Biogerontology最新文献

A newly identified specific category of non-coding RNA (ncRNA), circRNAs, is drawing interest for their role in controlling several biological processes including muscle regeneration, aging, and adaptation to physical activity. Unlike linear RNAs, circRNAs are very stable and can have long-lasting regulatory impact since they create a covalently closed loop structure. Emerging evidence indicates that circRNAs play a pivotal role in skeletal muscle biology by regulating myogenesis, satellite cell activation, protein synthesis, and cellular senescence-processes significantly influenced by aging. These molecules are crucial for muscle function and regeneration, acting as microRNA sponges, interacting with RNA-binding proteins, and modulating gene expression and translation. Exercise-especially resistance and endurance training-has been shown to change circRNA expression in skeletal muscle, therefore possibly reducing age-related muscle loss and improving regenerative capacity. Though encouraging, much of the circRNA in muscle biology research is still in its early stages, with few functional studies and varying outcomes across various species and exercise models. Moreover, the exact ways circRNAs affect muscular adaptation to exercise and stop aging-related degeneration are still not completely known. This review addresses the existing knowledge gaps regarding the potential therapeutic applications of circRNAs in combating muscle degeneration and sarcopenia, as well as their role in muscle health and aging.

Aging, a complex physiological and molecular process, has undergone significant changes, of which gut microbiome composition has surfaced as an important key in the maintenance of neurological health. Recent studies have revealed the significant impact of age-related gut dysbiosis in the induction of neuroinflammation, metabolic syndrome, disruptions in gut-brain axis, and age-related neurological decline. Although significant studies have revealed the impact of the microbiome-gut-brain axis in individual neurological diseases, an aging-focused holistic synthesis has not yet been adequately developed. This review provides a critical assessment of the involvement of age-related dysbiosis of gut microbiota in the development and progression of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cognitive aging of the elderly, and to focus on age-related microbial patterns and mechanisms of dysbiosis related to neurological aging, including inflammation and immune system dysregulation, metabolic changes, oxidative stress, barrier dysfunction, and gut-brain communication through enteroendocrine, enteric neural, and vagal mechanisms, and to emphasize disease-specific and common microbial patterns of dysbiosis and beneficial and harmful microbial roles in aging diseases. This review assesses some of the latest promising therapies aimed at the microbiota, such as probiotics, prebiotics, dietary therapies, fecal microbiota transplantation, as well as pharmacological therapies, and critically discusses their limitations in terms of interindividual variability and their generalisation and applicability. Focusing on mechanistic, comparative, and translation aspects, this review offers a comprehensive approach to neurological aging due to gut microbiota and identifies gaps for future precision microbiome-based interventions.

The Shaker (Sh) gene in Drosophila melanogaster encodes a voltage-gated potassium channel that regulates neuronal excitability and is well known for its role in sleep regulation; however, its contribution to cardiac physiology and neurocardiac communication remains insufficiently explored. In this study, we investigated how two Sh-mutations (Sh^mns and Sh⁵) influence heart function and sleep/circadian behaviors to identify potential age-dependent neurocardiac interactions. Cardiac performance and sleep/activity were examined across aging cohorts under normal conditions, circadian disruption, and with or without time-restricted feeding (TRF). Sh^mns mutants exhibited progressive cardiac decline with age, including increased heart period, elevated arrhythmicity, extended systolic and diastolic intervals, reduced contraction rate, and overall impaired cardiac output, along with disorganization of actin-rich myofibrils. These defects paralleled severe sleep loss and hyperactivity, suggesting a tight link between sleep/circadian dysregulation and cardiac impairment. Circadian misalignment further worsened both behavioral and cardiac deficits, whereas TRF partially improved select abnormalities, indicating feeding-time modulation of Sh-related phenotypes. Tissue-specific knockdown of Sh in cardiac and neuronal tissues recapitulated key mutant features, and notably, neuronal knockdown alone impaired cardiac behavior, supporting a functional neurocardiac regulatory axis mediated by Shaker-dependent electrical signaling. Together, these results demonstrate that Shaker channels contribute to an age-sensitive interplay between sleep/circadian regulation and cardiac homeostasis in Drosophila. Although direct extrapolation is limited, parallels with KCNA1-associated cardiac and neuronal abnormalities in humans suggest conserved Kv channel functions in neurocardiac dysfunction. Overall, this study identifies Shaker as a critical mediator of aging-, feeding-, and circadian-sensitive cross-tissue regulation of cardiac function, providing broader insight into mechanisms underlying neurocardiac communication. Our study establishes Shaker as a critical mediator of aging, circadian-sensitive, cross-tissue physiological regulation of cardiac function.

