In this issue, Shulman et al. present the results of the phase II TANGO trial, which demonstrate that gosuranemab — a monoclonal antibody directed at N-terminal tau — is safe and well-tolerated, with robust target engagement of unbound N-terminal tau in patients with early Alzheimer’s disease. However, the clinical efficacy end point — of change from baseline at week 78 on the Clinical Dementia Rating Scale – Sum of Boxes, compared with placebo — was not met. The cover image illustrates a crystal structure of gosuranemab, surface view.

See Shulman et al.

In this issue, Ernesto Llamas et al. investigate the absence of pathological aggregation of polyQ proteins in plants. Their work with Arabidopsis thaliana shows that this is achieved through chloroplast proteostasis and identifies the chloroplast stromal processing peptidase (SSP), which — when expressed ectopically — prevents polyQ aggregation in human cells and worms. The cover image shows A. thaliana outlines superimposed with fluorescence microscopy images from this study.

See Llamas et al.

In this issue, Ye et al. investigated the molecular mechanisms that govern cardiac aging in primates. They identify SIRT2 as a pivotal protein that exhibits a geroprotective role in safeguarding the primate heart and demonstrate the therapeutic potential of SIRT2-based gene therapy to protect against age-related cardiac dysfunction. The cover image illustrates the cardioprotective role of SIRT2, depicting its expression as a reparative thread embroidered onto a knitted heart.

See Ye et al.

In this issue, Lu, Fei, Raj, Horvath and the Mammalian Methylation Consortium report the development of pan-mammalian epigenetic clocks that accurately track chronological age in 59 tissue types across 185 mammalian species. The cover image depicts the high correlations between predicted and actual age (purple and red lines), on top of a circle plot in which each sector represents an individual species, irrespective of differences in species maximum lifespans (dashed line).

See Lu et al.

In this issue, Stacy Castner et al. explore the potential of the longevity protein klotho to improve cognition in primates. The team finds that a single injection of klotho enhances the performance of aged rhesus macaques on a spatial working-memory task. The cover image shows an old rhesus macaque. The Asian monkey species typically lives for 25–30 years in captivity, and its maximum recorded lifespan is 40 years. It shares a common ancestor with humans approximately 25 million years ago.

See Castner et al.

In this issue, Kate Warde et al. investigate the role of the adrenocortical carcinoma gene ZNRF3 in the context of the tissue microenvironment and uncover that loss of ZNRF3 induces an earlier senescence response in male mice as compared to female mice, which provides the male animals protection from later malignancy. The team finds that androgen at least in part shapes the senescence-associated secretory phenotype and immune cell recruitment, which leads to benign lesions in male mice (whereas female mice are more prone to tumor development). The cover image represents the pleiotropic effects of senescent cells in cancer as the normal world and the ‘Upside Down’ in the TV show, Stranger Things.

See Basham et al.

In this issue, Wu et al. profile the N 6-methyladenosine (m6A) epitranscriptomic landscape of aging nonhuman primate tissues.

Their study shows that m6A decoration correlates with gene expression homeostasis and that the methyltransferase METTL3 has a role in m6A epitranscriptomic regulation and myotube maintenance.

The cover image shows a dragon, a Chinese symbol of longevity, resembling an mRNA. The dragon has red ‘M’-shaped eyebrows and black pupils with the number 6 at the center. The image is inspired by a Chinese idiom, hua long dian jing — in English, to bring the painted dragon to life by dotting its eyes. The saying metaphorically means ‘providing the finishing touches’. In relation to the authors’ work, to bring this dragon to life — that is, to maintain mRNA stability — the finishing touch is the methylation (invoked by the M-shaped eyebrows) that occurs at the N 6 position of adenosine (invoked by the pupils displaying the number 6). The writing brush represents the METTL3 protein.

See Qu et al.

Dementia is a progressive, irreversible and currently incurable clinical syndrome with cognitive and behavioral symptoms that range from loss of memory to impairment of judgement and reasoning. Nature Aging presents a special issue on the transforming landscape of dementia research. This Focus issue brings together a selection of Reviews, Perspectives and Comments on the most recent advances in our understanding of Alzheimer’s disease and other dementias, as well as the challenges in diagnosis, prevention and treatment of these diseases. The issue cover depicts the need for an integrative research effort to resolve the dementia puzzle to improve the quality of life of millions affected.

See Editorial

In this issue, Yicheng Wu et al. use chronic intravital imaging to monitor neural stem cells in the hippocampal niche of young and middle-aged mice for several months. Their study reveals multiple aging-associated alterations in the behavior of neural stem cells and their progeny that lead to reduced clonal output. The image cover shows an artistic overlay of Nestin–GFP-labeled neural stem cells in young (blue) and middle-aged (red) mice, which makes the decline in neural stem cells with advancing age apparent. Nuclei are counterstained with DAPI in young mice (grey).

See Wu et al.

In this issue, Duan and colleagues explore how aging reshapes liver endothelial cells to cause steatohepatitis. They report that liver endothelial-cell senescence leads to steatosis by reprogramming liver endothelial zonation and disruption of C-kit in liver endothelial cells, promoting inflammation, fibrosis and lipid accumulation in the aging liver. The therapeutic potential of C-kit infusion is demonstrated to counter aging-induced liver senescence and steatohepatitis in mice. Our issue cover shows a liver running down as sand in an hourglass, evoking the detrimental effects of aging on liver structural and functional integrity.

See Duan et al.

In this issue, Berry and colleagues use an optogenetics approach to oppose the age-associated decline in the membrane potential of mitochondria with a light-activated proton pump, and show that it increases both the healthspan and lifespan of worms. The issue cover evokes the experimental paradigm used in the study with light being shone onto a mitochondrion, placing the organelle in the spotlight.

See Berry et al.

In this issue, Kabir and colleagues report that aged bone marrow promotes polyclonal expansion of smooth muscle cells and exacerbates disease in the atherosclerotic plaque. The cover image illustrates that a transplantation of aged bone marrow to young atheroprone mice leads to the accumulation of multicolor, fluorescently labeled smooth muscle cells from several lineages in the plaque.

See Kabir et al.