Reviews & Analysis

In vivo reprogramming by expression of the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM factors) has been associated with early mortality and cancer. We report that these adverse effects are associated with liver and intestinal dysfunction. Strategic control of OSKM expression in these organs through a newly developed transgenic mouse model reduced adverse effects. Our model yields valuable insights into the potential of in vivo reprogramming for rejuvenation and regeneration.

Senescent cells in the brain contribute to age-related neurodegeneration. Analysis of SARS-CoV-2 infection in human brain organoids, animals and post-mortem brain samples from patients with COVID-19 reveals virus-induced senescence. Pharmacological senolytic treatment following SARS-CoV-2 infection improves COVID-19 neuropathology and could help to protect people from long COVID.

Intrinsic capacity (IC) — a metric that reflects the composite of a person’s physical and mental capacities — varies across adulthood and between individuals of the same age. People with an IC below the tenth percentile suffer from a high burden of diseases, frailty, disabilities and recent falls.

Plants have an additional organelle to animals (the chloroplast), which means that they have a greater repertoire of protein homeostasis (proteostasis) mechanisms. We find that chloroplast proteostasis components prevent aggregation of a pathogenic fragment of human huntingtin expressed in plants, which reveals a potential avenue for therapeutic intervention in human proteinopathies.

Senescent cells accumulate with age and promote tissue decline. A broad genomic screen reveals that senescent cells can be eliminated from aged mice by interfering with their unique secretory program. Reducing the capacity of the endoplasmic reticulum by inhibiting the YAP–TEAD complex sensitizes senescent cells to apoptosis.

Microglia exhibit unexpected sex differences in gene expression and accessibility and compromised inflammatory responses during the aging process in mice. We established a mouse model with accelerated microglial turnover (3xDR), which results in aged microglia in non-aged brains. Analysis of this model revealed that aged microglia themselves contribute to cognitive decline.

By using multimodal MRI in aging humans, we found that noradrenergic brain regions are associated with episodic memory impairment, whereas dopaminergic areas are implicated in working memory impairment. Unravelling the role of changes in these neurotransmitter systems in age-related memory loss contributes to our understanding of the development of neurodegenerative diseases.

Cost-effective and scalable means for detecting amyloid-β positivity in clinical practice are urgently needed. Here, in three memory clinic cohorts, we show that risk stratification with a plasma p-tau217-based model can substantially reduce the need for expensive or invasive testing, while still accurately determining the amyloid-β status of patients with cognitive impairment.

Leveraging a single regression model based on conserved cytosines, we can now measure age in all mammalian tissues. This pan-mammalian epigenetic clock model confirms that aging is conserved across mammalian species at select regions of the DNA, which will accelerate the applicability of research findings from model organisms to humans.

Our understanding of the genetics that underlies healthy aging can be improved by integrating complementary traits related to chronological and biological aging. We present a multitrait genome-wide association study that reflects the genetics of a broad healthy aging factor and use genetics methods to investigate potential therapeutic relationships among various drug targets.

By applying deep molecular profiling to our long-term mouse parabiosis model, we reveal reduced epigenetic age in old mice that shared circulation with young mice. The rejuvenation effect is sustained at two months after detachment, leading to lifespan extension and improved physical function, and is associated with rejuvenated transcriptomic signatures.

We treated aged monkeys with a dose of the longevity factor klotho, which is known to increase synaptic and cognitive functions in mice. We found that a relatively low dose of klotho enhanced cognition in aged monkeys. These findings are important because they suggest that klotho replenishment could prove to be therapeutic in aging humans.

Quantification of tau peptides in blood samples using a new mass spectrometry method suggests that individual phosphorylated tau peptides have distinct patterns of emergence in Alzheimer’s disease and differential associations with amyloid and tau pathologies. This method has the potential to stage patients along the disease continuum and for clinical trials.

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.

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.

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.

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.