Zuogui pill ameliorates DNA damage and the senescence-associated secretory phenotype in ovarian stem cells to delay ovarian ageing through activation of SIRT1.

Cellular senescence in neurodegenerative diseases: A bibliometric analysis and mechanistic synthesis linking translational pathways to therapeutic implications.

Osteoarthritis (OA), a leading cause of chronic disability worldwide, is increasingly recognized to be driven by the accumulation of senescent chondrocytes (sCDs) and their deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Existing therapies, including senolytics and senomorphics, lack cell-specific targeting and fail to neutralize the heterogeneous components of SASP. Here, we develop a dual-engineered macrophage membrane camouflaged, self-assembled nanoplatform (BS@MD) that combines senolytic and senomorphic functions synergistically. Within the OA microenvironment, BS@MD acts as a "nanosponge" to broadly neutralize SASP through overexpressed cytokine receptors derived from LPS-primed macrophage membranes. This process alleviates chondrocyte senescence and facilitates the phenotypic shift of pro-inflammatory M1 macrophages toward an anti-inflammatory M2 state. Additionally, surface conjugation with an anti-DPP4 antibody enables BS@MD to selectively target sCDs and disassemble in the acidic lysosomal environment, releasing bortezomib (BTZ) and sabutoclax (Sab). These agents act synergistically to inhibit the NF-κB and BCL-2 pathways, thereby inducing sCDs apoptosis and suppressing SASP production, effectively disrupting the senescence-inflammation feedback loop. In the anterior cruciate ligament transection (ACLT)-induced OA mouse model and naturally aged OA mouse model, BS@MD enhances joint retention, reduces cartilage degradation and inflammation, and promotes cartilage homeostasis. Overall, this work pioneers a dual-pronged senotherapeutic strategy for non-surgical OA management.

Age-associated regulation of chondrocyte hypertrophy in osteoarthritis: Mechanisms, therapeutic implications, and cartilage fate reprogramming.

CD8+ TEMRA cells: A double-edged sword in immunity and disease-Mechanisms and therapeutic targets.

Genome-wide CRISPR/Cas9 screen identified MCL1 as a senolytic target for clearing palbociclib-induced senescent and PD-L1-positive cells in colorectal cancer.

Glial dynamics in brain aging: Cellular heterogeneity and regional vulnerability.

Neighborhood opportunity and cellular senescence in a national sample of U.S. adults.

The STAT3 paradox in aging: Molecular mechanisms and targeted therapeutic strategies.

How molecular mechanisms of aging drive Alzheimer's disease pathology.

The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.

Lactylation: Unlocking the regulatory code of exercise-mediated anti-aging.

Renal inflammaging: Mechanisms, pathophysiology and therapeutic prospects.

Lipid metabolic reprogramming regulates macrophage senescence in the tumor microenvironment.

Inflammaging in Geriatric Liver Disease: Mechanistic Insights and Therapeutic Frontiers.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by unresolved inflammation, yet precise mechanisms linking immune metabolism to disease progression remain elusive. Here, we identified myeloid-expressed Mas, a G protein-coupled receptor, as a critical metabolic checkpoint in MASLD. Mas expression is elevated in hepatic myeloid cells from patients and diet-induced mouse models. Myeloid-specific Mas1 deletion attenuated MASLD by restraining glycolytic reprogramming and inflammatory senescence. Single-cell RNA sequencing analyses revealed that this deletion specifically impaired the glycolytic flux and subsequent pathogenic differentiation of FN1⁺CCR2⁺ monocyte precursors. Mechanistically, Mas interacts with the glycolytic enzyme PKM2, enhancing lactate production that drives lactylation of the transcription factor Spi1 at lysine 208. Spi1-K208 lactylation promotes its nuclear localization and transcriptional activation of senescence-associated secretory phenotype (SASP) genes. Myeloid-specific Pkm2 ablation phenocopied the protective effect of Mas1 deletion, and PKM2 overexpression rescued the metabolic and transcriptional defects caused by Mas loss. Virtual screening identified theaflavin-3,3'-digallate (TFDG) as a Mas inhibitor that disrupts the Mas-PKM2 interaction. A macrophage membrane-coated nanoparticle (MM@NP-TFDG) delivered TFDG specifically to hepatic macrophages, suppressed the Mas-PKM2-Spi1 lactylation axis, and ameliorated MASLD pathology in vivo. Our findings define a novel Mas-PKM2-Spi1 lactylation axis that orchestrates glycolytic reprogramming, monocyte precursor differentiation, and macrophage-driven inflammation in MASLD, presenting a targeted nanotherapeutic strategy for its treatment.

