Longevity Papers

Ovarian aging, characterized by declining ovarian reserve, is a pacemaker of aging in the female body. Oxidative stress leads to apoptosis, mitochondrial dysfunction, inflammation, and telomere shortening, accelerating ovarian aging. Scavenging reactive oxygen species (ROS) has been shown to delay ovarian aging; however, there remains a significant lack of antioxidants with both proven efficacy and minimal side effects. DNA tetrahedral nanostructure (DTN) is a promising nucleic acid framework with antioxidant and anti-apoptotic properties. We developed FSH-DTN, a modified nanoparticle equipped with a follicle-stimulating hormone receptor-targeting peptide (FSH33-53) to enhance ovarian accumulation. Compared to native DTN, FSH-DTN showed superior ovarian targeting efficiency as confirmed by in vivo imaging. In both in vivo and in vitro models of acute, subacute, and chronic ovarian aging, FSH-DTN demonstrated superior antioxidant, anti-apoptotic, and anti-aging effects. Further investigation revealed that FSH-DTN can directly eliminate ROS in the ovaries while enhancing ovarian antioxidant capacity by activating the NRF2 signaling pathway, thereby protecting ovarian function. In this study, we offer a new strategy for neutralizing oxidative stress to delay ovarian aging.

Osteoporosis is characterized by impaired bone formation and disrupted bone marrow homeostasis, largely driven by mitochondrial dysfunction in bone marrow mesenchymal stem cells (BMSCs). To address this, a live mitochondrial delivery system composed of CXCR4-engineered macrophages loaded with nanozyme-functionalized mitochondria (CM-MTBM). This system integrates bone-targeted migration, reactive oxygen species scavenging, and communication-mediated mitochondrial transfer. CM-MTBM restores mitochondrial respiration, enhances osteogenic differentiation, and alleviates oxidative apoptosis in BMSCs, thereby promoting metabolic recovery and redox balance. In osteoporotic mice, CM-MTBM treatment markedly improved the trabecular bone microarchitecture and promoted osteogenic repair. Single-cell transcriptomic analysis further revealed the enrichment of osteogenic BMSC subpopulations and functional reprogramming of the bone marrow immune-metabolic microenvironment. Mechanistically, CM-MTBM activated mitochondrial oxidative metabolism while suppressing inflammation and senescence-associated signaling, achieving coordinated metabolic and osteogenic activation. Collectively, this work established a communication-driven mitochondrial transfer paradigm that reframes mitochondrial therapy from passive structural supplementation to communication-driven metabolic reprogramming, establishing a conceptual and technological framework for precision treatment of metabolic bone disorders.

Foxp3+ regulatory T cells (Tregs) maintain immune homeostasis, yet the process that preserves their stability during aging remain unclear. Mechanistic progress has been hindered by models that ablate Tregs or delete Foxp3, which induce acute autoimmunity and prevent longitudinal study of physiological regulatory drift. Here, we establish a dose-dependent mitochondrial framework that preserves Treg lineage survival while permitting gradual metabolic attenuation. Using Treg-restricted TFAM modulation, a complementary haploinsufficient model, and whole-spleen single-cell profiling. We identify lineage-selective immune remodeling characterized by contraction of naive CD8+ and follicular B-cell pools, alteration of CD4+ states, expansion of activated Tregs, and emergence of neuroimmune stress linked transcriptional modules that parallel physiological aging. Mechanistically, mitochondrial insufficiency is associated with functional loss of FOXP3 centered chromatin coordination and enrichment of NF-kB/NFAT/AP-1 inflammatory and senescence programs while lineage identity remains detectable. Partial mitochondrial attenuation within Tregs alone is sufficient to drive chronic low-grade systemic inflammation, neuromuscular decline, gut microbial restructuring, and elevated microglial responsiveness without Treg depletion. Pharmacologic and microbiota-directed interventions partially reduce inflammatory tone and improve functional metrics. Together, our findings identify TFAM as a key regulator of immune aging and reveal that healthy mitochondrial function in Tregs is essential for protecting against inflammaging and age-associated functional decline.

Efforts to rejuvenate age-related cognitive decline have predominantly targeted neurons, often overlooking non-neuronal cell types in the aging brain. Here, we show that countering alterations in oligodendrocyte-derived extracellular matrix (ECM) in the aging hippocampus restores cognition. We identify broad age-associated transcriptional and proteomic changes in oligodendrocytes, including dysregulation of the matrisome, with marked upregulation of ECM components and associated regulators with age. Among these, we detect an increase in Hyaluronan and proteoglycan link protein 2 (HAPLN2), an oligodendrocyte-derived core matrisome protein that locates specifically at the nodes of Ranvier, in the hippocampus of aged mice and older humans. Hapln2 overexpression in oligodendrocytes of young mice recapitulated age-related memory impairments. Conversely, abrogating the age-related increase in Hapln2 induced synaptic plasticity-related hippocampal transcriptional signatures and improved memory in aged mice. Together, these data define oligodendrocyte-derived ECM remodeling as a hallmark of brain aging that can be targeted to rescue cognitive decline.

Aging is associated with progressive changes of cellular functional states, but whether these changes arise from novel programs or from distortion of normal developmental trajectories often remains unclear. Here, we investigate this question in the context of human immune aging by analyzing age-associated changes in CD4 T cells at single-cell resolution. We show that CD4 T cell subsets accumulate senescence-associated features at different rates and that the naive CD4 T cell compartment is highly heterogeneous with respect to senescence markers. Strikingly, transcriptional changes associated with aging of naive CD4 T cells parallel those observed during normal post-thymic maturation from recent thymic emigrants (RTE) to mature naive cells. This similarity defines a transcriptional aging trajectory that we term overmaturation, characterized by exaggerated execution of a physiological maturation program. This overmaturation is consequential for T cell function, as we demonstrate through perturbation of transcription factor TOX, which is predominantly expressed in RTE and whose expression decreases with age. Together, our findings identify transcriptional overmaturation as a major trajectory of naive CD4 T cell aging and suggest that aging-associated distortion of developmental programs can strongly contribute to immunosenescence.

