Ageing research reviews最新文献

Nicotinamide adenine dinucleotide (NAD⁺) declines with age, motivating "NAD⁺-boosting" strategies ranging from lifestyle interventions to supplementation with NAD⁺ precursors (e.g., nicotinamide riboside [NR], nicotinamide mononucleotide [NMN]) and, in some wellness settings, parenteral NAD⁺ administration. We conducted a PRISMA-guided systematic review of peer-reviewed human and rodent intervention studies (January 2010-October 2025) evaluating NAD-related compounds administered orally or parenterally. We identified 113 eligible studies: 33 human intervention studies (28 randomized; 5 nonrandomized) and 80 rodent studies. In rodent models, NAD⁺ augmentation was frequently associated with improvements in metabolic, mitochondrial, inflammatory, and functional outcomes, although effects varied across models and endpoints. In humans, oral NR and NMN consistently demonstrated biochemical target engagement (circulating (plasma/whole blood) or cellular (e.g., PBMC) NAD-related metabolites) and were generally well tolerated over weeks to months; however, effects on functional, metabolic, vascular, and other healthspan-relevant outcomes were heterogeneous and often null or endpoint-specific. No eligible outcomes trials evaluated intravenous or intramuscular NAD⁺ itself for anti-aging or wellness indications. One nonrandomized intravenous NMN study met inclusion criteria and primarily contributed short-term safety and biomarker information. An intravenous NAD⁺ pharmacokinetic pilot lacking eligible clinical outcomes was identified as contextual evidence only. Overall, NAD⁺ augmentation shows clear biological activity, but clinical effectiveness for anti-aging or wellness outcomes remains inconclusive. Larger, well-designed randomized trials with longer follow-up and prespecified clinically meaningful endpoints are needed, particularly for parenteral approaches.

Ageing is a multidimensional and heterogeneous process that progresses asynchronously across organ systems. Advances in multi-omics technologies have led to the development of diverse ageing clocks, including epigenetic, proteomic, metabolomic, and imaging-based models, which extend beyond estimating crude biological age to more precisely capture organ-specific ageing trajectories and predict age-related diseases and mortality risk. Population-scale studies demonstrate substantial within-individual variation in organ-ageing rates, showing that accelerated ageing in specific organs and increased numbers of aged organs markedly contribute to systemic dysregulation and elevated mortality risk. Multi-organ-ageing clocks further highlight the role of organ crosstalk networks, such as cardiovascular-pulmonary-cerebral interactions, in shaping healthspan and survival. Building on these insights, we propose a conceptual artificial intelligence (AI)-driven multi-omics health platform that integrates clinical data, imaging, wearable sensors, and organ-specific ageing clocks to enable continuous monitoring of biological age and early risk detection. This platform supports stratified management, whereby individuals with mild ageing may benefit from lifestyle-based interventions, while those with accelerated or multi-organ ageing receive personalised pharmacological and clinical strategies. Together, multi-omics ageing clocks and AI-enabled analytics provide a transformative framework for understanding human ageing, shifting from single-organ assessment to network-level evaluation and precision anti-ageing interventions. These advances lay the groundwork for a scalable national health ecosystem aimed at extending healthy lifespan and reducing population-wide mortality risk.

