Staging concept for ageing management: definition, mechanism and coping strategies

Staging concept for ageing management: definition, mechanism and coping strategies | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL View This is a preprint and has not been peer reviewed. Data may be preliminary. 25 November 2025 V1 Latest version Share on Staging concept for ageing management: definition, mechanism and coping strategies Authors : Zhonghan Wang , Shixian Liu , Shangyu Du , Xiangran Cui , Bo Chao , Minglei Liu , and Minfei Wu 0000-0001-8230-3774 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176405596.64227209/v1 222 views 164 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Ageing, as a gradual and largely irreversible biological process, characterised by declining organismal vitality and multi-organ functional impairment. While research on ageing constitutes a major scientific focus, current efforts concentrate on two domains: elucidating fundamental mechanisms of ageing and developing anti-ageing strategies, and addressing the social management of ageing populations. A critical gap persists in the clinical understanding and management of ageing itself. Specifically, there is insufficient recognition and structured approach towards ageing within clinical practice. To address this, we propose a novel clinical staging system for ageing, which based on manifestations observed by distinct stages. For each stage, we delineate the clinical presentations, biological phenomena, theoretical underpinnings, and key management priorities. This framework aims to bridge the current void in the clinical conceptualization and stage-specific management of ageing, establishing a novel foundation for a structured, staged management model. We anticipate this framework will contribute significantly to advancing the goal of healthy aging. Staging concept for ageing management: definition, mechanism and coping strategies Zhonghan Wang 1† , Shixian Liu 1† , Shangyu Du 1 , Xiangran Cui 1 , Bo Chao 1 , Minglei Liu 1 , Minfei Wu 1* 1 Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, China *Corresponding authors. E-mail addresses: [email protected] (M. Wu) † These authors contributed equally: Zhonghan Wang, Shixian Liu. Abstract Ageing, as a gradual and largely irreversible biological process, characterised by declining organismal vitality and multi-organ functional impairment. While research on ageing constitutes a major scientific focus, current efforts concentrate on two domains: elucidating fundamental mechanisms of ageing and developing anti-ageing strategies, and addressing the social management of ageing populations. A critical gap persists in the clinical understanding and management of ageing itself. Specifically, there is insufficient recognition and structured approach towards ageing within clinical practice. To address this, we propose a novel clinical staging system for ageing, which based on manifestations observed by distinct stages. For each stage, we delineate the clinical presentations, biological phenomena, theoretical underpinnings, and key management priorities. This framework aims to bridge the current void in the clinical conceptualization and stage-specific management of ageing, establishing a novel foundation for a structured, staged management model. We anticipate this framework will contribute significantly to advancing the goal of healthy aging. Keywords: Ageing; Clinical stages; Ageing management Introduction Today, global average life expectancy is over 73 years old, much more than 46 years old in 1956. Following that is the increasing ageing population, that 9% of the global population is over 65 years nowadays, and it is estimated that one in six people in the world will be over the age of 65 by 2050 [1]. Accompanied with ageing, health conditions of ageing people declined, manifested as the loss of physical capabilities, cognitive functions, psychological well-being, social well-being, susceptible to chronic diseases, which remains major medical and social challenges. Currently, the major research field of ageing concentrates on its sociological and biological aspects. Gerontologists mainly focus on the macro-perspective in ageing influencing social behaviors. Views involving active ageing, successful ageing, productive ageing are all used to describe the capabilities in maintaining optimal physical and mental functioning, delayed age-associated disease onset and the extension of the lifespan on individual or groups scope. Gerontologists propose relevant policies in improving health education and healthcare services to deal with population ageing [2]. In terms of biological scope, researchers give an insight into mechanisms of ageing, and put forward that genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis are all contributed to ageing-related manifestations [3]. Over the past decades, anti-ageing interventions have been identified to slow down the ageing process. Lifestyle intervention is highly acceptable for publics, including exercise, caloric restriction, nutritional supplements and adequate sleep. Besides, numerous drugs consist synthetic agents or defined natural compounds display pharmacological effects on anti-ageing. Inspiringly, eight types of drugs have been approved by Food and Drug Administration (FDA) for anti-ageing clinical tests, namely metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories, which exerts broad ageing-related disease-preventing or -attenuating functions by regulating genetics, molecular biology and cytobiology effects [4]. Given the diverse array of stressors and damaging factors individuals encounter, coupled with varying coping mechanisms, individuals of the same chronological age may exhibit distinct biological age profiles. Hence, there is a trend to conceptualize ageing as a treatable and preventable disease. While the management of diseases, particularly chronic conditions, adheres to well-defined staging frameworks and corresponding therapeutic protocols, ensuring standardized care based on clinical guidelines, the current classification of ageing stages is primarily grounded in sociological and biological principles, lacking a clinical staging system [5]. Furthermore, there is a dearth of consensus regarding the optimal intervention strategies to be employed at specific stages of ageing. In this personal view, we aim to summarize existing ageing stages and propose a new ageing staging framework to explain existing theories of ageing phenomena, and to summarize the corresponding ageing therapies in each stage, providing a new framework for clinical treatment of ageing. Measurement, definition and staging of ageing Ageing can be described both as a state of being old and as an ongoing process. We absolutely cannot describe that an adolescent is ageing, but it is indeed in the continuous process of ageing. Hence, there is a need to establish a standardized method for measuring and defining ageing, in order to comprehend this ubiquitous biological process and evaluate the efficacy of anti-ageing interventions. Given that ageing manifests at multiple levels, including subcellular, cellular, tissue, and organismal, the approaches to measuring ageing are correspondingly varied. Firstly, ageing is related to, yet distinct from, the lifespan. Extending life is one of the main goals of anti-ageing, but there are differences in their connotations. For example, cancer is a key factor limiting human life. Through systematic cancer treatment, it is possible to extend individual life and increase the survival period of the population. However, we cannot define cancer treatment methods such as surgical resection, radiotherapy, and chemotherapy as ”anti-ageing treatments.” Therefore, our primary task is to clarify and define ageing-related phenotypes, which are the impairments of tissues, functions, and other aspects that occur in parallel with ageing. And by exacerbating or intervening these phenotypes, ageing state can be accelerating or slowing down. The most intuitive method to measure ageing is by comparing ageing-related phenotypic differences between old and young individuals. The most obvious external performances include hair thinning or whitening, decreased physical strength, and increased weakness [6]. As deeper changes at the cellular and subcellular levels, nine biomarkers of ageing were proposed including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication [7]. Among these phenotypic changes, selecting and screening appropriate indicators for measuring ageing is a major challenge. Currently, the measurement of ageing mainly focuses on the microscopic omics level and macroscopic symptom changes, which will be elaborated in the following text. 2.1. Biological Measurements of Ageing In 1961, Hayflick discovered the ”Hayflick limit” phenomenon, which indicates that somatic cells have a limited number of proliferation and division cycles, typically ranging from 40 to 60 times. This