Longevity Papers

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Chronic inflammation and aging skew hematopoiesis toward myelopoiesis at the expense of lymphoid output. We screened type 2 and anti-inflammatory cytokines to identify extrinsic signals capable of restoring lymphoid lineage commitment in hematopoietic stem and progenitor cells (HSPCs). Interleukin 4 (IL-4) specifically inhibited inflammation-induced myelopoiesis and shifted multipotent progenitor (MPP) differentiation toward the lymphoid lineage. IL-4 activated a signal transducer and activator of transcription 6 (STAT6)-dependent transcriptional program in MPPs, increasing the expression of lymphoid-specific genes. Mechanistically, the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3), which is highly expressed in MPPs, interacted with IL-4Rα to facilitate STAT6 activation. In vivo, IL-4 reversed inflammation-induced hematopoietic imbalance and accelerated lymphoid recovery. In aged mice, IL-4 administration shifted the MPP composition toward a lymphoid bias and restored B and T lymphocyte output. Long-term IL-4 treatment in aged mice improved immune, metabolic, physical, and cognitive functions; these rejuvenating effects were recapitulated by transplantation of IL-4-treated HSPCs. Promoting IL-4 signaling in MPPs may enable correction of hematopoietic dysregulation in inflammatory and aging-related conditions.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

Aging is a global issue that affects human health and increases disease risk. The traditional concept of the "age gap (AG)," defined as the difference between estimated biological age and an individual's chronological age, has been used for self-monitoring the risk of age-related diseases. However, the current AG does not account for the stratified aging patterns across different stages of chronological age, which may lead to biased or paradoxical interpretations of aging acceleration. To address these limitations, we propose Personalized-context-Aware Age Gap (PAAG), a robust metric to estimate aging acceleration, based on our new pre-training model AOE-Net (Age Order Enhanced Network). AOE-Net employs age-order enhanced contrastive learning on multi-omics data from healthy populations to learn latent representations that accurately reconstruct aging trajectories by capturing biological deviation rather than technical deviation in omics data. We demonstrate that PAAG, generated via fine-tuning AOE-Net, significantly outperforms AG of conventional first- and second-generation aging clocks in predicting clinical outcomes. This superior predictive power was validated across diverse age-related diseases and phenotypes: pan-cancer (overall survival), subclinical atherosclerosis (PESA score), and osteoporosis (bone mineral density). Crucially, PAAG serves as a context-aware metric that may improve the clinical outcome prediction of existing aging clocks. Furthermore, interpretive analysis of PAAG's molecular drivers revealed a strong functional enrichment for immune-response pathways, providing a shared mechanistic link between accelerated aging and disease. Collectively, PAAG could serve as a stable indicator of aging acceleration for clinically assessing age-related diseases, and AOE-Net provides an effective pre-training model for aging study and PAAG evaluation.

Brain maintenance may help explain why some individuals remain cognitively resilient despite aging, but its biological basis is not well understood. Here, we show that brain maintenance can be quantified from the relationship between brain structure and function. Using structural MRI and resting-state functional MRI from 1280 older adults, we built a model based on young adults to estimate the functional capacity supported by preserved brain structure, and defined brain maintenance as the difference between predicted and observed function. Brain maintenance was most evident in prefrontal, cingulate, and precuneus regions and was enriched in higher-order functional networks. Higher brain maintenance was associated with slower cognitive decline, lower amyloid-β burden, and domain-specific variation in memory, attention, and processing speed. These findings provide a biologically grounded marker of resilience in healthy and pathological aging.

Despite its strong regenerative capacity, liver aging paradoxically increases susceptibility to fibrosis and metabolic dysfunction-associated steatotic liver disease through dysregulated inflammation, senescence-associated secretory phenotypes, and immune-metabolic crosstalk. To systematically characterize these processes, we integrated longitudinal transcriptomics, single-cell RNA sequencing, and machine-learning approaches. We identified 252 aging-associated genes and developed an Aging Gene Score (AGS) to quantify senescence burden across hepatic cell populations. Single-cell analysis revealed macrophages as key drivers of fibrosis progression, with high-AGS myeloid subsets markedly expanded in cirrhotic livers. Using combined Boruta and LASSO algorithms, we established a five-gene biomarker panel (EFEMP1, LUM, DKK3, GPRC5B, NCAM2) that accurately predicts advanced fibrosis (AUC > 0.77). Furthermore, a network pharmacology framework was applied to screen medicine-food homology (MFH) herbs, identifying Fagopyrum dibotrys (Jinqiaomai) and Astragalus membranaceus (Huangqi) as top candidates. Molecular docking demonstrated strong binding between the bioactive compound MOL000098 and the fibrosis-related target COL3A1. Functional assays showed that Jinqiaomai-containing serum alleviates oxidative stress, improves HepG2 cell viability, reduces ALT and AST levels, and suppresses macrophage lipid accumulation, accompanied by reduced expression of inflammatory and fibrosis-related markers. Collectively, our findings highlight macrophage-centered mechanisms linking liver aging and fibrosis and suggest MFH-derived compounds as promising anti-aging and anti-fibrotic dietary interventions.

