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At single-cell resolution, Tarkhov et al. delineate stochastic and co-regulated components of epigenetic aging, revealing a simultaneous loss of regulation at the epigenetic and transcriptional levels in aging.

Previous studies have identified common genetic variants linked to longevity, but the impact of rare damaging mutations remains unclear. Here, the authors show that centenarians carry fewer harmful loss-of-function mutations and identify genes that may contribute to extreme longevity and healthy aging

Here the authors show that rRNA methylase DIMT-1 regulates aging by acting after mid-life in the germline, regulating specialized ribosomes that perform selective translation of mRNAs important for longevity. Thus revealing an additional layer of proteome dysfunction as an aging regulator.

Dissecting the effects of hypothermic and hypometabolic states on aging processes, the authors show that activation of neurons in the preoptic area induces a torpor-like state in mice that slows epigenetic aging and improves healthspan. These pro-longevity effects are mediated by reduced T_b, reinforcing evidence that T_b is a key mediator of aging processes.

The freshwater planarian S. mediterranea is an important model organism for regeneration research but its use in aging research is little explored and S. mediterranea is commonly referred to as immortal. Here Dai et al. report age-associated physiological and molecular changes in the sexual lineage of S. mediterranea, and global reversal of such changes after regeneration.

Castro, Shindyapina et al. explore how aging promotes B cell lymphoma in mice, identifying a population of age-associated clonal B cells that expands through mutation, c-Myc activation and epigenetic alterations to drive age-associated malignancy.

By individually replacing 16 yeast genes encoding ABC transporters by GFP, mating and selecting for strains with accumulated mutations the authors create a Green Monster, a strain with deletions in all 16 genes.

DNA methylation (DNAm) is a key biomarker of aging, with age-related DNAm changes being well-characterized. Here, the authors show that low-methylated regions (LMRs) bound by PRC2 in embryonic stem cells gain methylation with age in somatic cells, proposing the “PRC2-AgeIndex” as a universal biomarker of cellular aging.

Osteoarthritis is caused by the gradual accumulation of oxidative stress in cartilage. Here, the authors show that dysregulation of the selenium metabolic pathway underlies a shift in redox homeostasis in chondrocytes, leading to chronic osteoarthritic changes in joints.

The authors identify causality-enriched CpGs linked to aging using Mendelian randomization. They develop new epigenetic clocks, DamAge and AdaptAge, that more reliably track age-related changes, offering insights into aging mechanisms and interventions.

On 1–2 November 2024, the annual Biomarkers of Aging conference welcomed academic and industry scientists, and partners from governmental and nongovernmental organizations, to Harvard Medical School in Boston, USA, to discuss new insights into measuring and monitoring human aging, with the aim of clinical translation. In this Meeting Report, we summarize the conference and offer potential future directions for the Biomarkers of Aging Consortium and the longevity science community at large.

Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

Aguado et al. show that SARS-CoV-2 induces senescence in human brain organoids and in the brains of COVID-19-infected mice and humans. They demonstrate the therapeutic potential of senolytic therapy in protection against COVID-19-induced brain aging.

Mice overexpressing Has2 from the naked mole-rat showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, attenuated inflammation through several pathways, extended lifespan and improved healthspan.

The exceptionally long-lived naked mole-rat is characterized by the lack of increased mortality with aging. Here the authors perform epigenetic studies to show that naked mole-rats epigenetically age despite their non-increasing mortality rate.

Aneuploidy (abnormal chromosome number) can enable rapid adaptation to stress conditions, but it also entails fitness costs from gene imbalance. Here, the authors experimentally evolve yeast while forcing maintenance of aneuploidy to identify the mechanisms that promote tolerance of aneuploidy.

A new quantitative proteomic approach can identify reactive cysteine residues in native proteins and distinguish them on the basis of reactivity. This resource-rich study offers a useful new technology and is a significant step toward understanding the reactivity and functions of cysteines in cells.

Dietary restriction of the amino acid methionine extends the lifespan of rodents. Here the authors systematically test diets with varying amino-acid content and show that methionine restriction extends the lifespan of yeast and flies only when the content of other amino acids in the diet is also low.

The authors show that FOXM1 transcription factor transgene induction in Hutchison–Gilford progeria and naturally aged mice significantly extends their lifespan via restoring the loss of Foxm1 function with age that contributes to the aging phenotypes.

Expression of three Yamanaka transcription factors in mouse retinal ganglion cells restores youthful DNA methylation patterns, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice, suggesting that mammalian tissues retain a record of youthful epigenetic information that can be accessed to improve tissue function.

