Epithelial-Mesenchymal Transition (EMT) is a fundamental biological process involved in embryonic development, wound healing, and cancer progression. In lung cancer, EMT is a key regulator of invasion and metastasis, significantly contributing to the fatal progression of the disease. Age-related factors such as cellular senescence, chronic inflammation, and epigenetic alterations exacerbate EMT, accelerating lung cancer development in the elderly. This review describes the complex mechanism among EMT and age-related pathways, highlighting key regulators such as TGF-β, WNT/β-catenin, NOTCH, and Hedgehog signalling. We also discuss the mechanisms by which oxidative stress, mediated through pathways involving NRF2 and ROS, telomere attrition, regulated by telomerase activity and shelterin complex, and immune system dysregulation, driven by alterations in cytokine profiles and immune cell senescence, upregulate or downregulate EMT induction. Additionally, we highlighted pathways of transcription such as SNAIL, TWIST, ZEB, SIRT1, TP53, NF-κB, and miRNAs regulating these processes. Understanding these mechanisms, we highlight potential therapeutic interventions targeting these critical molecules and pathways.

As the population is aging, multimorbidity has become an increasingly important global health challenge. Clinical practice guidelines are essential references to guide daily practice for health care providers. This systematic review aims to assess whether existing multimorbidity guidelines adhered to the principles outlined in a previously developed framework for multimorbidity management recommendations, Ariadne, and evaluate their methodological and reporting quality.

In China, it is expected that every one in three people will be aged 60 years and above in 2040, surpassing other low- and middle-income countries. The noncommunicable disease (NCD) burden and trends among elderly people must be clarified.

Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.

Neurodegenerative diseases, as common diseases in the elderly, tend to become younger due to environmental changes, social development and other factors. They are mainly characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system, and common diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease and so on. Mitochondria are important organelles for adenosine triphosphate (ATP) production in the brain. In recent years, a large amount of evidence has shown that mitochondrial dysfunction plays a direct role in neurodegenerative diseases, which is expected to provide new ideas for the treatment of related diseases. This review will summarize the main mechanisms of mitochondrial dysfunction in neurodegenerative diseases, as well as collating recent advances in the study of mitochondrial disorders and new therapies.

With an aging population, the investigation of therapies that promote healthy aging becomes increasingly urgent. Here we discuss how Semaglutide can be a potential therapy to contribute to this goal by targeting key hallmarks of aging, such as inflammation, oxidative stress and stem cell exhaustion.

Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function impairs intercellular interactions as well as extracellular matrix production, further hindering muscle regeneration. Other muscle-resident cells, such as fibro-adipogenic progenitors (FAPs), pericytes, and immune cells, also deteriorate with age, reducing local growth factor activities and responsiveness to stress or injury. Systemic signaling, including hormonal changes, contributes to muscle cellular catabolism and disrupts muscle homeostasis. Collectively, these cellular and environmental components interact, disrupting muscle homeostasis and regeneration in advancing age. Understanding these complex interactions offers insights into potential regenerative strategies to mitigate age-related muscle degeneration.

A major goal of aging research is to identify ways of extending productive and disease-free lifespans. Here we present the catabolic - anabolic cycling hormesis (CACH) model for optimizing health. The CACH model is based on the concept that cells and organ systems respond to catabolic challenges in ways that bolster their resilience and that an anabolic recovery period is required to effectuate the benefits of the catabolic challenge. As two prominent real-world examples we highlight the literature on the molecular and cellular mechanisms by which physical exercise and intermittent fasting bolster cellular and organismal performance and resilience, and suppress disease processes. Over periods of weeks and months the CACH of exercise and fasting promote optimal health. The hormesis concept is integral to the CACH model and predicts an upper limit to the beneficial effects of catabolic - anabolic cycling that reflects a limit of biological plasticity. This paper extends the hormesis model of health by proposing that 1) it is comprised of two complementary phases: catabolic (adaptive stress responses and conservation of resources) and anabolic (growth and plasticity) and, 2) that CACH is metabolically integrated, quantitatively flexible and dynamically regulated. This model has important implications for future basic and translational research in the fields of aging and related disease processes.