phenomenon illustrates the lifespan of somatic cells, caused by the depletion of telomeres [8]. Telomeres are cap-like DNA sequence-protein complexes resided at the ends of eukaryotic chromosomes. With each cell division, the length of the telomeres shortens. When the telomeres are completely consumed, cell division will result in the loss of normal DNA segments, leading to an accumulation of cellular damage, ageing, and death. Based on this characteristic, telomere length has been used as an indicator to assess cellular ageing [9]. Tsuji et al. measured the telomere length of peripheral blood mononuclear cells and found that its correlation coefficient with actual physiological age reached -0.832. Subsequently, telomere length has also been applied to assess the relationship between ageing-related diseases, that atherosclerotic coronary artery disease and all-cause mortality were proved to be positive correlation with telomere length [10]. Epigenetic clocks are another commonly used molecular biological method for measuring ageing. Research has found that the methylation status of millions of CpG dinucleotides among the 28 million CpG dinucleotides in the human genome changes with age [11]. Based on this, in 2011, Bocklandt established the first methylation epigenetic clock to predict the state of physiological ageing, with an error of less than 5 years in the detection of physiological age [12]. Subsequently, epigenetic clocks such as the Horvath methylation clock and the Hannum methylation clock have been developed for ageing detection. These epigenetic clocks have gradually reduced the error in ageing testing by increasing the sample size to enhance the robustness of the data set, expanding CpG sites, seeking combinations of CpG sites with higher sensitivity, and screening sample testing types [13]. By combining artificial intelligence technology, more accurate and efficient epigenetic biomarkers can be obtained to further reduce noise interference and achieve better ageing detection accuracy. Through these epigenetic clocks, researchers can evaluate the ageing state of multiple organs in cross-sectional studies, as well as body function and mortality. Other researchers have applied epigenetic clocks to measure the ageing state of diseased tissues, such as precancerous tissues, and have verified that epigenetic ageing state of lesion tissue showed significantly accelerated. Moreover, the expression of molecular agents variated during the ageing process, including mRNA, proteins, metabolites, microorganisms, polysaccharides, chromatin, etc. [14]. Based on omics analysis methods, a series of molecular biological markers relating to ageing were screened out. It showed considerable potential of these markers for assessing ageing state through multimodal fusion methods, which still required further word to explore. 2.2. Symptomatic Measurements of Ageing Frailty is deemed as a common manifestation in ageing individuals, characterized by the declined physical vitality and multiple organ functions. Although diseases, such as fever, can cause signs of frailty in people of all ages, it is generally believed that the manifestation of frailty is a typical sign of aged population. During the ageing process, cardiac function situation, skeletal muscle strength, and neurological function are several indicators that are susceptible to lead to frailty. The frailty phenotype is commonly used to assess the state of frailty, typically includes low hand grip strength, slow walking speed, low level of physical activity, lack of energy or self-reported fatigue, and weight loss due to non-voluntary weight reduction [15]. Subsequently, the frailty index (FI) has also been used to assess the state of frailty, evaluating it by incorporating variables that are strictly selected and related to health status. FI is a continuous variable, shows a better discrimination for the risk of adverse health outcomes in adults with lower levels of frailty. Large cohort studies have shown that FI can effectively predict the all-cause and multiple cause-specific mortality risks in the population, making it a promising proxy indicator of biological age [16]. In addition, researchers have constructed animal models of frailty, which can be used to evaluate the effects of anti-ageing drugs and therapies. For example, widely accepted interventions such as caloric restriction, rapamycin, and antioxidants have been tested in frailty animal models, verifying that they reduced the degree of frailty through anti-ageing treatment [17]. 2.3. Existing Staging methods of Ageing Introducing the staging concept of disease into ageing can further enhance ageing management. The staging theory, based on a large amount of clinical data, practical experience, large group control studies, epidemiology and rigorous follow-up results, can not only serve as a guidance for clinical diagnosis and treatment, but also as a basis for judging outcomes and prognosis. At present, the staging of ageing still stay at the organ level, that STRAW+10 staging system for assessing female reproductive ageing and the facial skin ageing staging system are widely recognized. The reproductive state of women determines the level of hormones in the body, which is crucial for understanding the growth and development potential, reproductive capacity, and assessing the occurrence of diseases closely related to estrogen levels in women. In 2011, the STRAW+10 staging system, which was reached at a special discussion meeting on reproductive ageing held in Washington, is currently widely recognized and applied for evaluating female reproductive ageing. This system divides the period from menarche to the end of life into fertility, menopausal transition, and postmenopausal periods, based on menstrual status, endocrine status, follicle number, and symptoms, with each major cycle further divided into smaller cycles [18]. The STRAW+10 staging system is of great significance for the assessment, prevention, and treatment of female pregnancy and childbirth, sexual health status, cardiovascular and cerebrovascular diseases, malignant tumors, and estrogen-dependent diseases. Facial skin ageing is the most primary concern for women regarding ageing manifestations. Yi et al. staged the manifestations of facial skin ageing, comprehensively staging statistics based on 5 dimensions and 24 parameters, including skin wrinkles, skin texture, spots, skin color, and barrier function, dividing it into the latency period, the onset period of ageing, the rapid ageing period, and the stable ageing period [19]. Latency period (18-30 years old): At this stage, the skin begins to show slight signs of ageing, such as the formation of pigmentation. This is the initial stage of skin ageing, with few wrinkles and obvious changes, but there are already slight changes in texture. Onset period of ageing (31-42 years old): At this stage, the skin begins to experience more obvious ageing, including harder texture and the appearance of more wrinkles. The overall color and luster of the skin begin to decline, and the number of pigmentation and freckles starts to increase. Rapid ageing period (43-47 years old): This is the accelerated stage of skin ageing, with significant increases in wrinkles and pigmentation, and the overall condition of the skin deteriorates rapidly. The skin becomes drier and rougher, and blackheads and pore problems become more severe. Stable ageing period (48-60 years old): At this stage, skin ageing reaches its most severe state, with the most noticeable wrinkles and pigmentation. The elasticity and luster of the skin further decline, which may lead to dry and sensitive skin. Although this staging has not been widely recognized, it still helps to better understand the process of skin ageing and take appropriate skin care measures to slow down this process [20]. 2.4. Proposing new staging criteria of ageing Among the existing ageing staging theories, only the local system or tissue ageing staging is referred, while the evaluation and grading of the system ageing status is vague and has no specific definition. Based on the above problems, we are going to build a staging framework for systematic ageing in this review. In this framework, we divided the overall ageing stage into ”pre-ageing”, ”ageing compensation” and ”ageing disability” (Fig. 1). This framework aims to summarize the manifestations of clinical stage ageing and various ageing related mechanisms and management schemes, summarize a complete set of systematic ageing staging theory and treatment framework, and provide a new paradigm for the management and treatment of ageing. Fig. 1: Schematic diagram of a person going through the pre-ageing stage, the ageing compensation stage, and finally to the ageing disability stage. 