Replicative senescence frequently occurs in in vitro cell cultures and certain in vivo pathological conditions, characterized by multiple phenotypes, including cell cycle arrest. Previous studies suggested that the main mechanism underlying replicative senescence is that under continuous subculture, cells sense DNA damage during G1, which triggers G1/S arrest and the subsequent geroconversion. However, this explanation does not account for phenomena such as how DNA damage caused by replication stress in the mother cell directly affects the G1/S transition in the daughter cell. Recent advances in single-cell analysis techniques have enabled more detailed investigation of the G1/S transition process, leading to the development of new models. The updated model extends the window for cells to sense DNA damage from daughter G1 backward to mother G2, significantly prolonging the period during which DNA damage can regulate the G1/S transition. Despite these developments, the mechanistic understanding of replicative senescence has not been comprehensively revised based on the updated model. Therefore, this review systematically elaborates on the key process of G1/S arrest in inducing replicative senescence, based on the existing evidence: DNA damage accumulated during continuous passaging activates the p53-p21 and p16-Rb pathways at different cell cycle stages. The p53-p21 pathway promotes the initiation and progression of replicative senescence by primarily inactivating cyclin-dependent kinase complexes during mother G2 and daughter G1, thereby temporarily arresting the cell cycle. In the final stages of replicative senescence, the p16-Rb pathway predominantly substitutes for p21 to enforce an irreversible cell cycle arrest. The geroconversion process associated with these pathways ultimately facilitates the emergence of diverse senescence phenotypes.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 (Aβ42) neurotoxic peptides that cause oxidative stress and neurodegeneration. The current study examined the neuroprotective properties of salvianolic acid A (SalA), an antioxidant polyphenol, in a Drosophila melanogaster model of AD. Transgenic flies expressing human Aβ42 were assayed for eye morphology, life span, and locomotor function after SalA diet supplementation. RNA-seq and RT-qPCR were used to quantify transcriptional regulation with SalA treatment. Aβ42 expression resulted in classic AD phenotypes, including retinal degeneration, shortened lifespan, and compromised climbing ability. Partial rescue of the rough-eye phenotype, significant prolongation of lifespan, and improved locomotor function in aging flies were induced by SalA treatment. Transcriptome profiling showed the upregulation of glutathione metabolism-associated, cytochrome P450 activity-associated, and antioxidant defence-associated genes, while muscle development-associated, cell adhesion-associated, and apoptosis-associated genes were downregulated. Network analysis identified a SalA-responsive gene module enriched in detoxification and immune pathways that was conducive to enhanced cellular resistance to Aβ42 toxicity. These findings identify a redox-regulated aging mechanism whereby SalA maintains neuronal and systemic homeostasis during aging. SalA inhibits Aβ42-induced neurotoxicity in Drosophila via promoting redox equilibrium and detoxification. These findings present SalA as a potential multi-target lead drug for AD and other age-related neurodegenerative diseases.

FOXOs constitute a class of evolutionarily conserved transcription factors that play pivotal roles in diverse cellular processes, including glucose and lipid metabolism, energy homeostasis, oxidative stress response, and autophagy. They are recognized as central regulators of longevity. This review details the mechanisms linking FOXO to aging. FOXO activity is regulated via nucleocytoplasmic shuttling, a process controlled by phosphorylation and dephosphorylation through the insulin/insulin-like growth factor (IIS) signaling pathway. This shuttling influences the expression of aging-related genes, thereby modulating aging-related phenotypes in tissues such as muscle and liver. Furthermore, FOXO can also regulate the autophagy pathway through multiple mechanisms: On one hand, it transcriptionally activates core autophagy genes such as Ulk2 and Becn1; on the other hand, it enhances autophagic activity by modulating miRNAs or epigenetic modifications, thereby promoting the elimination of damaged cellular components, and ultimately delaying organismal aging. Moreover, as a key sensor of oxidative stress, FOXO is activated by reactive oxygen species (ROS), thereby inducing the expression of antioxidant enzymes that mitigate oxidative damage and delay cellular aging. This review provides an in-depth exploration of the dual roles of FOXO in various aging-related diseases. This includes neurodegenerative diseases (such as Huntington's disease, Parkinson's disease, and Alzheimer's disease), metabolic disorders (such as type 2 diabetes), and various cancers. Meanwhile, this review also discusses drugs targeting the FOXO pathway in recent years (such as canagliflozin, metformin, resveratrol, and berberine). These FOXO-targeting compounds demonstrate great potential in improving metabolic disorders and delaying the onset of aging phenotypes.