In neurodegenerative diseases (NDDs), disruptions in protein homeostasis hinder the clearance of misfolded proteins, causing the formation of misfolded protein oligomers and multimers. The accumulation of these abnormal proteins results in the onset and progression of NDDs. Removal of non-native protein is essential for cell to maintain proteostasis. In recent years, targeted protein degradation (TPD) technologies have become a novel means of treating NDDs by removing misfolded proteins through the intracellular protein quality control system. The TPD strategy includes the participation of two primary pathways, namely the ubiquitin-proteasome pathway (for instance, PROTAC, molecular glue and hydrophobic tag), and the autophagy-lysosome pathway (such as LYTAC, AUTAC and ATTEC). In this review, we systematically present the mechanisms of various TPD strategies employed for neurotoxic protein degradation in NDDs. The article provides an overview of the design, in vitro and in vivo anti-NDD activities and pharmacokinetic properties of these small-molecular degraders. Finally, the advantages, challenges and perspectives of these TPD technologies in NDDs therapy are discussed, providing ideas for further development of small molecule degraders in the realm of NDDs.

Homeostasis of proteins (proteostasis), which governs protein processing, folding, quality control, and degradation, is a fundamental cellular process that plays a pivotal role in various neurodegenerative diseases and in the natural aging process of the mammalian brain. While the role of neuronal proteostasis in neuronal physiology is well characterized, the contribution of proteostasis of glial cells, particularly of astrocytes, has received fairly less attention in this context. Here, we summarize recent data highlighting proteostasis dysfunction in astrocytes and its putative implication to neurodegenerative diseases and aging. We discuss how distinct proteostasis nodes and pathways in astrocytes may specifically contribute to brain function and different age-associated pathologies. Finally, we argue that the understanding of astrocytic proteostasis role in neuronal physiology and functional decay may arise as a potential new avenue of intervention in neurodegenerative diseases and grant relevant data in the biology of aging.

Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.

The conception of coffee consumption has undergone a profound modification, evolving from a noxious habit into a safe lifestyle actually preserving human health. The last 20 years also provided strikingly consistent epidemiological evidence showing that the regular consumption of moderate doses of coffee attenuates all-cause mortality, an effect observed in over 50 studies in different geographic regions and different ethnicities. Coffee intake attenuates the major causes of mortality, dampening cardiovascular-, cerebrovascular-, cancer- and respiratory diseases-associated mortality, as well as some of the major causes of functional deterioration in the elderly such as loss of memory, depression and frailty. The amplitude of the benefit seems discrete (17% reduction) but nonetheless corresponds to an average increase healthspan of 1.8 years of lifetime. This review explores evidence from studies in humans and human tissues supporting an ability of coffee and of its main components (caffeine and chlorogenic acids) to preserve the main biological mechanisms responsible for the aging process, namely genomic instability, macromolecular damage, metabolic and proteostatic impairments with particularly robust effects on the control of stress adaptation and inflammation and unclear effects on stem cells and regeneration. Further studies are required to detail these mechanistic benefits in aged individuals, which may prompt new insights into understanding of the biology of aging and the development of new senostatic strategies. Additionally, the safety of this lifestyle factor in the elderly prompts a renewed attention to recommending the maintenance of coffee consumption throughout life as a healthy lifestyle and to further exploring who gets the greater benefit with what schedules of which particular types and doses of coffee.

Functional brain connectivity of resting-state networks varies as Alzheimer's disease (AD) progresses. However, our understanding of the dynamic longitudinal changes that occur in the brain over the course of AD is sometimes contradictory and lacking.

Alzheimer's disease (AD), commonly known as senile dementia, is a neurodegenerative disease with insidious onset and gradually worsening course. The brain is particularly sensitive to senescence, and neuronal senescence is an important risk factor for the occurrence of AD. However, the exact pathogenesis between neuronal senescence and AD has not been fully elucidated so far. Neuronal senescence is characterized by the permanent arrest of the cell cycle, and the changes in its structure, function, and microenvironment are closely related to the pathogenesis and progression of AD. In recent years, studies such as the Aβ cascade hypothesis and Tau protein phosphorylation have provided new strategies for the treatment of AD, but due to the complexity of the etiology of AD, there are still no effective treatment measures. This article aims to deeply analyze the pathogenesis between AD and neuronal senescence, and sort out various existing treatment methods, to provide new ideas and references for the clinical treatment of AD.