3. Pre-ageing stage Cells are the fundamental structural and functional units of living organisms, as well as the basic units for studying life activities. Therefore, to discuss the origins and development of aging as a classical life process, we must begin with the most basic cellular senescence. Cellular senescence occurs throughout all stages of human life. During embryonic and infant stages, it often serves positive functions by preventing damaged cells from dividing and becoming cancerous, while supporting tissue remodeling functions to facilitate important physiological processes such as wound healing and tissue repair [21]. When entering old age, cells in various organs and tissues undergo senescence due to multiple factors. However, the body’s normal immune surveillance and clearance functions, along with normal regulatory compensatory mechanisms, can effectively eliminate senescent cells from the body, maintaining a relatively healthy state. In this state, elderly individuals have more senescent cells compared to normal young people, but the number has not reached a certain threshold. Their physical indicators remain relatively normal compared to young people, with no significant differences even when declining. We refer to this relatively healthy life stage in elderly individuals as pre-ageing. 3.1. Mechanisms of cellular senescence DNA damage, a crucial mechanism of cellular senescence is partly caused by endogenous factors, such as telomere shortening and proto-oncogene activation, and partly by exogenous factors, such as ultraviolet rays and viral infections. DNA double-strand breaks (DSBs) activate the DNA Damage Response (DDR) pathway, forming detectable focal points at damage sites that contain phosphorylated histone H2AX, MDC1, 53BP1, and ATM kinase. However, persistent DNA damage leads to prolonged DDR signaling and cellular proliferation arrest. Furthermore, p53 at the downstream end of the DDR cascade becomes activated, stimulating p21 expression, where p21 serves as a key mediator of senescence-associated cell cycle arrest [22]. Telomere length shortening is one of the earliest recognized and most thoroughly studied mechanisms of cellular senescence induction. Telomeres are protective structures located at chromosome ends that function to prevent genomic damage. In the absence of telomere maintenance mechanisms, each DNA replication leads to telomere shortening. When telomere length falls below a critical threshold, the loss of protective structures causes short telomeres to resemble one-ended DNA double-strand breaks, triggering a DDR similar to that of double-strand breaks. Research has shown that shelterin proteins can prevent DNA damage responses at chromosome ends and protect telomere. Deficiencies in shelterin components can lead to decreased tissue regenerative capacity and accelerated aging, even when telomere length is normal. Even in non-dividing cells, telomeric DNA damage can induce cellular senescence, a phenomenon independent of telomere length [23]. Oncogene activation is a potent inducer of cellular senescence. Oncogene expression initially triggers hyperproliferation, leading to abnormal DNA replication and ultimately activating the DDR pathway to induce senescence [24]. The accumulated reactive oxygen species (ROS) in tumors can function both as DNA-damaging agents and as signaling molecules mediating mitogenic oncogene functions. Oncogene-induced ROS generated by NADPH oxidase promotes cellular senescence through facilitating the initial hyperproliferation phase. This hyperproliferation is associated with altered DNA replication and DNA damage accumulation [25]. Additionally, senescence-associated heterochromatin foci (SAHF) are most prominent following oncogene activation, and SAHF formation depends on DNA replication and the ATR pathway. SAHF limits DDR signaling by forming heterochromatic structures that are resistant to DNA damage responses [7]. According to ”the information theory of aging” proposed by Sinclair, the accumulation of epigenetic noise lead to cell senescence [26]. With advancing age, human DNA methylation patterns undergo multiple changes. While showing global hypomethylation overall, certain specific sites (such as tumor suppressor genes and polycomb target genes) exhibit hypermethylation. During the aging process, there is a global loss of histones and tissue-specific changes in post-translational modifications. In fibroblasts from elderly individuals and premature aging patients, increased H4K16 acetylation and H3K4 trimethylation are observed, while H3K9 and H3K27 trimethylation levels are decreased. The SIRT family proteins (deacetylases) play crucial roles in aging: SIRT1 overexpression improves genomic stability and metabolic efficiency; SIRT6 deficiency leads to accelerated aging while its overexpression can extend lifespan; and SIRT7 deficiency results in global genomic instability and premature aging [27]. Genomic instability, particularly damage to mitochondrial DNA induces mitochondrial dysfunction, which in turn triggers a significant increase in oxidative stress, thereby accelerating cell senescence. Senescent cells exhibit changes in mitochondrial mass, membrane potential, and morphology [28]. The reduction of mitochondrial sirtuins (a group of evolutionarily conserved proteins) triggers senescence. Humanin (a mitochondria-derived peptide) levels decrease with age but show higher levels in centenarians and their offspring. Another mitochondria-encoded micropeptide, MOTS-c, also declines with age but can be induced through exercise, with its mechanism of action related to AMPK activation [29]. 3.2. The characteristics of cellular senescence The main characteristics of cellular senescence include: lysosomal expansion, which can be detected through SA-β-galactosidase staining; upregulation of CDK inhibitors (particularly p16 and p21); loss of nuclear envelope protein LMNB1; loss of chromatin component HMGB1 from the nucleus and its release as an alarmin into the extracellular space; heterochromatic foci manifesting as HP1γ nuclear foci or SAHF; elevated levels of ROS; increased DNA damage as evidenced by γH2AX nuclear foci; and high levels of senescence-associated secretory phenotype (SASP) factors, especially IL-6, TGF-β, and PAI1 [30]. The SASP significantly impacts the microenvironment by recruiting and activating immune cells through chemokines (CCL2, CXCL2, CXCL3) and cytokines (IL-1β, IL-2, IL-6, IL-8), while secreting TGF-β to suppress the immune system. SASP also triggers fibroblast activation through pro-fibrotic factors (TGF-β, IL-11, PAI1) and remodels the extracellular matrix via matrix metalloproteinases. Additionally, it stimulates progenitor cells through growth factors (EGF and PDGF), while senescent cells induce paracrine effects in neighboring cells through TGF-β, TNF-α, and IL-8 secretion [31]. 3.3. The impact of psychological status and social behavior during childhood/youth on the aging process The psychological state during childhood and adolescence, including stress, anxiety, and depression, influences the body’s aging process to varying degrees. Extensive research indicates that individuals with good mental health experience slower cellular aging and maintain physiological indicators closer to a youthful state [32]. Regarding childhood adversity and biological aging, studies have found that adverse childhood experiences correlate with telomere length shortening, which reflects accelerated biological aging. This effect shows gender differences, with females being more susceptible than males. Nearly all types of childhood adversity experiences correlate with telomere shortening in females, while males show this association only in cases of physical abuse [33]. Furthermore, people who have experienced childhood adversity, especially sexual and physical abuse, are more likely to be exposed to unhealthy lifestyles (such as smoking and drinking) and psychological disorder, which can accelerate aging. Unhealthy lifestyle patterns mediate 4.1% to 18.5% of the association between childhood adversity and telomere shortening, while psychological disorder indices mediate 5.1% to 11.2% of this association. This mediating effect is most pronounced in cases of sexual and physical abuse [34]. 3.4. Preventive pharmacological/nutraceutical intervention In pre-ageing stage, the key to anti-aging revolves around mitigating genomic instability and enhancing mitochondrial function to delay cellular senescence. Firstly, drugs like potassium iodide and damage suppressor protein (Dsup) that inhibit DNA damage can effectively prevent cellular senescence. Furthermore, DNA repair agents, such as poly (ADP-ribose) polymerase (PARP) inhibitors, ataxia telangiectasia mutant protein (ATM) inhibitors, CHK1 inhibitors, and DNA-PK inhibitors target the DDR pathway to impede cellular senescence [35]. Another promising approach involves protection of telomere. For instance, Vitamin D3 and ω-3 fatty acids have been shown to preserve or elongate cellular telomere length [36]. In terms of epigenetic regulation, Gilbenclamide delays cellular senescence by inhibiting the activity of mitochondrial malate dehydrogenase 2, promoting histone methylation [37]. Furthermore, nutraceutical compounds such as NAD+ precursors, including NMN (nicotinamide mononucleotide), are believed to improve mitochondrial function and delay aging [38]. 