Research Briefing

Our analysis of the spatiotemporal transcriptional features of human ovarian aging at the single-cell level identified the DNA damage response as a fundamental attribute in oocyte senescence. FOXP1, a gatekeeper both in granulosa and in theca and stroma cellular senescence, can be activated by quercetin treatment to delay ovarian aging.

Staging Alzheimer’s disease on the basis of the disease’s biological underpinnings might help with stratification and prognostication, both in the clinical setting and in clinical trials. We propose a staging model based on only five biomarkers, which are related to amyloid-β and tau pathologies in different ways and can be measured with a single sample of cerebrospinal fluid.

Intensive blood pressure control has been suggested to reduce the risk of adverse cardiovascular events. However, the effect of intensive blood pressure control on cardiac conduction system disease has not been clarified. Our study in older patients with hypertension identified no effect of intensive blood pressure control on cardiac conduction system diseases.

After discovering the sensitivity of the adrenal zona reticularis region to aging, we found that low-density lipoprotein receptor (LDLR) deficiency hampers both cholesterol uptake and dehydroepiandrosterone sulfate (DHEA-S) production. This finding reveals the cellular basis for age-related adrenal insufficiency and provides insights for the development of interventions to delay endocrine and systemic aging.

Our study demonstrates how clinical data can be used to build machine-learning models to predict the risk of Alzheimer’s disease (AD) onset and can be integrated with knowledge networks to gain insights into the pathophysiology of AD, with a focus on a better understanding of disease sex differences.

Using a data-driven proteomics strategy from a prospective community-based cohort with long-term follow-up, this study reports that plasma levels of glial fibrillary acidic protein (GFAP) can predict the risk of dementia, even 15 years before disease diagnosis. Our findings have important implications for early screening and interventions for dementia.

Using a multi-omics strategy, we uncovered location- and sex-specific aging heterogeneity of the large intestine in monkeys and identified a range of potential gut aging regulators. We explored the roles of several regulators in intestinal function and lifespan in Caenorhabditis elegans. Finally, we investigated potential links between gut aging and colorectal cancer.

Proteomics analysis of cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease (AD) identified five subgroups with distinct underlying mechanisms and genetic risk profiles. These subtypes might be a step forward in realizing personalized treatment for AD.

Tagmentation-based methylation sequencing (TIME-seq) is an efficient and cost-effective solution for measuring and generating epigenetic clocks. We applied TIME-seq to over 2,800 mouse and human DNA samples to produce clocks that demonstrate accuracy and robustness; the method also outperforms conventional methods in speed and cost. The simple and practical design of TIME-seq facilitates large-scale epigenetic clock analysis, which makes it a valuable tool for advancing aging research.

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.