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aging serves as the predominant risk factor. Emerging research underscores the importance of bile acids (BAs), traditionally recognized for their role in digestion, as key signaling mediators involved in both systemic metabolism and neural communication. Disruption of bile acid (BA) metabolism during aging arises from altered hepatic synthesis, gut microbial imbalance, and defective receptor signaling. These changes have been implicated in several neurodegenerative processes, including Aβ accumulation, tau protein abnormalities, mitochondrial impairment, and disturbances in immune regulation. Aging induces a shift in BA composition toward more cytotoxic species, contributing to blood-brain barrier disruption and enhanced neuronal damage. Multi-omics analyses have identified distinct BA signatures in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and AD. These alterations show strong correlations with brain atrophy and progressive cognitive decline. Experimental and early clinical findings suggest potential neuroprotective effects of hydrophilic BAs such as ursodeoxycholic acid and tauroursodeoxycholic acid, along with therapeutic opportunities through modulation of BA receptors and microbiome-driven BA regulation. In the current era of AD research, the gut-liver-brain BA axis emerges as a novel mechanistic framework linking systemic metabolic aging to neurodegeneration. This review examines the molecular pathways through which BA dysregulation influences aging and AD, emphasizing its therapeutic relevance and supporting the development of biomarker-based and precision medicine approaches for neurodegenerative disorders.

The gastrointestinal (GI) barrier maintains gut homeostasis by regulating nutrient absorption and preventing the entry of harmful agents. While its disruption has been linked to chronic disease, stress and dietary lifestyle, the role of aging in intestinal permeability remains subject of debate. Understanding how aging and age-associated inflammation affect barrier integrity is crucial for promoting GI health in the elderly. In this study, we used the Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice and their normally aging Senescence-Accelerated Mouse-Resistant 1 (SAMR1) counterparts to investigate GI homeostasis at 2, 5, 9 and 11 months of age under basal conditions and during chronic colitis induced by repetitive dextran sodium sulphate (DSS) treatment. Until 9 months of age, no histological deviations were observed in either strain. At 11 months, SAMP8 mice exhibited low-grade colon inflammation marked by immune cell infiltration, including neutrophils and macrophages, and elevated expression levels of pro-inflammatory genes (Il1b, ccl5, cxcl1, cxcl10, Tnf and Saa3), while GI barrier function remained intact. However, after DSS-induced chronic colitis, aged SAMP8 mice showed a heightened disease activity index and intestinal hyperpermeability, unlike age-matched SAMR1 mice. Mechanistically, this impaired GI barrier recovery correlates with aberrant STAT3 signaling. Notably, SAMP8 mice exhibited increased epithelial proliferation and macrophage abundance at baseline, which did not further increase after DSS treatment. In conclusion, our findings support the notion that aging alone does not compromise GI barrier function but rather predisposes the gut to barrier dysfunction upon inflammatory challenge due to impaired resolution mechanisms.

Locomotion in animals depends on muscle activity, controlled by the central nervous system. The neuromuscular junctions (NMJs) are specialized synapses pivotal in neural control of muscle function. Declining muscle function is a characteristic of aging (sarcopenia), and gradual loss of NMJ function could contribute to sarcopenia. The NMJs are cellular ensembles comprising presynaptic axon terminals, postsynaptic muscle cell, and the perisynaptic glial cells, and a coordination between these components is essential for NMJ development and functioning. At the molecular level, gene expression regulation is fundamental to drive these coordinated cellular processes. Though RNA-binding proteins (RBPs) have emerged as a major class of regulatory factors and are also implicated in several neuromuscular disorders, there is no comprehensive understanding of their potential involvement in aging-associated loss of muscular activity. The present study aimed at analysing the expression levels of RBP transcripts showing differential expression patterns during aging and are conserved in Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Mus musculus, and Homo sapiens. DDX helicases from D. melanogaster and humans were found to be downregulated in young muscles, while in young mouse muscle samples, they were upregulated. Also, CPEB transcripts showed differential expression in D. melanogaster, D. rerio, M. musculus, and humans. Further, these proteins interact with other major regulatory factors, and any variations in their levels within the cell can alter the stoichiometry of these interactions, affecting diverse regulatory pathways.