Reviews & Analysis

This Perspective describes the clinical relevance of animal models in dementia for translational research. The authors emphasize incorporating aging as a component in model organisms to understand its contribution to disease pathogenesis.

This Review provides an update on the most promising blood-based biomarkers relevant to Alzheimer’s disease and how they can be used to substantially improve the diagnostic and prognostic work-up in clinical practice and trials.

This Review provides evidence-based update on the association between social interaction and risk of dementia. The authors propose a policy framework to promote social interaction as a preventative strategy against dementia.

This Review highlights the need for targeting Alzheimer’s disease in the preclinical stage for an effective therapeutic strategy. The authors provide an update on candidate therapies in development, current preclinical Alzheimer’s disease trials, recruitment challenges and future directions.

This Perspective outlines a strategy to move towards a future with personalized medicine for Alzheimer’s disease by empowering patients in orchestrating diagnosis, prediction and prevention of the onset of dementia.

We used graph neural networks trained on experimental data to identify senolytic compounds from vast chemical libraries of over 800,000 compounds and discovered structurally diverse senolytics that have potent in vitro and in vivo activity, as well as favorable medicinal chemistry properties.

Lamming and Mannick discuss work over the past decade showing that rapamycin promotes survival in multiple species and how recent clinical trials have finally begun to explore whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging in humans.

The mysteries behind immune aging and its related inflammation are being unmasked. Jin et al. reveal that the defective turnover of damaged mitochondria in CD4⁺ T cells from older individuals results in the exacerbated secretion of mitochondrial DNA, which fuels inflammaging and impairs immune responses.

Despite the central role of immune regulation in tissue repair, the contribution of immune dysfunction to regenerative failure in aging is mostly unknown. We discovered a mechanism of immune modulation that operates during skeletal muscle regeneration that is compromised in aged animals and can be harnessed to improve regenerative capacity in aging.

Clinical predictors of type 2 diabetes can be improved by considering blood-based DNA methylation scores. We derive the scores in 9,835 Scottish individuals and then test their performance against clinical predictors in 4,778 additional Scottish volunteers and 1,451 German volunteers.

We characterized the enterotypes of a large cohort of individuals of 20–117 years of age and found that the gut microbiome of centenarians has features that are usually associated with gut microbiomes of young individuals: dominance of Bacteroides spp., increase in species evenness, enrichment of potentially beneficial Bacteroidetes and depletion of potential pathobionts.

Moderately cold temperatures trigger the removal of aggregation-prone proteins in the invertebrate model Caenorhabditis elegans and cultured human cells, preventing the accumulation of pathological aggregates linked with age-related neurodegenerative disorders such as amyotrophic lateral sclerosis and Huntington’s disease.

Epigenetic changes are a driver of senescence and occur during aging. A study in Nature Aging shows how chromatin-mediated loss of transcription fidelity, previously shown in yeast and worms, also occurs in mammalian cells and could constitute a new hallmark of senescence and aging.

The ability of adult neural stem cells to produce new neurons (neurogenesis) declines markedly during aging, but exactly how this occurs is largely unknown. Using sophisticated in vivo imaging, a study in Nature Aging shows that aging affects several steps of neurogenesis — most notably, increasing the death of newborn clones.

Wang Lin and his colleagues explore how aging reprograms spatially unique pathways in liver endothelial cells to cause fibrosis. They find that loss of KIT in liver endothelial cells close to the central vein upregulates the chemokine receptor CXCR4 to stimulate inflammation, enhance fibrosis and increase lipid accumulation in aged liver.

We found evolutionarily conserved astrocyte and microglia subpopulations shared across multiple brain regions. We reveal similarities and differences between Alzheimer’s disease glia and Parkinson’s disease glia, as well as regional variance linked to disease pathology and neurodegeneration.

Aging is known to be associated with a decline in memory and mood, but the molecular mechanisms that underlie these changes remain unclear. Moigneu, Abdellaoui and colleagues show that growth differentiation factor 11 reverses deficits in these functions in aged mice, pointing the way towards a novel pro-mnemonic and antidepressant therapeutic target.

Zhang and colleagues demonstrate how the premature aging phenotypes in progeria involve a mitotic spindle-assembly-checkpoint protein, BUBR1. BUBR1 is misanchored to the nuclear membrane by progerin and its mRNA is destabilized in progeria, preventing it from functioning properly.

Cellular senesence is believed to be a driver of aging. We designed and synthesized a photosensitive prodrug that destroys senescent cells by integrating multiple technologies that combine biomarker guidance with a fluorescence tag, target-site anchoring and photodynamic therapy, providing a strategy for monitoring and specifically eliminating senescent cells to regulate aging.

Age-related decline in brain health is associated with poor blood flow and limitations in energy supply, although the vascular mechanisms are poorly understood. We report an age-related decrease in responsivity of brain microvessels, accompanied by a decrease in vessel density and loss of vascular mural cell processes.