Longevity Papers

The gut microbiota plays a pivotal role in modulating host physiology and longevity through the production of microbial-derived molecules. Among these, bacterial exopolysaccharides (EPS) represent a structurally diverse group of surface polysaccharides with emerging roles in regulating host well-being. Here, we investigated the role of Lactobacillus strains with the capability to produce EPS, using Caenorhabditis elegans as a model organism. Results revealed significant lifespan extension in worms fed with EPS-producing bacteria, accompanied by improved health-span markers such as enhanced pharyngeal pumping and reduced lipofuscin accumulation. Transcriptomic profiling identified robust upregulation of the host detoxification and immune defense pathways, highlighting the flavin-containing monooxygenase gene fmo-2, as one of the major mediators of longevity and stress resistance triggered by EPS-producing lactobacilli. The effect was confirmed using fmo-2p::GFP reporter animals and was abrogated in fmo-2, hlh-30, and nhr-49 mutant backgrounds. Mechanistically, we demonstrated that EPS acts through a conserved transcriptional network that primarily relies on the activation of nhr-49/PPAR-α, with purified EPS being sufficient to activate fmo-2 expression. Our findings reveal that bacterial EPS activates host xenobiotic pathways to modulate aging, positioning it as a potential tool for microbiota-based longevity interventions. These insights show how microbial products can modulate fundamental biological processes across species, opening new strategies for age-related health interventions.

Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer's disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations.

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.

Nutritional, genetic, and pharmacological interventions can extend lifespan; however, fewer have been shown to extend healthspan-the period of life free from chronic, debilitating diseases. In line with this, the molecular effectors that drive healthspan are even less understood than those responsible for lifespan extension. We recently reported that activation of Alcohol Dehydrogenase 1 (ADH-1) extends lifespan in yeast and C. elegans. In addition, adh-1 is transcriptionally activated in yeast, worms, mice, and humans in response to caloric restriction-an intervention that extends not only lifespan but also healthspan. Therefore, we investigated whether activating adh-1 could also extend healthspan. We demonstrate here that adh-1 activation has broad and robust effects on health, including resistance to age-related obesity, delayed sarcopenia, and attenuated neurodegeneration. Mechanistically, ADH-1-driven healthspan extension is associated with improved proteostasis. These findings position ADH-1 as a promising target for future research aimed at promoting healthy aging.

Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.

Bone marrow exhibits functional decline, yet cellular heterogeneity and molecular mechanisms remain unclear due to limitations of traditional research methods. This study aims to characterize age-related changes and identify key drivers in bone marrow. Integrated multi-omics analysis was performed using scRNA-seq, proteomics, pseudo-bulk transcriptomics, weighted gene co-expression network analysis (WGCNA)-based transcription factor (TF) network modeling, and CellChat analysis. Samples included 6 young and aged bone marrow specimens. Statistical validation involved differential expression analysis, Cox regression modeling, and receiver operating characteristic (ROC) curve analysis. A novel hematopoietic subpopulation (3.19% of aged samples) was identified, activating the cellular senescence pathway (KEGG) and enhancing inflammatory crosstalk with CD8⁺ T cells via NMU signaling (|avg_log2FC|> 0.58, p < 0.001). Pseudo-bulk and proteomic analyses identified CAPN1, MAP2K1, and JUND as potential signal modules. Immunohistochemistry and Western blot confirmed their co-expression, while molecular docking revealed interaction interfaces. In two independent bulk-RNA cohorts (n = 58), a Cox model based on the CAPN1-MAP2K1-JUND module showed robust predictive value for aging, with AUCs of 0.7507 (p = 0.0154) and 0.90 (p = 0.0274). This study identifies a pivotal molecular module linking single-cell dynamics to tissue-level senescence in bone marrow, providing new insights into aging mechanisms and potential therapeutic targets.

Exposure to microgravity induces a rapid and profound loss of bone mass, particularly in weight-bearing skeletal regions, closely resembling accelerated osteoporosis on Earth. Traditionally attributed to mechanical unloading, bone loss in space is now recognized as being strongly regulated by oxidative stress. Excessive production of reactive oxygen species (ROS)-driven by mitochondrial dysfunction, cosmic radiation, altered circadian rhythms, and fluid shifts-disrupts osteoblast differentiation, enhances osteoclastogenesis, and compromises osteocyte viability. These effects are mediated through redox-sensitive signaling pathways, including RANK/RANKL/OPG, Wnt/β-catenin, and MAPK, as well as transcriptional regulators such as NF-κB, ERK, and FoxO. Moreover, oxidative stress modulates epigenetic regulators, notably microRNAs and long non-coding RNAs, tipping gene networks toward apoptosis, autophagy dysregulation, and cellular senescence in bone cells. Beyond mechanistic insights, recent studies highlight the long-term persistence of skeletal deficits after spaceflight and reveal sex- and age-related vulnerabilities, particularly in postmenopausal women due to estrogen deficiency. These findings position oxidative stress as a central driver of skeletal deterioration with clear translational relevance to age-related osteoporosis. Current and emerging countermeasures target both the mechanical and redox dimensions of bone loss. Pharmacological strategies include antioxidants, bisphosphonates, NADPH oxidase inhibitors, mitochondrial stabilizers, and autophagy modulators. Nutritional interventions emphasize antioxidant-rich diets, vitamin D and calcium supplementation, and omega-3 fatty acids. Mechanical and biophysical countermeasures-resistance training, vibration therapy, and artificial gravity-remain essential, while innovative approaches such as redox-sensitive gene therapy, siRNA-based modulation, and mitochondria-targeted antioxidants offer new therapeutic avenues. By integrating mechanistic, epigenetic, and translational perspectives, this review underscores the centrality of redox imbalance in spaceflight-induced bone loss and identifies actionable targets for prevention. Ultimately, dissecting ROS-mitochondria-cell fate signaling provides a unifying framework for protecting astronaut skeletal health and advancing therapies for terrestrial osteoporosis.