3.5. Psychological and lifestyle Interventions Stress management, active social interaction, elimination of unhealthy habits, and dietary regulation help slow down the aging rate during pre-ageing stage. Long-term social stress can lead to chronic inflammatory state and senescence of white blood cell, increasing the risk of various diseases [39]. Hence, adopting positive stress management strategies such as hypnosis and meditation, as well as active social engagement reduce ageing levels. Additionally, health education and knowledge promotion enhance individual self-management awareness and increase proactive participation in aging intervention strategies. Furthermore, stay away from unhealthy habits, including smoking and drinking that accelerate ageing, especially ageing of facial skin cells. As for dietary regulation, calorie restriction (CR) had been found to activate AMPK, a key regulator of cellular energy metabolism, thereby effectively prolonging the lifespan of mice, and the longevity effect was proportional to the degree of CR [40]. 4. Ageing compensation stage The ageing compensation stage refers to a sub-health period in which the elderly begin to suffer from a decline in physical functions due to the accumulation of senescent cells, but they are still able to perform daily activities independently. In this period, the elderly may experience some systemic manifestations associated with aging, specifically, decreased physical strength, easy fatigue, diminished reaction time and poor mental state. Meanwhile, the levels of some aging-related biochemical indicators of the elderly are reduced compared with those in the early-state aging, but the tissues and organs are still able to work in a compensatory manner. At this point, suitable interventions can be implemented to mitigate further aging of the organism. Notably, it is crucial to avoid risk factors, for instance, preventing accidental fractures resulting from falls, which can precipitate an early onset of the disabling stage. 4.1. Mechanism Over time, senescent cells progressively displace young cells, and the depletion of stem cells severs the pathway for generating new, youthful cells. Concurrently, senescent cells recruit additional senescent cells via intercellular communication, while the deteriorating immune system fails to promptly eliminate these senescent cells, ultimately leading to decline of various tissues, encompassing epithelial, connective, muscle, and nerve tissues. Epithelial tissue is an important structure lining or covering other tissues, with protective, absorptive, secretory, and excretory functions. Renal tubular epithelial cells are coated with renal tubules, and their senescence is thought to be closely related to the decline of renal function. In the ageing compensation stage, decreased filtration and reabsorption functions of aging renal tubular epithelial cells affect renal excretion of metabolic wastes. Accumulation of senescent intestinal epithelial cells leads to reduced intestinal nutrient absorption and interferes with immune homeostasis in gut [41]. Currently, kidney and intestine are slightly less functional, but the younger cells work compensatorily to prevent further deterioration, so that the elderly do not show pathological changes in tissues. The accumulation of senescent melanocytes leads to the destruction of stratum corneum of the skin and a reduction in melanin synthesis, while the remaining young melanocytes work hard to prevent skin pigmentation and hair whitening [42]. Connective tissue includes blood, lymph, cartilage, bone, fat, and so on, with connection, support, nutrition, protection and other functions. The dermis of the skin is a connective tissue, mainly composed of fibroblasts. With the accumulation of senescent fibroblasts in the skin, production of collagen and elastin decreases. The remaining normal fibroblasts compensatively replenish collagen and elastin to prevent the loss of skin elasticity and the formation of wrinkles [43]. Body fat percentage rises with age, and fat distribution changes. Specifically, there is a decrease in fat in the hands, feet, and face, and an increase in the trunk area, possibly to ameliorate the thermoregulation failure due to adipocyte senescence [44]. The accumulation of senescent chondrocytes will lead to the imbalance of cartilage synthesis and decomposition. Normal chondrocytes synthesize cartilage to combat the degeneration of cartilage caused by aging chondrocytes. As age increases, osteoblasts continuously age and undergo apoptosis, which leads to the formation of more and more bone marrow fat rather than bone tissue. Simultaneously, the remaining osteoblasts secrete osteoprotegerin compensatively to maintain as much balance between bone formation and resorption as possible and ensure the normal shape and function of bone [45]. Muscle tissue includes smooth muscle, cardiac muscle, and skeletal muscle, with the primary function of being responsible for the movement of the body and organs. The accumulation of smooth muscle cells in aging blood vessels leads to a decrease in the elasticity of blood vessel walls, which affects the contraction and relaxation of blood vessels. However, during the compensation period of aging, the body tries to maintain the structure of blood vessels to prevent arterial remodeling (thickening of the middle layer and narrowing of the lumen) [46]. In addition, it has been reported that fast muscle fibers are more susceptible to atrophy during the aging process compared to slow muscle fibers, while slow muscle fibers tend to transform into fast muscle fibers, as a compensation for the loss of fast muscle fibers [47]. Nervous tissue has the capabilities to receive stimuli, conduct impulses, and integrate information. During the aging process of nervous tissue, the myelin sheath outside the axons of neuronal cells undergoes continuous deformation and fragmentation, which increases the clearance burden on microglia in the central nervous system, leading to their functional impairment. Degenerative changes in neuronal axons and at the neuromuscular junctions lead to a slowing of nerve conduction velocity, resulting in a decline in sensory and motor functions. The accumulation of aging astrocytes may lead to impairments in neurotransmitter reuptake and ion homeostasis imbalances [48]. Interestingly, during the compensatory phase of aging, the rate of neurotransmitter release from the brain’s blue-spot-frontal cortex circuit increases rather than decreases, due to the compensatory work of young neuronal cells. At this point, although the speed of nerve conduction is accelerated, it is disorganized, resulting in the elderly being more sluggish and prone to errors when encountering complex matters [49]. Stem cells are key to tissue maintenance and regeneration. Aging stem cells not only have a reduced ability to differentiate into other cells, but their capacity for self-renewal also diminishes, finally leading to the exhaustion of the stem cell pool. In the compensatory phase of aging, accumulation of senescent alveolar epithelial stem cells, such as alveolar type 2 (AT2) cells, leads to impaired alveolar homeostasis and obstructive alveolar gas exchange, while young AT2 cells work hard to prevent further fibrosis [50]. In the process of aging, the number of hematopoietic stem cells decrease, and they are more inclined to produce myeloid cells rather than lymphoid cells. This leads to weakened adaptive immunity and persistent inflammation in the elderly [51]. Starting from middle age, neural stem cells in the hippocampus gradually enter a state of deep quiescence, which reduces the generation of neurons and contributes to neurofunctional impairment [52]. In the compensatory phase of aging, body struggles to maintain the homeostasis of the neural stem cell population to prevent the occurrence of neurodegenerative diseases. In addition, the communication and interaction between senescent cells also promote the progress of the ageing compensation stage. It has been reported that senescent cells transmit senescence-associated secretory phenotypes (SASP), including TGF-β, IL-6, CCLs and CXCLs, to surrounding cells through paracrine pathways, causing the spread of senescence. SASP, like IL-6 and IL-8, can also further worsen the aging of senescent cells themselves by autocrine. SASP secreted by senescent lung fibroblasts, including IL-6, CCL2, and MMP, can break down the extracellular matrix, promoting fibrosis and tissue dysfunction [53]. Aging cells can also interact with each other through juxtacrine signaling. For example, IL-1A on the surface of senescent cell membranes bind to IL-1R secreted by other cells, thereby controlling the degree of