Osteoarthritis (OA) is an age-related disease characterized by cartilage degeneration, subchondral bone remodeling, and chronic low-grade inflammation, with knee osteoarthritis (KOA) being a leading cause of functional impairment and reduced quality of life in middle-aged and elderly individuals. In recent years, advances in stem cell biology and aging research have highlighted the critical role of mesenchymal stem cells (MSCs) in maintaining joint homeostasis, regulating inflammatory responses, and mediating cartilage repair. Accumulating evidence indicates that reductions in MSC quantity and functional decline-particularly age-associated decreases in proliferative capacity, impaired differentiation potential, mitochondrial dysfunction, and activation of the senescence-associated secretory phenotype (SASP)-constitute key biological mechanisms driving KOA onset and progression.This review systematically summarizes the major molecular mechanisms underlying MSC senescence, including telomere shortening, DNA damage accumulation, mitochondrial dysregulation, and SASP activation, and emphasizes the roles of senescent MSCs in impaired cartilage regenerative capacity, disruption of extracellular matrix homeostasis, and imbalance in inflammatory and immune microenvironments. Additionally, we highlight recent research on potential interventions targeting MSC senescence, including senescent cell clearance, metabolic and mitochondrial restoration, MSC-derived exosome therapy, and advances in engineered culture and delivery technologies.In conclusion, MSC senescence represents not only a fundamental pathological basis for KOA development but also a critical target for future OA interventions, providing important theoretical and translational value for advancing regenerative medicine strategies toward clinical application.

ABSTRACTSenescent cells accumulate with age following stress‐induced cell cycle arrest triggered by DNA damage, oncogene activation, and replicative exhaustion. While they contribute to tissue repair and tumor suppression, their persistent senescence‐associated secretory phenotypes (SASPs) drive age‐related diseases. The heterogeneity of senescent cell populations, particularly the distinction between primary and secondary senescence, remains incompletely understood at single‐cell resolution. Here, we established models of primary senescence by X‐ray irradiation of human renal epithelial cells and secondary senescence by exposing proliferating cells to conditioned media from primary senescent cells. Single‐cell RNA sequencing revealed structured transcriptional trajectories culminating in distinct terminal clusters in primary (C5, C6, and C8) and secondary (C3, C5, and C7) senescence. Primary senescence preferentially converged on extracellular matrix‐ and fibrosis‐associated programs, whereas secondary senescence exhibited more inflammatory and signaling‐responsive programs, while both contexts shared a partially overlapping transcriptional module enriched in stress‐response and cytokine‐related transcriptional modules. We identified subtype‐associated genes distinguishing primary from secondary senescent cells, as well as candidate transcriptional regulators—such as HMGA1, NFKB1, and JUNB—associated with conserved and context‐specific senescence programs. This study provides a single‐cell‐resolved transcriptional map of divergent and shared molecular features relevant to renal aging and disease.

ABSTRACTThe genotoxic agent doxorubicin induces premature vascular aging, defined by vascular endothelial dysfunction and aortic stiffening. Excess vascular cell senescence and the accompanying senescence‐associated secretory phenotype (SASP) are key mechanisms underlying doxorubicin‐induced vascular dysfunction, in part, by promoting excess mitochondrial oxidative stress, which reduces the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed if the natural senolytic fisetin mitigates doxorubicin‐induced cellular senescence and the SASP to improve vascular function following doxorubicin administration and explored the underlying mechanisms. Young adult (6 months) mice were treated with doxorubicin, followed by oral, intermittent fisetin supplementation (100 mg/kg/day; 1 week on treatment–2 weeks off treatment–1 week on treatment). Vascular endothelial function, aortic stiffness, cellular senescence markers, SASP expression, NO bioavailability, and mitochondrial oxidative stress were assessed. Parallel experiments in human aortic endothelial cells were conducted to provide further mechanistic insight. Fisetin mitigated excess vascular cell senescence and the SASP in young mice administered doxorubicin and reversed doxorubicin‐induced endothelial dysfunction (p < 0.001) and aortic stiffening (p < 0.001), in part through suppression of excess cellular senescence, higher NO bioavailability, and lower mitochondrial oxidative stress. Modulation of the circulating SASP (plasma) also contributed to the observed vascular improvements with fisetin. In vitro, fisetin reduced cellular senescence in doxorubicin‐exposed endothelial cells, supporting isolated artery and in vivo observations. These findings identify oral intermittent fisetin supplementation as a promising therapeutic strategy for targeting excess cellular senescence to improve vascular function in settings of premature vascular aging.

Skin aging is an inevitable biological process caused by cellular senescence and overexposure to harmful environmental factors such as ultraviolet (UV) radiation. Senescent fibroblasts with proliferation arrest, mitochondrial dysfunction and nicotinamide adenine dinucleotide phosphate (NADPH) depletion have been proposed as a major mechanism driving skin photoaging, but the specific therapies are currently lacking. Inspired by the self-powering potential of plant-derived photosynthetic system, we herein fabricated a novel nanophotosynthetic platform that integrated Chlorella-derived nanothylakoid units (NTUs) with hyaluronic acid (HA)-based microneedles (MNs) to specifically target senescent fibroblasts for treating skin photoaging. By equipped with photosynthesis (PS)-I/II and quinolinate phosphoribosyltransferase (QPRT), the NTU-MN photosystem remarkably increased mitochondrial biogenesis and adenosine triphosphate (ATP) generation, resumed NAD(P)H pool and increased cellular anabolism, addressing the heighted bioenergetic and biosynthetic requirement for highly turnover of fibroblasts during photoaging. Furthermore, with skin penetrating ability of MNs and camouflaging of fibroblast membranes, topical application of the nanophotosystem facilitated the intradermal release of NTUs, leading to regeneration of damaged tissues, increased collagen synthesis, decreased senescence-associated secretory phenotype (SASP), and hence alleviated photoaging of skin. Thus, we developed a "green nanoplatform" with significantly anti-aging efficacy, biocompatibility, and biosafety, opening new avenues for light-driven therapies for degenerative diseases.