Ageing

Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

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.

The Dog Aging Project is an open-data, community science study to identify genetic, environmental and lifestyle factors associated with canine healthy lifespan, generating knowledge that could readily translate to human ageing.

Circadian-regulated autophagy contributes to the health benefits of intermittent time-restricted feeding in Drosophila.

An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.

This Review discusses how the activity of retrotransposons influences ageing and the role of these mobile genetic elements in age-related diseases and their treatment.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Global loss of targeted protein degradation with age results in harmful accumulation of specific proteins in worms.

Glial metabolic reprogramming by gut-derived cytokines in Drosophila results in lasting changes in the sensory system of an ageing organism

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.

This Review examines the evidence showing that DNA damage is associated with ageing phenotypes, suggesting that it may have a central role as the cause of ageing.

Meningeal lymphatic drainage can affect the microglial inflammatory response and anti-amyloid-β immunotherapy in mouse models of Alzheimer’s disease.

Haematopoietic stem cells show progressive functional decline with age that can be reversed by stimulation of chaperone-mediated autophagy in old mice and aged humans.

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.

Ageing in humans is associated with an increase in circulating methylmalonic acid, which induces expression of SOX4 and promotes tumour progression.

A systematic analysis of the proteostasis network of secreted proteins in Caenorhabditis elegans identifies numerous regulators of protein homeostasis outside the cell, and highlights the contribution of extracellular proteostasis to host defence.

Two epigenetic regulators—identified in an RNA interference screen in Caenhorhabditis elegans, and conserved in mammals—diminish mitochondrial function and accelerate the age-related deterioration of behaviour.

A subpopulation of Caenorhabditis elegans, in which there is a naturally occurring transient increase in reactive oxygen species during early development, exhibits increased stress resistance, improved redox homeostasis and prolonged lifespan, which are linked to a global decrease in level of the histone mark H3K4me3.

Fibroblasts from old mice are heterogeneous, which affects the ability of these fibroblasts to reprogram into induced pluripotent stem cells in vitro and influences wound healing rate in vivo.

Aged progenitor cells in the rat central nervous system can be made to behave as young cells by reducing the stiffness of the tissue microenvironment, or by inhibiting the mechanosensitive protein PIEZO1.

Ageing-associated decline in intestinal stem cell function is mediated by increased Notum, a protein inhibitor of stemness-maintaining Wnt signalling, which is secreted by Paneth cells.

COL17A1-driven stem cell competition and symmetric cell divisions initially govern skin homeostasis, but the same mechanisms result in skin ageing later in life.

During cellular senescence in human and mouse cells, L1 transposons become transcriptionally derepressed and trigger a type-1 interferon response, which contributes to age-associated inflammation and age-related phenotypes.

A cynomolgus monkey model deficient in SIRT6 protein exhibits severe retardation in prenatal development, in which neuronal differentiation is delayed by activation of the H19 long non-coding RNA.

A knock-in mutation in beclin 1 that increases autophagy in mice extends animal lifespan, improves healthspan, and also rescues early lethality in mice deficient in the anti-ageing protein klotho.

The crystal structure of shed ectodomain of α-klotho bound to the FGFR1c ligand-binding domain and FGF23 unveils the mechanism by which klotho co-receptors promote hormonal FGF signalling.

Maternal age is found to be a major source of phenotypic variation in isogenic C. elegans populations living in a controlled environment, with the progeny of young mothers impaired for multiple fitness traits.

RNA polymerase III is a key evolutionarily conserved regulator of longevity that may have potential as a therapeutic target for age-related conditions.

Sperm-activated lysosomes enhance proteostasis in nematode oocytes just before fertilization; this could prevent transmission of damaged proteins to the next generation and may explain the immortality of the germ-cell lineage.

Identifying the gene polymorphisms that are the foundations of variation in glia–neuron signalling in Caenorhabditis elegans provides insight into highly variable age-related declines in worm behaviours.

Ablation of hypothalamic stem/progenitor cells in mice leads to ageing-related decreases in physiological parameters and lifespan, and the speed of ageing is partially controlled by these cells through the release of exosomal miRNAs.

A deficiency in H3K4me3 methyltransferase causes accumulation of mono-unsaturated fatty acids, which is important for lifespan extension in C. elegans and could be relevant in mammals.

Loss of autophagy increases the accumulation of mitochondria and the respiration status of haematopoietic stem cells, which perturbs their self-renewal and regeneration activities, and promotes cellular aging.

Precursor mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans and defects in global pre-mRNA splicing associated with age are reduced by dietary restriction via splicing factor 1.

Changes in active chromatin marks in old activated satellite cells lead to Hoxa9 activation, which induces the expression of developmental pathway genes with a known inhibitory effect on satellite cell function and muscle regeneration in aged mice.

Demographic analysis of life expectancy and maximum reported age at death provides evidence that human lifespan has reached its natural limit.

When senescent cells accumulate during adulthood they negatively influence lifespan and promote age-dependent changes in several organs; clearance of these cells delayed tumorigenesis in mice and attenuated age-related deterioration of several organs without overt side effects, suggesting that the therapeutic removal of senescent cells may be able to extend healthy lifespan.

A diverse range of molecular and genetic manipulations all alter lifespan distributions of Caenorhabditis elegans by an apparent stretching or shrinking of time.

Increased maternal age is known to increase the risk of congenital heart disease in offspring; here, this link is investigated by transplanting ovaries between young and old mice, revealing that the maternal-age-associated risk is independent of the age of the ovaries but depends on the age of the mother, and that this risk can be mitigated by maternal genetic background or exercise.

Here, DNA damage is shown to occur as a direct consequence of inducing haematopoietic stem cells to exit quiescence in response to conditions of stress; in mice with mutations modelling those seen in Fanconi anaemia, this leads to a complete collapse of the haematopoietic system.

In Caenorhabditis elegans, reduced insulin/IGF-1 signalling can promote longevity through a program that is genetically distinct from the dauer developmental pathway, and requires SKN-1-dependent collagen remodelling that is a broadly essential feature of longevity assurance pathways.

An investigation of the influence of age on the generation of insulin-producing cells after β-cell loss in mice reveals that, whereas α-cells can reprogram to produce insulin from puberty to adulthood, efficient reconstitution in the very young is through δ-cell reprogramming, leading to complete diabetes recovery.

Haematopoietic stem cell (HSC) function is known to degrade with age; here, replication stress is shown to be a potent driver of the functional decline of HSCs during physiological ageing in mice due to decreased expression of mini-chromosome maintenance helicase components and reduced activity of the DNA replication machinery.

Bone homeostasis and repair declines with ageing and the mechanisms regulating the relationship between bone growth and blood vessel formation have remained unknown; this mouse study identifies the endothelial cells that promote the formation of new bone, a small microvessel subtype that can be identified by high CD31 and high Emcn expression.