senescence through regulation of IL-6 and IL-8 [54]. Increased secretion of SASP causes a persistent inflammatory state. During the compensatory phase of aging, body attenuates inflammation through compensatory immunosuppression, such as suppression of macrophages, T cells, and natural killer (NK) cells. However, this is tantamount to tearing down the east wall and repairing the west wall. These immune cells are the mainstay for immune surveillance and clearance of senescent cells, and inhibition of their function would accelerate rate of aging. In the early stage of senescence, the immune system of the body, especially various immune cells clear senescent cells, keeping the body healthy and vibrant. As the human body’s first line of defense against ”enemies”, the backbone of innate immunity, macrophages and NK cells directly eliminate senescent cells. Macrophages directly engulf senescent cells. For example, in the process of red blood cell aging, the membrane protein phosphatidylserine (PS) increases its ectropion, sending out the ”eat me” signal, mediating the recognition and phagocytosis of macrophages [55]. Activating receptors on the NK cell surface, such as NKG2D and DNAM-1, rapidly recognize the corresponding ligand expressed in large quantities on the surface of senile cells, thereby promoting the secretion of perforin and granzyme, which kill senile cells. For example, senescent hepatic stellate cells up-regulate MICA and ULBP2 on the cell surface, which are ligands that activate the receptor NKG2D on NK cells [56]. DC cell, an antigen presenting cell bridges innate immunity and adaptive immunity. In theory, DC cells transmit the antigen information of processed senescent cells to T cells, so that T cells recognize and kill senescent cells. However, the specific mechanism by which DC cells participate in senescent cell clearance remains unclear. As the body’s long-acting weapon against ”enemies”, adaptive immune cells, especially T cells, play an important role in anti-aging. High levels of CD4 + cytotoxic T cells in the blood are a distinguishing feature of supercentenarian. Senescent skin fibroblasts overexpress human leukocyte antigen Class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), and by recognizing these biomarkers CD4 + cytotoxic T cells directly killed senescent skin cells [57]. However, during the compensation period of aging, immune system is also constantly weakened. On the one hand, senescence of immune cells occurs under internal and external stimulation, on the other hand, the senescent cells make immune cells senescent and dysfunctional through the continuous secretion of SASP. Specifically, the chemotaxis and phagocytosis activities of macrophages and NK cells gradually decreased, the ability of phagocytosis and antigen presentation of DC cells is declining, and the co-receptors that promote antigen recognition sensitivity of lymphocytes are down-regulated [58]. With the increase of age, the proportion of immune cells will also change. For example, the proportion of Natural Killer Group 2 Member A (NKG2A)-positive CD8 + T cells will increase sharply, which protects more aging dermal fibroblasts from immune clearance [59]. Weakened immune system promotes accumulation of senescent cells, which causes a decline in functions of various tissues and poor physical status of the elderly. Although the body is still able to compensate for these changes without causing histopathological alterations, interventions are urgently needed to slow down the aging process to prevent the elderly from prematurely entering the disabling stage. 4.2. Coping strategies In the early stage of senescence, the rate of cell senescence is not as fast as the rate of immune clearance. The main strategy to deal with senescence is to delay the rate of cell senescence, such as reducing the intensity of internal and external stimuli. However, the ageing compensation stage is characterized by the accumulation of senescent cells, interactions between senescent cells, stem cell exhaustion and immune dysfunction. Therefore, more targeted prevention and treatment strategies are needed, such as artificial elimination of senescent cells, stem cell supplementation, neutralization of SASP, activation of the immune system, and lifestyle guidance. Since the immune system gradually degrades during the compensation period of aging, could it be possible to remove senescent cells by artificially introducing natural or synthetic drugs instead of the immune system? Scientists at the Mayo Clinic have identified a drug called AP20187, which uses ”genetic recognition” technology to precisely identify and eliminate p16Ink4a-positive senescent cells in mice. This drug has extended the lifespan of the mice by 36% [60]. However, the specificity of AP20187 in killing senescent cells is not strong, because not all p16Ink4a-positive cells are senescent cells. In recent years, it has been discovered that senescent cells resist natural apoptosis through some senescence-cell anti-apoptotic pathways (SCAPs), thereby accumulating in large numbers within the body. Many drugs targeting these SCAPs have been developed to precisely and specifically kill senescent cells, and these drugs are collectively referred to as ”senolytics”. Zhu et al. compared the transcriptomics of healthy and senescent adipocytes and screened several SCAPs by RNA interference, including cyclin-dependent kinase inhibitor 1A (p21), the phosphatidylinositol-4,5-bisphosphate 3-kinase delta catalytic subunit (PI3Kδ), ephrins, B cell lymphoma (Bcl), and so on [61]. The exploration of SCAPs has led to the development of the first generation of senolytic drugs. For example, dasatinib promotes apoptosis of pre-adipocytes by affecting ephrin receptors, while quercetin promotes apoptosis of senescent human umbilical vein endothelial cells (HUVECs) through molecules such as Bcl-2, p21, and PI3Kδ [62]. Because aging typically involves multiple cell types and the therapeutic effect of a single drug is limited, the combination of dasatinib plus quercetin (D + Q) has been widely applied to alleviate aging in various tissues and organs, such as adipose tissue, skin, intestines, and intervertebral discs [63]. Other senolytic drugs like ABT263 work by inhibiting Bcl-2 to promote apoptosis in aging human WI-38 lung fibroblasts [64]. Second-generation senolytic drugs that kill senescent cells through pathways other than SCAPs have also gradually emerged. A common feature of senescent cells is high lysosomal beta-galactosidase activity, and Galactose modified Dukaramycin or doxorubicin has been shown to prefertively kill senescent cells, showing therapeutic potential for pulmonary fibrosis [65]. Senescent cells typically upregulate kidney-type glutaminase (KGA) to induce ammonia production, which neutralizes the decrease in pH caused by lysosomal membrane rupture. Inhibition of glutaminolysis reduced the proportion of CD26-positive populations in pulmonary mesenchymal cells of aged mice and significantly improved the function of organs such as the lungs and kidneys in aged mice [66]. A series of methods targeting stem cell exhaustion have been developed to slow down aging, among which the most direct method is transplantation of stem cells. It has been reported that after receiving mesenchymal stem cells from young donors, elderly patients with frailty saw an increase of 10% in their 6-minute walk distance, and there was also an improvement in their average cognitive scores [67]. Aging hematopoietic stem cells highly express CD150, CD41, CD62p, and NEO1, and antibodies targeting these molecules have been proven to reverse the myeloid differentiation tendency of aged hematopoietic stem cells and restore youthful immunological characteristics [51]. Additionally, blocking the inducing factors of stem cell exhaustion is also a strategy. For instance, inhibition of ABL1 through Imatinib blocks the aging of neural stem cells, and silence of circular RNA SERPINE2 inhibits the senescence of mesenchymal stem cells [52, 68]. Senomorphics are a class of drugs that target the SASP to inhibit aging. Compared to senolytics which selectively eliminate senescent cells, senomorphics tend to regulate aging-associated properties. On the one hand, senomorphics inhibit the production of SASP by regulating signaling pathways such as NF-κB, p38, and mTOR [53]. For example, metformin inhibits SASP secretion of senescent endothelial cells through NF-κB signaling pathway [69]. On the other hand, some senomorphics directly neutralize SASP. The use of IL-6 antibody significantly reduced the level of IL-6 secreted by senescent osteoblasts and inhibited high tumor colonization tendency driven by senescence-associated IL-6 [70]. By supplementing exogenous immune cells, eliminating senescent immune cells, or blocking the senescent state of immune cells, the immune system can be activated to enhance immune clearance. One method of immune activation is to inject high-quality