Age-associated dysbiosis, marked by shifts in the composition of gut microbiota and gut microbiota-derived metabolites (GMDMs), is increasingly implicated in driving systemic low-grade inflammation during aging. The disrupted GMDM pools, including altered levels of short-chain fatty acids (SCFAs), secondary bile acids (BAs) and tryptophan (Trp) metabolites, lead to mucosal barrier dysfunction, immunometabolic dysregulation, and modulation of innate and adaptive immune cells. In turn, this cascade of events drives tissue degeneration, chronic inflammation, and the onset of age-related diseases (ARDs). Here, we summarize the immunomodulatory role of major GMDMs and how aging may increase susceptibility to ARDs through changing GMDMs. We then explore the latest findings linking altered GMDM profiles to immune dysfunction across major gut-organ axes, including the liver, adipose tissue, muscle, and brain. Last, we highlight recent advances in harnessing GMDMs as geromedicine to improve aging parameters and discuss the potential of artificial intelligence (AI) in accelerating the bench-to-bedside translation of GMDM research. Together, this review positions GMDMs as actionable targets in a dysbiosis-driven network of immune aging, offering new possibilities for the development of healthspan-extending precision geromedicine.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive memory loss and cognitive decline. With the global population ageing, the prevalence of AD continues to rise, posing a significant public health challenge. Historically, AD research has centred on two hallmark pathological features: β-amyloid (Aβ) deposition and tau protein hyperphosphorylation. However, repeated failures of therapeutic strategies targeting these pathways in clinical trials have prompted a paradigm shift toward a more integrated understanding of disease mechanisms. Accumulating evidence now demonstrates that neuroimmune dysfunction is not merely a secondary response but a central driver throughout AD progression, contributing to the initiation of pathology and perpetuating neuroinflammation, synaptic damage, and cognitive deterioration. This review highlighting the primary pathways involved in inflammation and neuroimmune dysregulation in AD, and the role of gut microbiota dysbiosis and systemic immunity in the pathogenesis. Furthermore, it discusses emerging neuroimmune-targeted intervention strategies such as activation of TREM2, CD33 antagonists or antisense oligonucleotides, aiming to provide a conceptual foundation for broadening mechanistic insights and guiding the development of novel therapeutic approaches.

In recent years, the immune metabolism of central nervous system cells has gained increasing attention from researchers. Microglia (MG) are innate immune cells of the central nervous system. They can metabolize a wide range of energy substrates. The pathways and products generated through these processes play a critical role in the onset and progression of Alzheimer's disease (AD). This paper provides a comprehensive review of metabolic reprogramming in MG during AD. It focuses on the three primary energy substrates: glucose, fatty acids, and amino acids. It delves deeply into the molecular signaling pathways that regulate this reprogramming, including TREM2, PI3K-AKT-mTOR, HIF-1α, AMPK, PPARs, and LXRs. Additionally, the paper explores the potential of metabolomics as a tool for early diagnosis of AD, identifying biomarkers that could enhance detection in its early stages. Therapeutic strategies targeting the regulation of microglial phagocytic function, mitochondrial activity, and glycolysis are also examined, highlighting their potential to alleviate disease progression. This review article aims to uncover the dynamic network of microglial metabolic reprogramming. It also explores its causal relationship with the pathological cascade of AD. The findings provide theoretical support for developing innovative drugs that combine metabolic regulation and neuroprotective functions.

As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.

While human lifespan has increased dramatically over the past century, the extension of healthspan, the period free of chronic age-related disease, has lagged behind. Blood flow and angiogenesis are significantly reduced in aging humans, playing a crucial role in mediating cardiovascular disease and heart failure - major causes of reduced lifespan. However, these mechanisms have not been studied as extensively as cellular and molecular mechanisms in animal models. Healthful aging, due to angiogenesis and improved blood flow, is the focus of this review. Here we considered 25 rodent models of healthful longevity. Seven of these had direct evidence of improved blood flow and angiogenesis contributing to enhanced exercise, preserved organ function and resistance to ischemic injury and heart failure. Four others exhibited mixed results, but did not show clearly improved blood flow and angiogenesis Fourteen models did not examine these mechanisms. The mechanisms mediating the improved angiogenesis and, as a result enhanced blood flow, include not only vascular growth hormones and mitochondrial protection, but also a role for a less well studied factor, namely brown adipose tissue (BAT). For example, a recently studied rodent model, the Regulator of G Protein Signaling 14 knockout mouse, exhibited a marked increase in angiogenesis and improved blood flow through a BAT mechanism, i.e., when BAT was removed, blood flow and angiogenesis were no longer improved, but when it was transplanted into wild type mice, blood flow and angiogenesis were enhanced. Given the potential importance of angiogenesis and improved blood flow, these factors need to be considered for future healthful longevity therapeutic translation.