Somatic mutations are associated with disease, including cancer. Here, the authors analyse cancer genomic data and show that somatic mutations increase with age and that cancer incidence lags 15 years behind this increase, later in life, mutation and cancer incidence are reduced.

In January 2024, a Hevolution Alliance for Aging Biomarkers thinktank convened at Cold Spring Harbor to discuss the framework for creating an open and diverse data resource for developing reliable aging biomarkers. As the funding for this initiative has now been confirmed, we summarize recommendations and key milestones for its implementation.

A comprehensive transcriptomic survey of the pig could enable mechanistic understanding of tissue specialization and accelerate its use as a biomedical model. Here the authors characterize four distinct transcript types in 31 adult pig tissues to dissect their distinct structural and transcriptional features and uncover transcriptomic variability related to tissue physiology.

This Review examines how hallmarks of aging manifest in the skin and interact with systemic aging, positioning the skin as both an indicator and driver of age-related physiological decline.

Among rodent species, there is a wide diversity in lifespans and cancer susceptibilities, which makes comparative studies of rodents an attractive strategy for identifying molecular mechanisms that underlie ageing and cancer. This Review describes the various biological insights provided by comparative rodent genomics, including those from whole-genome sequencing of long-lived and highly cancer-resistant species. Such progress has potential implications for understanding and modulating human disease.

Bats account for 20 per cent of all mammals, these are the only mammals with powered flight, and are among the few animals that echolocate. Here, Seim et al. sequence the genome of the long-lived (>40 years) Brandt’s bat, Myotis brandtiiand provide clues to its evolution, longevity and other traits.

Whales, dolphins and porpoises are adapted to various aquatic habitats. Here, Zhou et al. show that polymorphisms associated with renal function and the urea cycle have undergone selection in the freshwater Yangtze finless porpoise and provide genomic evidence of incipient speciation.

Although the emerging field of geroscience holds great promise for identifying new approaches to improve healthspan, several risks of the current framework are underappreciated. Long time horizons, challenges in identifying causality-driven surrogate biomarkers of aging, and the potential for biological trade-offs and antagonistic effects across various timescales mean it will be hard to know when such interventions have a net benefit. We propose eight strategies to mitigate these risks going forwards.

Griffin et al. present a versatile method for scalable and low-cost sequencing for the construction of epigenetic clocks. They assay 2,892 human or mouse samples, benchmark their method and assess diverse interventions.

The lack of existing tools has made it difficult to detect and quantify methionine sulfoxide in cells. The introduction of the MetSOx and MetROx fluorescent sensors allows detection of stereospecific forms of methionine sulfoxide in cells.

The composition of trace elements in human cells (the ionome) is an important component of metabolism. Here, the authors carry out a high-throughput, genome-wide analysis of the human ionome and identify cellular regulators of important trace elements such as selenium, copper and iron.

Large-scale sequencing approaches reveal that the genetic code of Euplotes ciliates supports widespread ribosomal frameshifting at stop codons, and that additional mechanisms are required for efficient translation termination.

Lore et al. explore how biological and synthetic replacement therapies, from engineered tissues to advanced prosthetics, could restore aging cells and organs, offering strategies to extend healthy human lifespan and combat age-related decline.

Epigenetic clocks emerged as crucial biomarkers of the aging process, but their use has so far been limited to bulk samples. Trapp et al. unveil a new statistical framework that enables epigenetic age profiling at single-cell resolution.

Biomarkers of aging have potential to accelerate the clinical translation of interventions that promote healthy aging but are currently limited to research. The authors identify six barriers to be overcome to enable biomarker translation, providing a roadmap to clinical implementation.

A regulatory mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene encoding adenosylmethionine decarboxylase 1.

Selenoproteins—proteins that contain the twenty-first amino acid selenocysteine—were previously thought to be lacking in fungi. Analysis of genomes from early-branching fungal phyla identified selenocysteine machinery and selenoproteins, indicating that these proteins are present in all kingdoms of life.

Robust validation of biomarkers of aging will be critical to their clinical translation; here, authors review the key challenges and propose recommendations to overcome them.

Rejuvenation and partial reprogramming are two frontier areas in the field of aging. Here, the authors summarize advances in these fields and suggest future directions for research and therapy.

Aging is associated with a variety of changes; however, which of the observed changes drive aging is incompletely understood. In this Perspective, the authors discuss cellular senescence, epigenetics and stem cell alterations with this question in mind.

A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal—including 131 previously uncharacterized species—from the Zoonomia Project provides data that support biological discovery, medical research and conservation.

In this Review, the authors discuss the concept of molecular damage in aging, from theoretical models to experimental approaches and how to test interventions targeting aging that reduce its burden.