Aging, longevity and age-related diseases

Bringing together different strands of genetic research, including results from recent large-scale genome-wide association studies relevant to human ageing, the authors highlight how genetics can further our understanding of the underlying mechanisms of ageing.

This Review discusses mechanisms of cellular senescence and approaches to target this pathway therapeutically using ‘senolytic’ drugs or inhibitors of the senescence-associated secretory phenotype. In addition, evidence is presented that cellular senescence has a causative role in multiple chronic diseases associated with ageing and/or endocrine diseases.

The majority of cancers arise in individuals over the age of 60. This Review discusses how ageing tissues through changes in the extracellular matrix as well as in the functions of fibroblasts and immune cells can impact tumour initiation, progression and response to therapy.

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.

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

Dietary restriction (DR) late in life does not improve survival and has little benefit in metabolic health in mice. The absence of a DR gene-expression signature in fat tissue suggests that a ‘nutritional memory’ interferes with the benefits of DR.

Naked mole rats are the longest-lived rodents and produce very-high-molecular-mass hyaluronan (vHMM-HA). Here the authors show that naked mole rat vHMM-HA is better at protecting mouse and human cells from cell cycle arrest and cell death, compared to the high-molecular-mass hyaluronan produced by these species.

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.

Aging impacts lung functionality and makes it more susceptible to chronic diseases. Combining proteomics and single cell transcriptomics, the authors chart molecular and cellular changes in the aging mouse lung, discover aging hallmarks, and predict the cellular sources of regulated proteins.

Microglia in the aging hippocampus accumulate lipid droplets, and are functionally impaired and inflamed. Lipid droplet formation in microglia is regulated by genes linked to neurodegeneration such as progranulin.

Akbar and colleagues show that sestrins induce the reprogramming of non-proliferative, senescent-like CD27^–CD28^–CD8⁺ T cells to acquire an innate-like killing activity modulated by the NK receptor NKG2D and the adaptor molecule DAP12.

Longitudinal multiomics profiling of a cohort of healthy people reveals distinct aging patterns—termed ageotypes—in different individuals.

Biomarkers that predict mortality are of interest for clinical as well as research applications. Here, the authors analyze metabolomics data from 44,168 individuals and identify key metabolites independently associated with all-cause mortality risk.

The authors develop a noninvasive stimulation protocol to restore neural synchronization patterns and improve working memory in older humans, contributing to groundwork for future drug-free therapeutics targeting age-related cognitive decline.

Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.

Senolytic compounds have the ability to eliminate senescent cells from tissues and have been shown to be beneficial in various animal models of age-related diseases. Here the authors show that cardiac glycosides commonly used for heart diseases have senolytic properties in humanized mouse models of tumorigenesis and lung fibrosis.

In addition to having direct anti-cancer effects, the cardiac glycoside ouabain is shown to kill a broad range of senescent cells, thus suggesting that cardiac glycosides represent a novel class of senolytics.

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

Aparicio and colleagues identify gene expression changes in breast cancer datasets putatively associated with age-related endocrine effects, suggesting that patient age may influence the prognostic potential of certain biomarkers.

Fecal microbiome transplantation or probiotic therapy with Akkermansia muciniphila extends the lifespan and improves the health status of progeroid mice, pointing to the importance of the gut microbiome in regulating lifespan and healthspan.

Genome-wide association analyses identify 301 new loci influencing bone mineral density and 13 loci influencing fracture risk. Integrative analyses of epigenomic data and mouse knockout phenotypes provide additional insights into osteoporosis pathophysiology.

The authors report that mitophagy is impaired in Alzheimer’s disease. Stimulation of mitophagy reverses cognitive deficits in nematode and mouse models of Alzheimer’s disease, suggesting a potential therapeutic intervention.

It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.

A new subset of disease-associated astrocytes (DAAs) is identified in a mouse model of Alzheimer’s disease by single-nucleus RNA sequencing. DAAs are also found in aged wild-type mice, suggesting a link to genetic and age-related factors.

Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.

Supercentenarians are approaching the current longevity limit by avoiding or surviving major illness, thus identifying biomarkers for exceptional survival might provide insights into the protection against disease of aging. Here, the authors show low NT-proBNP and high albumin in plasma are the biological correlates of survival to the highest ages.

Risk of age-related chronic disorders and decrease in resilience is associated with ageing. Here the authors analyse the human blood metabolome and identify metabolites associated with frailty.