescent cells reduces hepatic steatosis in old, obese or diabetic mice.

Genomic analysis of neuroblastoma has revealed important disease etiology. In this study, the authors assembled whole genome, exome and transcriptome data from over 700 neuroblastomas and identified molecular signatures correlated with age, and rare, potentially targetable variants overlooked in smaller cohorts.

In most cancers, mutations that lead to oncogene activation and tumor suppressor inactivation synergize to promote tumorigenesis. However, in neuroblastomas, MYCN amplification and ATRX mutations are mutually exclusive and incompatible.

Some patients present with multiple lung tumours but it is unclear whether these are metastases or individual lesions. Here, the authors use genomics techniques to demonstrate in six patients that multiple tumours have individual genetic profiles and represent separate tumours.

Exhausted cytotoxic T lymphocytes (CTLs) express the receptor PD-1 as a key signature. Haining and colleagues show that there are different ‘depths’ of exhaustion with a subset of exhausted CTLs that retain polyfunctionality and are responsive to PD-1 blockade.

Xu and colleagues used partial OSKM reprogramming in aged mice to drive cell-type proportions of the subventricular zone to more youthful levels, which equates to qualified rejuvenation of a neurogenic niche that is defined, in part, by restoration of neuroblast levels.

Accumulation of senescent cells and compositional changes in gut microbiota have been independently reported to occur as a function of age. A study now suggests that these two seemingly disparate processes are more intimately linked than previously appreciated via a B cell–IgA–microbiota axis.

In a study of children with high genetic risk aged 2 years or older, a risk score integrating pancreatic islet autoantibodies, genetic factors and family history is highly predictive of type 1 diabetes in the subsequent 8 years.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a variable rate of cyst development, variable kidney function decline and variable presentation of renal and extrarenal manifestations. In this Review, the authors discuss pharmacological and non-pharmacological interventions for the treatment of patients with ADPKD and provide recommendations for the management of renal complications.