Epigenetic alterations are an important shared hallmark of ageing and cancer. The development of epigenetic markers of ageing using blood DNA methylation data has been an active area of research. These markers have been used to assess disease risk, with potential to shed light on the complex link between ageing and cancer. We comprehensively summarised the literature on the most widely used and recently developed epigenetic markers of ageing, and synthesised the findings from studies that assessed their associations with cancer risk. Using data from eight cancer case-control studies (N_cases = 3,624) nested in the Melbourne Collaborative Cohort Study, we assessed and compared associations of these epigenetic ageing markers with cancer risk (including breast, colorectal, gastric, kidney, lung, blood, prostate, and urothelial cancers). While cancer is generally considered an ageing-related disease, the combined evidence suggested that epigenetic markers of ageing, including the most recently developed, showed generally weak associations with cancer risk and heterogeneous across markers and cancer types. The strongest associations were for lung cancer with GrimAge and its derivatives. Some associations, particularly those between mitotic clocks / stochastic epigenetic mutations and risk of blood cancer, were largely explained by underlying immune cell type heterogeneity, which was more prominent using finer cell type deconvolution. These findings indicate the potential for blood DNA methylation to help uncover the complex link between ageing and cancer and the need for new ageing markers to capture additional ageing features to improve disease risk prediction.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, chronic neuroinflammation, and dysregulation of multiple regulated cell death pathways. Aging, as the primary risk factor for AD, is accompanied by the accumulation of oxidative stress, which serves as a pivotal contributor to AD pathogenesis and is intricately linked to the activation of diverse cell death modalities, including ferroptosis, pyroptosis, apoptosis, and autophagy-endoplasmic reticulum stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a master regulator of cellular redox homeostasis. By binding to the antioxidant response element (ARE), Nrf2 orchestrates the transcriptional activation of a cytoprotective gene network, including heme oxygenase-1 (HO-1). Activation of the Nrf2/HO-1 signaling axis not only enhances cellular antioxidant defenses but also critically regulates iron metabolism, suppresses inflammatory cascades, mitigates endoplasmic reticulum stress (ERS), and modulates autophagic and apoptotic processes. This review delineates the interplay between distinct cell death modalities in AD and their convergence with age-associated oxidative stress. It provides a comprehensive analysis of the neuroprotective mechanisms mediated by the Nrf2/HO-1 pathway in counteracting ferroptosis, pyroptosis, apoptosis and autophagic endoplasmic reticulum stress dysregulation. Furthermore, we discuss the therapeutic potential of pharmacologically targeting this pathway with various bioactive compounds, highlighting promising strategies for multi-targeted intervention in AD, particularly in the context of aging.

Combating aging has become a central challenge in the life sciences, and myocardial aging, as a fundamental pathological process underlying the development and progression of various cardiovascular diseases, has become a key area in anti-aging research. In recent years, lactylation and methylation, two metabolism-dependent epigenetic modifications, have garnered increasing attention in the context of myocardial aging. Lactylation, mediated by lactate accumulation due to metabolic dysregulation, modifies lysine residues on both histone and non-histone proteins, thereby participating in the regulation of gene transcription, metabolic homeostasis, and inflammatory responses. In parallel, methylation affects gene expression, metabolic remodeling, and mitochondrial function through DNA, RNA, and histone modifications. This review systematically summarizes the regulatory mechanisms of lactylation and methylation in myocardial aging, with a particular focus on their interplay in histone and non-histone protein modification, metabolic regulation, and signaling pathway integration. Furthermore, we evaluate the potential of these reversible modifications as early epigenetic biomarkers and discuss multilayered intervention strategies targeting both lactylation and methylation. Such strategies highlight their translational potential in delaying myocardial aging and mitigating cardiovascular disease. Precisely modulating lactylation and methylation may offer novel theoretical frameworks and therapeutic targets for the prevention and treatment of myocardial aging.