Aging & Longevity

Ceramides regulate diverse cellular processes through compartment-specific accumulation. While mitochondrial ceramide accumulation promotes apoptosis, its regulation and function during senescence remain incompletely understood. Here, we integrate lipidomics, transcriptomics, Raman spectroscopy, and biochemical characterizations to define sphingolipid remodeling in replicative senescence. Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins, despite...

Radiotherapy (RT)-induced senescent tumor cells (STCs) reinforce an immunosuppressive tumor microenvironment (ITM) and compromise therapeutic outcomes. However, current senolytic strategies lack specificity for STCs and often cause off-target toxicity. Here, we observe that STCs possess enhanced antigen-presenting capacity in patient-derived tumor tissues and murine tumor models. Leveraging this phenomenon, we engineer STC-derived nanovesicles (termed nano-APM) for preserving endogenous antigens...

The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests...

Long noncoding RNAs (lncRNAs) regulate transcriptional and epigenetic programs during aging and senescence. However, no comprehensive studies have systematically integrated multilayered analyses to reveal their diverse regulatory roles. Moreover, lncRNAs with therapeutic potential in age-related diseases remain unexplored. Here we systematically perturbed 32 high-abundance aging- and senescence-associated lncRNAs (PtbAlncs) using a Perturb-seq-based CRISPR-dCas9-KRAB knockdown system coupled...

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Immune responses vary between individuals due to age, sex, genetics, and environment, yet most systems immunology studies focus on populations of European ancestry. To address this gap, we established the Healthy Human Global Project - Hong Kong (HHGP-HK) to characterize immune variability in a healthy Asian population. Modeled on the French Milieu Intérieur study, we adapted inclusion and exclusion criteria and collected harmonized demographic, medical, and lifestyle data for cross-cohort...

Chimeric antigen receptor (CAR) T cells have transformed hematologic cancer therapy but remain limited in solid tumors by antigen heterogeneity and a suppressive, pro-fibrotic microenvironment. We previously identified the urokinase plasminogen activator receptor (uPAR) as upregulated in senescent, pro-fibrotic cells and showed that uPAR-directed CAR T cells could safely reverse fibrosis in mice. Integrative analyses now reveal that uPAR is broadly expressed in solid tumors enriched for TP53 and...

Phenotyping cells at transcriptomic and proteomic levels is an essential step to understanding cellular contributions to development, aging, injury, and disease. Since proteome and transcriptome level abundances modestly correlate, complementary profiling of both is needed. We report a method called simultaneous protein and RNA -omics (SPARO) to capture the cell type-specific transcriptome and proteome simultaneously in vitro using BV2 microglial and HEK293 cell lines and in vivo using...

Co-pathology is a common feature of neurodegenerative diseases that complicates diagnosis, treatment and clinical management. However, sensitive, specific and scalable biomarkers for in vivo pathological diagnosis are not available for most neurodegenerative neuropathologies. Here we present Proteomics-based Artificial Intelligence for Dementia Diagnosis (ProtAIDe-Dx), a deep joint-learning model on 17,187 patients and controls (age of 70.3 ± 11.5 years, 53.2% female), that uses plasma...

Breast cancer can develop over a wide age range and tumors in younger women differ from those in older women. Aging alters the spatial context of early tumors and may explain these differences, but breast tissue aging remains poorly characterized. Here, using imaging mass cytometry to profile the spatial expression of 40 proteins, we explore age-related remodeling of normal breast tissues in over 3 million cells from 527 reduction mammoplasties. Aged breast tissue was less cellular and less...

The coordination of proteostasis between the brain and peripheral tissues is essential for the health and survival of all animals. In C. elegans, glia coordinate organismal proteostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPR^(ER)). However, the signaling molecules required remain unknown. Here, we show that glial UPR^(ER) activation increases levels of specific neuropeptides. We identify a single neuropeptide, FLP-17, that is sufficient but not...

Mammals are constantly exposed to various stressors of internal and external origin. Though hair follicles (HFs) are exquisitely sensitive to stress, it remains largely unknown how stress-induced responses are linked with the intrinsic regulators of HF growth, cycling, and regeneration. Here, we characterize the long-range enhancer of Sonic hedgehog (Shh) gene which encodes a crucial mitogen in the HF, and identify a hair stress-responsive enhancer (HSRE) as a unified target on which various...

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In our society, the aging of the population is a major public health concern. Recently we have identified a new snoRNA (jouvence) in Drosophila, and showed that its deletion (F4) reduces lifespan, while its overexpression increases it. F4 deleted flies also present neurodegenerative lesions and a deregulation of metabolic parameters such as triglycerides and sterols. However, a deeper characterization of this genomic locus has revealed the presence of two additional snoRNAs. Here, we have...

Delirium is a common and severe neuropsychiatric syndrome with lasting cognitive consequences, yet its pathophysiology remains poorly understood. We hypothesize that impaired glymphatic flow represents a central mechanism by which delirium evolves. This hypothesis builds on recent evidence showing that major delirium risk factors, such as ageing, dementia, cardiovascular disease and renal failure, are all associated with reduced glymphatic clearance. Similarly, common delirium triggers,...

Sex differences in immune function arise from sex chromosome complement, which drives differential expression and activity of X-linked genes in immune cells, and gonadal steroids that transcriptionally regulate innate and adaptive immune cells through their respective receptors. These fundamental differences shape divergent outcomes between male and female individuals in viral and bacterial infections, post-acute infection syndromes and vaccine responses throughout the lifespan. Understanding...

Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly...

Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural,...

Age-related changes in synaptic function are central to the progression of brain pathologies, including neurodegenerative diseases, underscoring the need for experimental approaches that capture neuronal properties across the lifespan. However, obtaining high-quality tissue preparations from aged animals that permit combined structural and functional analyses of individual neurons is challenging due to increased tissue vulnerability. Here, we present a standardized protocol for acute brain slice...