Ageing is a major risk factor for various chronic diseases and offers a potential target for developing novel and broadly effective preventatives or therapeutics for age-related conditions, including those affecting the brain. Mechanisms contributing to ageing have been summarized as the hallmarks of ageing, with iron imbalance being one of the major factors. Ferroptosis, an iron-mediated lipid peroxidation-induced programmed cell death, has recently been implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Addressing ferroptosis offers both opportunities and challenges for treating neurodegenerative diseases, though the specific mechanisms remain unclear. This research explores the key processes behind how ferroptosis contributes to brain ageing, with a focus on the complex signaling networks that are involved. The current article aims to uncover that how ferroptosis, a specific type of cell death, may drive age-related changes in the brain. Additionally, the article also unveils its role in neurodegenerative diseases, discussing how understanding these mechanisms could open up new therapeutic avenues.

Alzheimer's Disease (AD) is the most common form of dementia among elderly people. This disease imposes a significant burden on the healthcare system, society, and economy due to the increasing global aging population. Current trials with drugs or bioactive compounds aimed at reducing cerebral Amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles, which are the two main hallmarks of this devastating neurodegenerative disease, have not provided significant results in terms of their neuropathological outcomes nor met the expected clinical end-points. Ageing, genetic and environmental risk factors, along with different clinical symptoms suggest that AD is a complex and heterogeneous disorder with multiple interconnected pathological pathways rather than a single disease entity. In the present review, we highlight and discuss various non-canonical, Aβ-independent mechanisms, like gliosis, unhealthy dietary intake, lipid and sugar signaling, and cerebrovascular damage that contribute to the onset and development of AD. We emphasize that challenging the traditional "amyloid cascade hypothesis" may improve our understanding of this age-related complex syndrome and help fight the progressive cognitive decline in AD.

The intricate organization of distinct cellular compartments is paramount for the maintenance of normal biological functions and the orchestration of complex biochemical reactions. These compartments, whether membrane-bound organelles or membraneless structures like Cajal bodies and RNA transport granules, play crucial roles in cellular function. Liquid-liquid phase separation (LLPS) serves as a reversible process that elucidates the genesis of membranelles structures through the self-assembly of biomolecules. LLPS has been implicated in a myriad of physiological and pathological processes, encompassing immune response and tumor genesis. But the association between LLPS and aging has not been clearly clarified. A recent advancement in the realm of aging research involves the introduction of a new edition outlining the twelve hallmarks of aging, categorized into three distinct groups. By delving into the role and mechanism of LLPS in the formation of membraneless structures at a molecular level, this review encapsulates an exploration of the interaction between LLPS and these aging hallmarks, aiming to offer novel perspectives of the intricate mechanisms underlying the aging process and deeper insights into aging therapeutics.

Large retrospective cohort studies have consistently shown that people who exercise regularly are at a markedly reduced risk of dementias such as Alzheimer's Disease (AD). Animal studies have also found that exercise can prevent cognitive decline, and recent studies have identified possible mechanisms. However, randomized controlled trials of exercise interventions in AD and mild cognitive impairment have not reached a consensus regarding the efficacy of this treatment, hampering clinical adoption of this technique. This review examines these randomized controlled trials to assess potential causes for the variability in the measured outcomes. We posit that great variance in the methods used in these studies may account for some of the differences seen in outcomes. We determined that aerobic exercise led to the most benefits, that many cognitive domains improve with exercise, and that aerobic exercise enhances the ability for independent living. However, cognitive improvements were more pronounced and consistent in patients with mild cognitive impairment than AD, suggesting a narrow window of opportunity for exercise intervention.