Osteoarthritis (OA), a leading cause of disability worldwide, impacts over 300 million people through progressive joint degeneration marked by chronic pain and functional impairment. A key driver of osteoarthritis progression is synovitis, characterized by inflamed synovial tissue harboring senescent fibroblasts and pro-inflammatory macrophages. These senescent cells secrete senescence-associated secretory phenotype (SASP) components, includining cytokines and proteases, which drive macrophage polarization toward a pro-inflammatory M1 state. Simultaneously, M1 macrophages release reactive oxygen species (ROS) and inflammatory mediators, amplifying cellular senescence and establishing a pathological feedback loop. Unfortunately, conventional single-target therapies, such as senolytics or macrophage modulators, fail to address this interdependence vicious cycle. Herein, guided by bioinformatics analysis integrated with clinical and murine specimen data, we developed an easy-to-produce combinatorial nanomedicine platform comprising: (i) synovium-targeting liposomes delivering senolytics to clear senescent fibroblasts and suppress SASP, and (ii) M2 macrophage-derived exosomes to convert M1 macrophages into regenerative M2 phenotypes. In rat OA models, this dual approach combined disrupted the senescence-inflammation cascade, achieving 73.53% synovitis index reduction and 75.00% OARSI score reduction. In summary, by concurrently clearing SASP-producing senescent cells and pro-inflammatory M1 macrophages, our strategy restores joint homeostasis and presents a translatable framework for treating age-related inflammatory disorders.

Different neuron types show distinct susceptibility to age-dependent degeneration, yet the underlying mechanisms are poorly understood. Here we applied aging clocks to single neuron types in Caenorhabditis elegans and found that distinct neurons differ in their biological age. Ciliated sensory neurons with high neuropeptide and protein biosynthesis gene expression show accelerated aging and degeneration, correlating with loss of function, which could be prevented by pharmacological inhibition of translation. We show that the C. elegans neuronal aging transcriptomes correlate with human brain aging patterns and anticorrelate with geroprotective interventions. We performed an in silico drug screen to identify potentially neuroprotective small molecules. We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration, and propose these compounds as neuroprotective interventions. Furthermore, we identify neurotoxins that accelerate neurodegeneration, indicating that distinguishing aging trajectories between neuron types can inform on protective interventions as well as risk factors.

Cellular aging is characterized by progressive changes in gene expression that contribute to tissue dysfunction; however, identifying genes that regulate the aging process, rather than merely serve as biomarkers, remains a significant challenge. Here we present PRISM (Pseudotime Reversion via In Silico Modeling), a computational pipeline that integrates pseudotime trajectory analysis with Boolean network analysis to identify cellular rejuvenation targets from single-cell RNA sequencing data. We applied PRISM to a published dataset of human skin comprising 47,060 cells from nine donors aged 18 to 76 years. Analysis of keratinocytes revealed two distinct aging trajectories with fundamentally different regulatory architectures. One trajectory (labeled Y_272) exhibited "aging as convergence," where cells were driven toward a single dominant aged attractor (aging score +2.181). A second trajectory (labeled Y_308) exhibited "aging as departure," where cells escaped from a dominant youthful attractor basin (aging score -0.536). Systematic perturbation analysis revealed a critical distinction between genes exhibiting age-related expression changes (phenotypic markers) and genes controlling attractor landscape architecture (regulatory controllers). Switch genes marking the aging trajectories proved largely ineffective as intervention targets, while master regulators operating at higher levels of the regulatory hierarchy produced substantial rejuvenation effects. BACH2 knockdown was identified as the dominant intervention for Y_272, shifting the aging score by {Delta}=-3.746 (98.9% improvement). ASCL2 knockdown was identified as the top target for Y_308, with synergistic enhancement observed through combinatorial perturbation with ATF6. These findings demonstrate that attractor-based analysis identifies different and potentially superior therapeutic targets compared to expression-based approaches and provide specific hypotheses for experimental validation of cellular rejuvenation strategies in human skin.

The nuclear envelope (NE) is essential for cellular homeostasis, yet its integrity declines with age, accelerating functional deterioration. Here we report a mitochondria-to-NE signalling pathway that safeguards NE integrity through redox-dependent lipid metabolism. In Caenorhabditis elegans, reducing mitochondrial ETC activity preserves NE morphology during ageing. This effect requires developmental mitochondrial superoxide, which downregulates SBP-1 (SREBP orthologue) and suppresses unsaturated fatty acid biosynthesis. The resulting reduction in unsaturated fatty acid levels limits lipid peroxidation, thereby preserving NE structure. Interventions targeting lipid peroxidation preserve NE integrity, extend lifespan in worms and ameliorate senescence-associated phenotypes in human fibroblasts and monkey cells mimicking Hutchinson-Gilford progeria syndrome disease. Our findings reveal a previously unrecognized role for mitochondrial superoxide as a protective developmental signal that programs long-term NE integrity. This work establishes lipid peroxidation control as a conserved strategy to delay nuclear ageing and highlights redox-lipid cross-talk as a therapeutic axis for healthy ageing.

Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimer's Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain.