The authors found that, across tissues and in multiple datasets, aging is accompanied by a length-associated transcriptome imbalance. In most cases, a decrease in the relative abundance of long transcripts was observed and could be reversed by interventions targeting aging.

Somatic mutations accumulate with age; however, the role they have in cardiac aging is unclear. Here Choudhury et al. describe the somatic mutation landscape of human heart muscle cells by single-cell whole-genome sequencing and report mutational signatures indicative of increased oxidative DNA damage and failed repair.

Transcription factors control cell identity and function in health, disease and aging. Here the authors identify age-associated changes of transcriptional regulatory networks in single cells, revealing cell-type and tissue-type-independent patterns in key pathways, including circadian rhythm, antigen processing, collagen processing and inflammation.

Martínez Corrales et al. show that the activation of the conserved pro-longevity transcription factor FOXO solely in youth promotes subsequent health and survival in female fruit flies, via chromatin remodeling and induction of Xbp1.

Regulatory T (T_reg) cells have an important role in age-related diseases and inflammation; however, the underlying mechanisms are not fully understood. Li et al. identify a T_reg-specific long noncoding RNA, Altre, that binds Yin Yang 1 to regulate liver T_reg mitochondrial function in old mice. Altre deletion accelerates aging-associated liver pathogenesis.

Seegren et al. demonstrate that the mitochondrial calcium uptake complex is a key molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation.

Microglia, the innate immune cells of the brain, exhibit diverse functions and can influence Alzheimer’s disease progression. This study explores human microglial diversity in Alzheimer’s disease, uncovering unique disease-associated microglial populations and predicting underlying gene regulatory networks.

The mechanisms underlying the influence of aging on cancer are incompletely understood. Warde et al. establish a new model of age- and sex-dependent adrenal cancer. Their work uncovers a tumor-protective role for myeloid immune cells that is enhanced by androgens.

Studies have identified sex and/or gender differences in Alzheimer’s disease, but few have examined other dementias. We highlight sex and gender differences in other dementias, discuss sociocultural factors and provide a framework for future global studies.

Rapid progress in the development of novel biomarkers and lifestyle interventions and the emergence of the first disease-modifying therapy have revolutionized our approach to dementia diagnosis, prevention and therapy. In this Focus issue, Nature Aging presents a collection of reviews and opinion pieces on recent advances in dementia research.