Alzheimer's disease (AD) is a leading cause of cognitive decline in the aging population, presenting a critical need for early diagnosis and effective prognostic tools. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, have emerged as promising biomarkers for AD due to their roles in regulating gene expression and potential for reversibility. This review examines the current landscape of epigenetic biomarkers in AD, emphasizing their diagnostic and prognostic relevance. DNA methylation patterns in genes such as APP, PSEN1, and PSEN2 are highlighted for their strong associations with AD pathology. Alterations in DNA methylation at specific CpG sites have been consistently observed in AD patients, suggesting their utility in early detection. Histone modifications, such as acetylation and methylation, also play a crucial role in chromatin remodelling and gene expression regulation in AD. Dysregulated histone acetylation and methylation have been linked to AD progression, making these modifications valuable biomarkers. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), further contribute to the epigenetic regulation in AD. miRNAs can modulate gene expression post-transcriptionally and have been found in altered levels in AD, while lncRNAs can influence chromatin structure and gene expression. The presence of these non-coding RNAs in biofluids like blood and cerebrospinal fluid positions them as accessible and minimally invasive biomarkers. Technological advancements in detecting and quantifying epigenetic modifications have propelled the field forward. Techniques such as next-generation sequencing, bisulfite sequencing, and chromatin immunoprecipitation assays offer high sensitivity and specificity, enabling the detailed analysis of epigenetic changes in clinical samples. These tools are instrumental in translating epigenetic research into clinical practice. This review underscores the potential of epigenetic biomarkers to enhance the early diagnosis and prognosis of AD, paving the way for personalized therapeutic strategies and improved patient outcomes. The integration of these biomarkers into clinical workflows promises to revolutionize AD management, offering hope for better disease monitoring and intervention.

More than a century after the discovery of nicotinamide adenine dinucleotide (NAD), our understanding of the molecule's role in the biology of ageing continues to evolve. As a coenzyme or substrate for many enzymes, NAD governs a wide range of biological processes, including energy metabolism, genomic stability, signal transduction, and cell fate. NAD deficiency has been recognised as a bona fide hallmark of tissue degeneration, and restoring NAD homeostasis helps to rejuvenate multiple mechanisms associated with tissue ageing. The progressive loss of skeletal muscle homeostasis with age is directly associated with high morbidity, disability and mortality. The aetiology of skeletal muscle ageing is complex, involving mitochondrial dysfunction, senescence and stem cell depletion, autophagy defects, chronic cellular stress, intracellular ion overload, immune cell dysfunction, circadian clock disruption, microcirculation disorders, persistent denervation, and gut microbiota dysbiosis. This review focuses on the therapeutic potential of NAD restoration to alleviate the above pathological factors and discusses the effects of in vivo administration of different NAD boosting strategies on skeletal muscle homeostasis, aiming to provide a reference for combating skeletal muscle ageing.

Alzheimer's Disease (AD) is one of the most devastating age-related disorder causing significant social and economic burden worldwide. It affects the cognitive and social behavior of individuals and characterized by accumulation of Aβ, phosphorylated tau and cytokines formation. The synthesis and release of cytokines are regulated by specific groups of immune and non-immune cells in response to microglia or astrocyte activation through multiple pathways. Physiologically, microglia assert an anti-inflammatory, quiescent state with minimal cytokine expression and little phagocytic activity in motion to carry out their housekeeping role to eliminate pathogens, aggregated Aβ and tau protein. However, they develop a phagocytic nature and overexpress cytokine gene modules in response to certain stimuli in AD. Microglia and astrocytes upon chronic activation release an enormous amount of inflammatory cytokines due to interaction with formed Aβ and neurofibrillary tangle. Gut microbiota dysbiosis also stimulates the release of inflammatory cytokines contributing to AD pathogenesis. In addition, the dysregulation of few signaling pathways significantly influences the development of disease, and the pace of advancement also rises with age. This review sheds light on multiple pathways results into neuroinflammation triggered by activated cytokines worsening AD pathology and making it an appropriate target for AD treatment. This review also included drugs targeting different neuroinflammation pathways under clinical and preclinical studies that are found to be effective in attenuating the disease pathology.