innate or acquired immune cells that have been grown and expanded in vitro back into the body. Adoptive infusion of NK cells has been shown to play a prominent role in many immune system-related diseases. Autologous NK cell infusion reduced the level of aging marker P16 mRNA in mouse liver tissue to only about 70% of the control group, while the combination of immunomodulator dopamine further reduced the level of P16 mRNA to 40% of the control group [71]. Another approach is to expand immune cells in vitro and equip them with the ability to recognize target cell-specific antigens, such as chimeric antigen receptor (CAR-T) cell therapy. Natural killer group 2 member D ligands (NKG2DLs) is usually highly expressed on the surface of senescent cells, so CAR-NK or CAR-T cells modified to express NKG2D can target and kill senescent cells [56]. After 21 days of treatment with NKG2D-CAR T cells, NKG2DL-positive cells in the liver and lungs of 24-month-old mice were significantly reduced. After 6 months of continuous treatment, the bone volume fraction of the mice increased by more than double that of the control group, and the physical function was also significantly improved [72]. However, it should be noted that NKG2D-CAR T cells may kill some cells with high expression of NKG2DL caused by inflammation, thus aggravating inflammation or tissue damage, so it is necessary to comprehensively evaluate the aging and inflammation status of the elderly when actually using them. The accumulation of senescent immune cells will occupy the proliferation space of normal immune cells and greatly reduce the immune capacity of the body. To solve this problem, selective elimination of aging immune cells is needed, such as blood filtration. Specifically, by using superparamagnetic nanoparticles coated with antibodies against the surface marker KLRG1 (Killer cell lectin-like receptor G1) of senescent cytotoxic T cells to selectively label senescent cells in the blood of mice, followed by magnetic separation, the percentage of senescent CD8 + T cells among total CD8 + T cells was reduced by 88% [73]. Blocking or reversing the aging state of immune cells may restore their immune activity. Inhibition of p38 MAPK signaling pathway enhances telomerase activity and proliferation ability of senescent CD8 + T cells.[74] Supplementation of type 2 cytokines, such as IL-4, improves DNA repair in macrophages, thereby preventing them from aging [75]. In addition to the coping strategies designed to target the molecular mechanisms of aging mentioned above, elderly individuals in the compensatory phase of aging also need to pay more attention to exercise, diet, and the use of nourishing Chinese herbs in their daily lives, as well as take measures to prevent progression to the decompensatory phase of aging. Firstly, according to report, after 12 weeks of scientific training, the physical functions of the elderly have significantly improved, and their CD3 + T cells have shown low levels of the aging-associated proteins p16 and p21 [76]. 4 weeks of swimming training prevent endothelial cell senescence in mice by increasing the level of FUN14 domain containing 1 (FUNDC1) in the coronary artery [77]. This indicates that a structured exercise program effectively combats aging at the cellular level. Secondly, in terms of dietary approaches, 2 years of moderate calorie restriction reduced cellular aging biomarkers such as the receptor for advanced glycation end-products (RAGE) in middle-aged individuals [78]. This demonstrates the benefits of calorie restriction in delaying aging, but it is also important to ensure adequate nutritional intake. Thirdly, Chinese herbs, the treasure of China, have played some magical roles in retardation of aging. Bazi Bushen Capsule (BZBS) is a Chinese patent medicine composed of ingredients such as dodder seeds and goji berries. After taking BZBS for 12 weeks, the subjects showed improvements in physiological parameters such as grip strength and balance test, as well as a 76.7% increase in telomerase activity compared to the placebo group [79]. In addition, a variety of herbs such as astragalus membranaceus, ganoderma lucidum, ginseng, psoralea corylifolia, and rhodiola rosea had also demonstrated potential effects in anti-aging [80]. Lastly, as aging progresses, the physical state of the elderly in the compensatory phase of aging is deteriorating, and even a certain degree of functional and structural damage has occurred in their organs. At this time, they must pay special attention to risk factors of their lives to prevent entering the compensatory phase of aging characterized by major diseases. For example, the elderly need to be prevented from falling, as their bones are more fragile and they are very prone to fracture after a fall. The aging of blood vessels and increased blood viscosity in the elderly indicate that they need to maintain appropriate exercise and avoid prolonged sitting or standing to prevent the occurrence of thrombotic diseases. Because of the reduced lung function and immunity, older adults need protection from colds or exposure to harmful gas particles to prevent chronic obstructive pulmonary disease. Additionally, they should also avoid emotional excitement, intense exercise, overeating, or excessive drinking to prevent stroke and coronary heart disease. During the compensatory phase of aging, capability of immune clearance continuously degenerates, and senescent cells accumulate gradually. At this stage, the tissues do not show pathological changes because the organism is able to compensate for the changes caused by senescent cells. As a result, the elderly only feel a deterioration of general state in their daily lives, but they do not have any pain and their quality of life is relatively good, so they do not seek medical attention in a timely manner. It is precisely this ”boiling frog” style accumulation of senescent cells that leads to severe organ failure and age-related diseases in the future. Therefore, we advocate that the elderly should seek medical attention promptly during the compensatory phase of aging, and ideally, regularly clear senescent cells from their bodies to slow down the pace of aging. 5. Ageing disability stage Ageing disability stage refers to a period in which elderly individuals are unable to independently perform daily activities due to the decline of physical functions, age-related diseases, or the influence of social factors. A notable deterioration in physiological functions is the hallmark of this stage, often manifesting as cognitive decline, sensory impairments, compromised motor coordination. As a result, individuals may require assistance from caregivers or medical support to manage their daily lives. This stage of aging disability not only profoundly impacts the quality of life for elderly individuals but also imposes a substantial caregiving burden and economic strain on families and society. 5.1. Cognitive and sensory dysfunction 5.1.1. Alzheimer’s disease (AD) As age increases, the production of amyloid β-protein in the brain of elderly individuals increases sharply, contributing to the formation of extracellular amyloid plaques between neurons—a hallmark of AD pathogenesis. Age-related activation of microglia exacerbates neurotoxicity by promoting inflammatory responses, which directly damage neurons and accelerate disease progression. Concurrently, age-associated declines in mitochondrial function and heightened oxidative stress induce neuronal apoptosis and compromise synaptic integrity, leading to progressive cognitive and functional deterioration [81]. Current treatments for AD include cholinesterase inhibitors and NMDA receptor antagonists to manage symptoms, along with emerging disease-modifying therapies such as amyloid-targeting monoclonal antibodies and tau pathology modulators [82]. Additionally, unique interventions addressing the aging process involve senolytics such as D+Q to clear senescent cells, mitochondrial homeostasis modulator such as curculigoside to reduce oxidative stress injury, and lifestyle modifications like cognitive training to enhance neuroprotection and overall brain health in older adults [81]. 5.1.2. Parkinson ’s disease (PD) PD is a neurodegenerative disease characterized by the progressive death of dopaminergic neurons. With the increase of age, the autophagy and mitochondrial function of neurons gradually decline, resulting in the accumulation of toxic substances in cells, which in turn leads to apoptosis. In addition, age-related oxidative stress aggravates the damage of dopaminergic neurons and promotes the formation of lewis body, which is an important pathological feature of PD [83]. Changes in the microenvironment, such as increased neuroinflammation caused by the release of activated microglia and cytokines during aging, also play a key role in the disease process. Current therapeutic approaches for PD associated with aging integrate symptomatic management and disease-modifying strategies. Pharmacological interventions include dopamine replacement therapy, deep brain stimulation, and emerging neuroprotective agents targeting α-synuclein aggregation. Regarding the pathological mechanisms related to aging, prostaglandin F2α helps with cerebrospinal fluid drainage, thereby effectively removing harmful wastes from the ageing brain [84]. 