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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.

A new generation of commercial entities is beginning to explore opportunities for new types of interventions and services in a graying world.

Is ageing in our genes? In this Viewpoint, six experts present their views on the extent to which ageing is genetic and discuss future strategies for research into ageing and longevity.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

Changes in intronic polyadenylation of the Pdgfra in fibro/adipogenic progenitors lead to increased expression of a shorter variant with a truncated kinase domain, which modulates pro-fibrotic pathways to reduce tissue fibrosis in muscle.

Adult muscle stem cells are used as a model system to show that the microRNA pathway, and specifically miR-489, is essential for the maintenance of the quiescent state of an adult stem-cell population by suppressing a key proliferation factor, Dek.

A mouse study reveals that the stem cell quiescent state is composed of two distinct phases, G₀ and G_Alert; stem cells reversibly transition between these two phases in response to systemic environmental stimuli acting through the mTORC1 pathway.

Duchenne muscular dystrophy is an X-linked recessively inherited disorder of skeletal and cardiac muscle that is caused by mutations in the dystrophin gene. In this article, Lim and Rando describe new mutation-specific therapeutic strategies that use nonviral agents to target nonsense point mutations or frameshift deletions at the dystrophin locus, with the ultimate aim of developing 'personalized' gene therapy for Duchenne muscular dystrophy.

A decellularized extracellular matrix scaffold containing nanocapsules orchestrates timed growth factor release to promote muscle stem cell proliferation and differentiation and effective muscle regeneration after traumatic injury.

The field of regenerative medicine would greatly benefit from the study of a non-human primate model. Here, the authors prospectively isolated two quiescent stem cell populations from the non-human primate mouse lemur.

Volumetric muscle loss leads to functional muscle impairment, and current stem cell-based treatments show limited efficacy. Here, the authors generate a stem cell scaffold, implant it in mice, and show that an exercise regimen enhances innervation and restoration of muscle function in mice.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Aging involves gradual loss of tissue function, and transcription factor (TF) expression can ameliorate this in progeroid mice. Here the authors show that transient TF expression reverses age-associated epigenetic marks, inflammatory profiles and restores regenerative potential in naturally aged human cells.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

An artificial niche prolongs the quiescence of muscle stem cells in vitro.

A spatially resolved single-cell transcriptomics map of the mouse brain at different ages reveals signatures of ageing, rejuvenation and disease, including ageing effects associated with T cells and rejuvenation associated with neural stem cells.

During ageing, S-adenosylmethionine (SAM) is depleted from muscle stem cells (MuSCs) because of increased synthesis of the polyamine spermidine, leading to loss of heterochromatin and dysfunction of MuSCs. SAM restoration rescues the mouse MuSC defects.

Subsets of mammalian adult stem cells reside in a reversible quiescent state. Recent studies of epigenetic, transcriptional and post-transcriptional events underlying quiescence suggest that this state is actively maintained by signalling pathways that keep cells poised for rapid activation, rather than this being a dormant state with minimal basal activity.

In this Perspective, Rando and Wyss-Coray discuss recent advances in the field of the biology of aging, focusing on new concepts related to the processes of cell and tissue aging and how they impact the healthspan and lifespan of an individual.

Satellite cells have important roles in homeostasis and regeneration of skeletal muscles. Urciuolo et al. show that the extracellular matrix protein collagen VI is required for preserving satellite cell self-renewal and muscle regeneration in vitro and in vivoby modulating muscle mechanical properties.

Observations of six transiting planets around the bright nearby star HD 110067 show that they follow a chain of resonant orbits, with three of the planets inferring the presence of large hydrogen-dominated atmospheres.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

Plasma from voluntarily running mice reduces baseline expression of neuroinflammatory genes and experimentally induced brain inflammation when infused into sedentary mice.

Stem cell therapeutics hold great promise, but obtaining optimal cell populations for transplantation remains a major challenge. High-throughput screens of zebrafish embryonic cells have enabled identification of small molecules that can direct the fate of pluripotent stem cells toward tissue-specific progenitors with high therapeutic potential.

Immortality is the stuff of myth and legend, but lifespan extension is the subject of serious scientific inquiry. Exploring the causes and effects of ageing in stem cells should aid this quest.

Brett et al. demonstrate that voluntary exercise improves quiescent muscle stem cell (MuSC) function and regenerative capacity in old but not young mice through exercise-induced upregulation of Cyclin D1 and repression of TGF-β activity in quiescent MuSCs.

Old cells and tissues become young again after a short dose of reprogramming factors.

Royal jelly is the queen-maker for the honey bee that also has effects on longevity, fertility, and regeneration in mammals. Here the authors provide evidence that its major protein component Royalactin, and the mammalian structural analog Regina, maintain pluripotency in mouse ESCs by activating a ground-state pluripotency-like gene network.

Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling.

Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

New data show that R loops differentially modulate binding of chromatin remodelers Tip60–p400 and PRC2 at coding and noncoding gene promoters of mouse ESCs and thereby control transcription and cellular differentiation.

Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.

Iris Heid, Gonçalo Abecasis, Sudha Iyengar and colleagues report the results of a large genome-wide association meta-analysis of macular degeneration based on over 43,000 subjects. They identify 16 new risk loci, including some very rare coding variants.

Melanie Bahlo and colleagues perform the first genome-wide association analysis for macular telangiectasia type 2. They identify three significant loci and report on a potential connection to the glycine/serine metabolism pathway.

A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis, provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

Adult stem cells can self-renew and can give rise to committed progenitors—but definitive evidence of cells with both properties is lacking in most tissues. A cell in skeletal muscle, the satellite cell, now meets these criteria.

Our understanding of stem cell biology is increasing, but the translation of this knowledge into regenerative medicine therapies for aged or diseased tissues is proving challenging. In this Perspective, four experts in the field discuss strategies for overcoming the major hurdles facing the translational regenerative field.

A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.