One of the most pressing scientific challenges of the current century is the mounting loss of cognitive function and vulnerability to neurodegenerative disorders associated with brain aging. This requires a paradigm shift beyond traditional neuron-focused models to address the central importance of non-neuronal glial cells, most notably astrocytes, in promoting age-related neuroinflammation. While the pro-inflammatory secretome of senescent cells, known as the senescence-associated secretory phenotype (SASP), is well-characterized in peripheral tissues, its specific role in the central nervous system remains a critical knowledge gap. This narrative review synthesizes current evidence to propose that the SASP of glial and vascular cells acts as a contributor mechanism, where it interacts with other aging hallmarks to amplify the pathological environment rather than acting as the sole link. Moving beyond standard biochemical signaling cascades, we propose conceptually transformative frameworks to explain central SASP aggression. The glymphatic-SASP traffic jam, establishing a bio-mechanical feedback loop where waste clearance failure traps secretomes in localized hotspots; and the metabolic energy vampire paradigm, demonstrating the active competition for resources between hyper-secretory glia and energy-starved neurons, were explored. Also, the innate immune mimicry triggered by retrotransposon awakening, explaining how unleashed genetic elements actively fuel self-propagating inflammation, and the loss of glial identity dictated by epigenomic state drift and SASP mosaicism were demonstrated. Furthermore, we evaluate the classic regulatory cross-talk between the SASP and nutrient-sensing pathways like AMPK and mTOR, and discuss the therapeutic potential of selectively targeting the SASP through senomorphics and metabolic resetters. Elucidating these complex, brain-specific SASP dynamics is paramount for translating these concepts into effective interventions against age-related neurological diseases.

Endogenous double-stranded RNAs (dsRNAs) are immunogenic self-molecules that drive aberrant immune activation under pathological conditions. Here, we show that dsRNAs and their regulation by RNA-binding proteins are key determinants of the fine balance between aging and immunity in Caenorhabditis elegans and cultured human cells. We find elevated levels of dsRNAs with organismal aging and cellular senescence. We identify a moonlighting function for phenylalanyl-tRNA synthetase, FARS-1/FARSA, as a key factor necessary and sufficient for extending lifespan by downregulating dsRNAs, in particular, mitochondrial dsRNAs. FARS-1/FARSA possesses a previously unrecognized dsRNA-binding domain and mediates dsRNA downregulation with the RNA helicase, RHA-2/DHX37, independently of its canonical role in translation. Notably, increased dsRNA expression resulting from genetic inhibition of fars-1/FARSA upregulates immune response-related genes and enhances innate immunity against pathogens. Our study establishes that FARS-1/FARSA is an evolutionarily conserved dsRNA-binding protein that delays aging and promotes longevity by suppressing dsRNA accumulation.

Nutrition, encompassing vital macro- and micronutrients (including carbs, proteins, fats, vitamins such as D and C, and minerals like iron and calcium), is fundamental to supporting life, fostering healthy ageing, and averting disease. The information on the combined impact of dietary patterns, nutritional content, and lifestyle factors on metabolic health, disease risk, and healthy ageing is summarised in this publication. According to the discussion, both macronutrient and micronutrient surpluses and deficiencies upset metabolic homeostasis, which leads to obesity, insulin resistance, cardiovascular disease, and hepatic steatosis. Dietary habits are one of the three cornerstones of health and longevity, according to biogerontological theories of ageing. The free radical theory emphasises oxidative stress in cellular damage, and the disposable soma hypothesis emphasises the trade-off between reproduction and somatic upkeep. Clinical and epidemiological data indicate that cardiometabolic outcomes, including elevated insulin sensitivity, lipid profiles, and inflammatory markers, are strongly influenced by diet quality, dietary timing (such as time-restricted eating), and overall energy balance. The review also demonstrates how nutrients can control gene expression, signalling pathways, and epigenetic alterations in addition to serving as energy sources. Nutrient availability and disease susceptibility are largely determined by interactions between the gut microbiota, food, and human metabolism. Furthermore, individual reactions to diet are very variable due to genetic, metabolic, and environmental factors, which explains why customised nutrition plans are becoming more and more popular. The findings also show that dietary habits during childhood and adolescence have an impact on long-term disease prevention, and that combining lifestyle treatments (diet and exercise) can consistently reduce the risk of chronic illness. In order to optimise health and wellness over the course of a lifetime, the data generally supports switching from reductionist, single-nutrient dietary methods to integrated, systems-oriented strategies that take into account molecular, clinical, and sociocultural factors.