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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.
Intestinal barrier dysfunction is a hallmark of aging. Zhang and colleagues examine the replenishment of adherens junctions in the intestine of aged Caenorhabditis elegans and discover the role of the SDPN-1–RAB-10 axis in the dysregulated endocytic recycling, offering new insights into the age-dependent impairment of the intestinal barrier.
Lysosomes are small vesicles in which cellular constituents are enzymatically degraded. Villalobos and colleagues now show that in Caenorhabditis elegans a shift in lysosome morphology from a vesicular to a tubular shape is critical for the lifespan extension triggered by calorie restriction. Moreover, tubular lysosomes form even in well-fed descendants of calorically restricted parents for up to four generations.
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.
Han et al. provide a substantial contribution to our limited comprehension of the mechanisms of aging in adipose tissue. They show that, with age, increased levels of adipose CRTC2 decrease the breakdown of branched-chain amino acids and activate mTORC1. This in turn leads to increased levels of senescence-associated secretory phenotype factors, which promotes senescence and adipose dysfunction.
Neuronal aging is highly associated with misfolded protein aggregates that predispose to neurodegeneration, but the cellular factors that are involved in removing misfolded proteins are yet to be identified. In this issue of Nature Aging, Li and colleagues identified LONRF2 as an important player in protecting aging neurons against the accumulation of protein aggregates.
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.
Aging increases vulnerability to respiratory viral infections, including by SARS-CoV-2. Delval et al. established a causal role for age-related pre-existing senescent cells in the severity of COVID-19 symptoms in an aging hamster model. Selective depletion of senescent cells using senolytic agents mitigated the risk of severe COVID-19 symptoms linked to aging.
SenNet Consortium members review current and emerging methodologies for spatially resolved mapping of senescent cells. They discuss their limitations and challenges involved in the aim of creating a comprehensive atlas of senescent cells during aging.
Aging is associated with a variety of changes; however, which of the observed changes drive aging is incompletely understood. In this Perspective, the authors discuss cellular senescence, epigenetics and stem cell alterations with this question in mind.
High-throughput analysis of cellular landscapes is an important tool to decipher the molecular mechanisms driving aging and disease. Here, Singh and Benayoun discuss key considerations in the design and analysis of omic data to gain robust and reproducible insights into the aging process.
Warde and colleagues demonstrate sex-specific differences in senescence in the adrenal glands of aged mice, with males eliciting a more robust, protective myeloid response that is associated with protection from adrenal cancer.
Li and colleagues address the effect of regulatory T (Treg) cells on the aging process and the role of long non-coding RNAs in Treg cell function. They show that a Treg cell-specific and age-induced long non-coding RNA, Altre, protects the aging liver from age-related apoptosis and metabolic abnormalities.
Liu and colleagues investigate the effects that ovarian aging may have in granulosa cell-to-oocyte communication and demonstrate that oocyte rejuvenation and the extension of reproductive lifespan is possible by increasing lipid metabolism in granulosa cells in mouse.
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.