5.1.3. Senile visual impairment As the age increases, proteins in the lens of elderly patients undergo progressive oxidative damage, culminating in the formation of cataracts and subsequent blurred vision. Glaucoma, another age-related ocular condition, is strongly associated with elevated intraocular pressure and degenerative changes in the optic nerve, often exacerbated by age-related vascular dysfunction and impaired aqueous humor outflow dynamics. Age-related macular degeneration (AMD) arises from inflammation and oxidative stress in the macular area of the retina, leading to lipid deposition and apoptosis of retinal cells [85]. The age-dependent decline in cellular function and antioxidant defenses further amplifies these ocular pathologies, collectively impairing visual health of elderly population. In treatments of AMD and cataracts, intravitreal injections of anti-VEGF agents and photodynamic therapy are employed to address AMD, while cataract surgery remains the standard intervention. Nutritional supplementation of lutein and zeaxanthin has been found to slow progression of AMD and other ageing-related visual impairment [86]. Furthermore, advancements in gene therapy and regenerative approaches, such as stem cell therapy, are being explored to restore vision and enhance retinal health in older adults. 5.1.4. Senile hearing impairment The hair cells and auditory neurons in the inner ear gradually degenerate and lose with age, resulting in a decrease in auditory conduction and processing ability. Oxidative stress is considered to be an important factor affecting hearing. During aging, the accumulation of ROS and chronic inflammation can damage the inner ear structure and aggravate cell damage [87]. Genetic factors and long-term noise exposure also accelerate the process of hearing loss, thus impairing auditory function. The interaction of these pathological mechanisms leads to a marked increase in the incidence of hearing impairment among the elderly population, which seriously affects their quality of life and social engagement, exacerbating isolation and cognitive decline. Hearing aids and cochlear implants remain primary management strategies. Ageing-related interventions include antioxidant supplementation, mitochondrial function modulators, and regenerative approaches targeting hair cell restoration. Gene therapies exploring DFNA5 and connexin 26 mutations are advancing, alongside stem cell technologies aimed at neural regeneration [88]. Complementary strategies involve noise exposure reduction, auditory rehabilitation, and lifestyle modifications to mitigate age-related cochlear degeneration and preserve auditory function. 5.2. Cardiopulmonary dysfunction 5.2.1. Heart failure Aging-related chronic low-grade inflammation (inflammaging) and elevated oxidative stress induce cardiomyocyte apoptosis and dysfunction. Gradually, myocardial tissue experiences fibrosis and infiltration of fat, contributing to the structural hallmarks of heart failure characterized by impaired cardiac contractility and reduced ejection fraction. Concurrently, the inherent adaptive mechanisms of the cardiovascular system, such as compensatory hypertrophy and autophagy diminish with age, impairing the heart’s capacity to respond to hemodynamic stressors [89]. Standard pharmacological interventions for age-related heart failure include ACE inhibitors, beta-blockers, and diuretics to improve cardiac function and manage fluid overload. The use of SGLT2 inhibitors reduces the preload of the heart and improves myocardial energy metabolism. Notably, inflammaging blockers, such as anti-IL-6R monoclonal antibodies, have been proven to improve cardiac function in mice with heart failure [90]. Engineered heart muscle derived from induced pluripotent stem cells enabled myocardial regeneration in a patient with advanced heart failure. Additionally, lifestyle changes such as exercise training, low-salt diet, and weight management are crucial for preventing the progression of heart failure. 5.2.2. Acute myocardial infarction (AMI) With increasing age, the incidence of atherosclerosis increases, making the plaques formed in the coronary arteries prone to rupture, resulting in blood flow obstruction and AMI. Additionally, the aging myocardium develops hypertrophy and reduced elasticity, impairing tolerance to acute ischemia. Ageing-related factors such as inflammatory responses and oxidative stress further increases the risk of cardiovascular events. Comorbidities, such as hypertension, diabetes, and hypercholesterolemia, are prevalent among older patients, significantly elevating the risk of myocardial ischemia [91]. Current treatment strategies for AMI in older adults emphasize rapid reperfusion therapies, including percutaneous coronary interventions (PCI) and thrombolytics, complemented by antiplatelet agents and statins [92]. Given the age-related alterations in pharmacokinetics and cardiac function, careful dosing and monitoring are essential. 5.2.3. Chronic obstructive pulmonary disease (COPD) Age is an important risk factor for COPD. The level of oxidative stress in the lung tissue of the elderly is significantly increased, causing cell damage, accompanied by the release of a large amount of inflammatory factors by airway epithelial cells, alveolar macrophages, etc. These changes lead to chronic bronchitis and emphysema, eventually causing a decrease in the elasticity of lung tissue, alterations in the structure of airway walls, and airflow limitation [93]. Current treatment options for COPD in aging populations primarily include bronchodilators, inhaled corticosteroids, and long-acting muscarinic antagonists (LAMAs) to alleviate symptoms and enhance lung function. The treatment strategy also includes some anti-ageing agents, such as antioxidants (e.g., N-acetylcysteine) and anti-inflammatory agents (e.g., roflumilast) [94]. 5.2.4. Idiopathic pulmonary fibrosis (IPF) IPF is closely related to aging, with mechanisms primarily involving cellular senescence, inflammatory responses, and changes in alveolar structure. As individuals age, telomere shortening leads to senescence of alveolar epithelial cells, accompanied by excessive deposition of collagen in aging lung tissue, trigger the remodeling of the pulmonary interstitium and pulmonary fibers [95]. Impaired autophagy restricts the clearance of damaged cells and the accumulation of ROS within cells damages DNA, proteins, and lipids, further driving pathological progression. Current treatment strategies for IPF in the aging population primarily involve antifibrotic agents, such as nintedanib and pirfenidone, which are effective in slowing disease progression. Given the complexities of aging, management often includes supportive therapies like supplemental oxygen and pulmonary rehabilitation to enhance quality of life. Additionally, novel drug therapies targeting age-related pathways, including immunomodulators such as pirfenidone, and investigational agents like thyme extract and stem cell therapies, are being studied to reverse fibrosis and promote lung regeneration, thereby improving outcomes in elderly patients with IPF [96]. 5.3. Metabolic dysfunction 5.3.1. Cirrhosis As individuals age, the regenerative capacity of hepatocytes declines, leading to limited repair of damaged liver and promoting the progression of fibrosis. Additionally, cellular senescence accumulates in the liver, with senescent hepatocytes and stellate cells releasing pro-inflammatory and pro-fibrotic factors, exacerbating inflammatory responses and collagen deposition [97]. Current treatments for liver cirrhosis in the aging population focus on managing complications, including portal hypertension, ascites, and hepatic encephalopathy, with beta-blockers and diuretics being commonly used. Therapies targeting age-related factors include the use of antifibrotic agents, such as simtuzumab, which aim to inhibit collagen deposition and fibrosis progression [98]. Additionally, regenerative medicine, stem cell therapy, and anti-aging compounds like metformin, is ongoing to improve liver function and quality of life in elderly patients with cirrhosis. 