Aging & Longevity
The uniqueness of human vulnerability to brain aging in great ape evolution
Aging is associated with progressive gray matter loss in the brain. This spatially specific, morphological change over the life span in humans is also found in chimpanzees, and the comparison between these great ape species provides a unique evolutionary perspective on human brain aging. Here, we present a data-driven, comparative framework to explore the relationship between gray matter atrophy with age and recent cerebral expansion in the phylogeny of chimpanzees and humans. In humans, we show...
Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based...
Egr1 regulates regenerative senescence and cardiac repair
Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in...
Cellular senescence is required for cardiac regeneration
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Accelerated biological aging elevates the risk of cardiometabolic multimorbidity and mortality
Associations of biological aging with the development and mortality of cardiometabolic multimorbidity (CMM) remain unclear. Here we conducted a multistate analysis in 341,159 adults of the UK Biobank. CMM was defined as the coexistence of two or three cardiometabolic diseases (CMDs), including type 2 diabetes, ischemic heart disease and stroke. Biological aging was measured using the Klemera-Doubal Method Biological Age and PhenoAge algorithms. Over a median follow-up of 8.84 years, biologically...
Biological aging - a new tool to detect cardiometabolic multimorbidity and mortality
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Biological aging as a predictor of cardiometabolic multimorbidity
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p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia
Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found that the stress kinases p38γ and p38δ are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that, upon activation, p38γ and p38δ cooperatively increase the susceptibility to...
Macrophages enable heart-on-a-chip longevity
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Author Correction: Accelerated biological aging elevates the risk of cardiometabolic multimorbidity and mortality
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A transcriptional enhancer regulates cardiac maturation
Cardiomyocyte maturation is crucial for generating adult cardiomyocytes and the application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). However, regulation at the cis-regulatory element level and its role in heart disease remain unclear. Alpha-actinin 2 (ACTN2) levels increase during CM maturation. In this study, we investigated a clinically relevant, conserved ACTN2 enhancer's effects on CM maturation using hPSC and mouse models. Heterozygous ACTN2 enhancer deletion led to...
Systemic and local regulation of hematopoietic homeostasis in health and disease
Hematopoietic stem cells (HSCs) generate all blood cell lineages responsible for tissue oxygenation, life-long hematopoietic homeostasis and immune protection. In adulthood, HSCs primarily reside in the bone marrow (BM) microenvironment, consisting of diverse cell types that constitute the stem cell 'niche'. The adaptability of the hematopoietic system is required to respond to the needs of the host, whether to maintain normal physiology or during periods of physical, psychosocial or...
Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ(2) mediated modification and control of HRas
Senescent cells are characterized by multiple features such as increased expression of senescence-associated β-galactosidase activity (SA β-gal) and cell cycle inhibitors such as p21 or p16. They accumulate with tissue damage and dysregulate tissue homeostasis. In the context of skeletal muscle, it is known that agents used for chemotherapy such as Doxorubicin (Doxo) cause buildup of senescent cells, leading to the inhibition of tissue regeneration. Senescent cells influence the neighboring...
Premature cognitive decline in a mouse model of tuberous sclerosis
Little is known about the influence of (impaired) neurodevelopment on cognitive aging. We here used a mouse model for tuberous sclerosis (TS) carrying a heterozygous deletion of the Tsc2 gene. Loss of Tsc2 function leads to mTOR hyperactivity in mice and patients. In a longitudinal behavioral analysis, we found premature decline of hippocampus-based cognitive functions together with a significant reduction of immediate early gene (IEG) expression. While we did not detect any morphological...
The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice
The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24^(-/-) mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a...
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells
The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result...
Rejuvenating liquid crystal elastomers for self-growth
To date, only one polymer can self-grow to an extended length beyond its original size at room temperature without external stimuli or energy input. This breakthrough paves the way for significant advancements in untethered autonomous soft robotics, eliminating the need for the energy input or external stimuli required by all existing soft robotics systems. However, only freshly prepared samples in an initial state can self-grow, while non-fresh ones cannot. The necessity of synthesizing from...
Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence
Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS...
What accelerates brain ageing? This AI 'brain clock' points to answers
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Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated...
Aging and Longevity: Latest results from PubMed
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