5.3.2. Diabetes and renal failure Diabetes and its complications, including metabolic disorders of renal function (acute kidney injury (AKI) and chronic kidney disease (CKD), are closely related to age-related biological changes. Firstly, ageing-associated decline in pancreatic β-cell function and decreased insulin sensitivity triggers hyperglycemia and the onset of diabetes. Senescence cells accumulate in pancreatic and renal tissues, and the ageing-related chronic inflammation and oxidative stress damage renal tubular epithelial cells, accelerating the process of interstitial fibrosis in the kidney. Moreover, hyperglycemia and hypertension resulting from diabetes further impair glomerular endothelial function, leading to microvascular complications [99]. During the aging process, the regenerative capacity of the kidneys decreases, resulting in irreversible damage to the renal tubules and glomeruli, which heightens the risk of AKI progressing to CKD. Current treatment strategies for diabetes and renal failure in aging populations integrate glycemic control with tailored insulin regimens and nephroprotectors such as SGLT2 inhibitors and DPP-4 inhibitors. Emerging anti-ageing agents like metformin and rapamycin aim at mitigating cellular senescence and inflammation. Personalized treatment plans emphasize careful medication dosing, comprehensive metabolic monitoring, and lifestyle modifications to optimize glycometabolism and kidney function [100]. 5.4. Locomotor dysfunction 5.4.1. Osteoporotic fracture As individuals age, bone mass gradually decreases, leading to the degradation of bone microstructure and a reduction in bone strength, which increases the risk of fractures. Osteoblasts and bone marrow mesenchymal stem cells show more senescent phenotypes over time, with decreased proliferation and differentiation capacities, significantly reducing osteogenic activity. Senescent cells promote inflammaging by secreting pro-inflammatory SASPs, inhibiting bone repair. Meanwhile, increased activity of osteoclast exacerbates bone metabolic imbalance and contributing to bone loss [101]. Additionally, factors such as nutrient deficiencies, reduced physical activity, and vitamin D deficiency negatively impact bone health, further raising the risk of fractures. Decreased muscle strength in older adults makes them susceptible to fall resistance and also increases the incidence of fractures. Current treatment approaches for osteoporotic fractures in the elderly population emphasize the use of bisphosphonates, denosumab, and selective estrogen receptor modulators (SERMs) to enhance bone density and reduce fracture risk. The supplementation of calcium and vitamin D also help improve bone density. Additionally, anabolic agents like teriparatide and romosozumab are emerging as effective options, promoting new bone formation in elderly patients. Tailored fall prevention strategies, along with exercise programs aimed at improving balance and strength, play a critical role in comprehensive care for elderly individuals with osteoporosis, addressing the unique challenges associated with aging [102]. 5.4.2. Muscular dystrophy Sarcopenia is a progressive decline in skeletal muscle mass and function that occurs with aging. Firstly, aging leads to reduced levels of growth hormone and testosterone, which hinders muscle synthesis. Secondly, senescence cells accumulate in muscle tissue, resulting in decreased proliferation and differentiation capabilities of satellite cells, limiting muscle repair. Neuro-muscular junction degeneration leads to the loss of neural innervation in muscle fibers, resulting in decreased muscle strength [103]. Endocrine changes, such as declines in growth hormone and sex hormone levels, further impact muscle metabolism and protein synthesis. Additionally, nutritional deficiencies, particularly inadequate protein intake, negatively affect muscle synthesis. Current treatment strategies for muscular dystrophy in aging populations focus on preserving muscle function and enhancing quality of life. Therapeutic approaches include corticosteroids, which reduce inflammation and slow muscle degeneration, and exon-skipping therapies (e.g., eteplirsen) designed to address specific genetic mutations [104]. Additionally, myostatin inhibitors are being investigated to promote muscle regeneration and mitigate the effects of muscle dystrophy associated with ageing. 5.4.3. Joint and intervertebral disc lesions Chondrocytes in articular cartilage partly undergo cell senescence with ageing, resulting in diminished synthesis of extracellular matrix and cartilage degeneration. At the same time, the expression of degrading enzymes (e.g., MMP) increases, accelerating cartilage degradation. Inflammaging induces joint pain through pro-inflammatory factors (e.g., IL-6 and TNF-α) [105]. Meanwhile, Reduced water content in the intervertebral disc diminishes its elasticity and load-bearing capacity. Senescence of nucleus pulposus cells is associated with proteoglycan loss, which impairs the intervertebral disc’s shock-absorbing capacity, contributing to disc degeneration and pain. Immunosenescence and cumulative mechanical stress further exacerbate joint and disc degeneration, ultimately predisposing individuals to osteoarthritis and degenerative disc disease. Mitigating degeneration and promoting regeneration are effective therapeutic strategies for treating joint and intervertebral disc lesions. Anti-inflammatory treatments such as NSAIDs and topical steroid injections can effectively relieve inflammation and pain. Rehabilitation training enhances joint stability and improves functions. Stem cell therapy and gene therapy restore tissue function by activating the regenerative potential of cartilage or intervertebral disc cells. Joint replacement surgery also provides an effective solution for patients with severe lesions [106]. 5.5. Cancer Cell senescence is driven by telomere shortening and oncogene activation as a protective mechanism against tumor formation. However, the persistence of senescent cells promotes tumorigenesis through secretion of SASPs (e.g., IL-6, IL-8, and CXCL1), which enhance inflammation, promote angiogenesis. In addition, immunosenescence weakens immune surveillance and immune clearance, promoting cancer progression [107]. In current cancer treatment strategies for elderly populations, immunotherapy (e.g., checkpoint inhibitors and CAR-T cell therapy), molecularly targeted therapy, and precision medicine techniques are increasingly employed. Tailored treatment protocols incorporate reduced-intensity chemotherapy, adaptive dosing strategies, and supportive care interventions to minimize toxicity while maintaining therapeutic effectiveness. Combination approaches integrating genomic profiling, immunomodulatory agents, and anti-aging compounds represent promising strategies for optimizing cancer management in elderly patients [108]. Author Contribution declaration Writing-original draft, Zhonghan Wang, Shixian Liu, Shangyu Du, Xiangran Cui; Conceptualization, Zhonghan Wang, Minfei Wu; Investigation, Zhonghan Wang, Shixian Liu, Shangyu Du, Xiangran Cui, Bo Chao, Minglei Liu; Writing-review and editing, Zhonghan Wang, Shixian Liu, Minfei Wu. All authors have read and approved to the published version of the manuscript. Competing Interest declaration The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics and Consent to Participate declarations Ethics and Consent to Participate declarations: not applicable Funding Declaration The study was financially supported by the Jilin Provincial Science and Technology Department Project (Grant No. YDZJ202401434ZYTS, YDZJ202301ZYTS031), the Jilin Provincial Budget Capital Construction Fund (Innovative Capability Building) (Grant No. 2024C017-9), the Jilin University Bethune Plan Project (Grant Nos. 2023B10), and the Jilin University Graduate Innovative Research Program Project (Grant Nos. 2024CX263 and 2025CX294). References 1. Beard JR, Officer A, de Carvalho IA, Sadana R, Pot AM, Michel JP, Lloyd-Sherlock P, Epping-Jordan JE, Peeters G, Mahanani WR, et al: The World report on ageing and health: a policy framework for healthy ageing. Lancet 2016, 387: 2145-2154.2. Behr LC, Simm A, Kluttig A, Grosskopf Grosskopf A: 60 years of healthy aging: On definitions, biomarkers, scores and challenges. Ageing Res Rev 2023, 88: 101934.3. 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Collection View Keywords ageing ageing management clinical stages healthy lifespan Authors Affiliations Zhonghan Wang The Second Hospital of Jilin University View all articles by this author Shixian Liu The Second Hospital of Jilin University View all articles by this author Shangyu Du The Second Hospital of Jilin University View all articles by this author Xiangran Cui The Second Hospital of Jilin University View all articles by this author Bo Chao The Second Hospital of Jilin University View all articles by this author Minglei Liu The Second Hospital of Jilin University View all articles by this author Minfei Wu 0000-0001-8230-3774 [email protected] The Second Hospital of Jilin University View all articles by this author Metrics & Citations Metrics Article Usage 222 views 164 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Zhonghan Wang, Shixian Liu, Shangyu Du, et al. Staging concept for ageing management: definition, mechanism and coping strategies. 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