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| The seven pillars of ageing. The seven pillars are inflammation, stem cell regeneration, macromolecular damage, stress, proteostasis, metabolism and epigenetics 1 . The relationships between the pillars are shown by the interconnected network. The pillars are shared by ageing and age-related diseases.
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Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pa...
Citations
... The increase of senescent cells can also disrupt tissue homeostasis and contribute to chronic low-grade inflammation that develops with age (inflammaging) [20]. The senescence-associated secretory phenotype (SASP) consists of a complex mixture of cytokines, chemokines, growth factors, proteases and reactive oxygen species (ROS) that may induce senescence in surrounding cells [21]. ...
Citation: Miller, A.; Kwiecień, I.; Bednarski, M.; Zygmunt, M.; Sapa, J.; Sablik, M.; Lombardo, G.P.; Condurso, C.; Merlino, M.; Kotańska, M. Promising Dietary Supplements with Abstract: In the present study, the primary by-products of the hemp-seed oil process-hemp seed cake flour and hemp seed protein concentrate-underwent enzymatic hydrolysis using proteases and carbohydrases, either individually or in combination. The effectiveness of these enzymatic treatments in releasing bioactive compounds was evaluated by assessing the antioxidant and anti-inflammatory properties of the aqueous extracts of both hydrolysed and untreated hemp by-products. The aim was to explore their potential senotherapeutic properties and promote their application as dietary supplements. Secondary metabolites such as flavonoids, phenolic acids, and catechins were analysed using high-performance liquid chromatography. Total phenolic, flavonoid, and protein contents were determined using spectrophotometric methods. Scavenging activity (2,2-Diphenyl-1-picrylhydrazyl scavenging assay (DPPH assay)), antioxidant power (Ferric reducing antioxidant power assay (FRAP assay)), and lipid peroxidation-reducing activity (thiobarbituric acid-reactive substance analysis) were assessed through in vitro assays. Possible anti-inflammatory effects were evaluated by assessing haemolysis inhibition. The impact of extracts on albumin glycation induced by exposure to fructose was also determined. To assess the toxicity of extracts, a zebrafish larvae model was employed. All extracts contained significant amounts of phenolic compounds, flavonoids, and proteins, and they exhibited notable activities in reducing lipid peroxidation and stabilising erythrocyte cell membranes. However, they did not significantly influence protein glycation (the glycation inhibition was only in the range of 15-40%). Our research demonstrates the substantial health-promoting potential, including senescence delay, of aqueous extracts from by-products of the hemp-seed oil process, which are available in large quantities and can serve as valuable supplements to support the health of animals, including humans, rather than being discarded as waste from oil production.
... 2 Intriguingly, the well-known aging pillars converge on inflammation since the impairment of any single pillar powers inflammation, which subsequently affects all the other pillars. [3][4][5] Similarly, López-Otín et al. proposed that inflammation is an interconnection with the twelve integrative hallmarks of aging and recognized the gut microbiome as a new hallmark of aging. 6,7 Studies have revealed the uniqueness of an individual's microbiome and identified microbial metabolites involved in immune regulation, inflammation, and aging. ...
Aging involves the accumulation of various forms of molecular and cellular damage over time. Key features of aging, such as mitochondrial dysfunction, dysbiosis, and oxidative stress, are closely linked and largely driven by inflammation. This study examines the role of succinate, a key metabolite produced and utilized by cells of both host and microbes, and its receptor, succinate receptor 1 (SUCNR1), in age-related oral dysbiosis and inflammation. We examined young and aged wild-type (WT) and SUCNR1 knockout (KO) mice for this analysis. Our findings revealed significant aging-associated alveolar bone loss and succinate elevation in aged WT mice, along with notable changes in the oral microbiome. Conversely, aged KO mice showed reduced bone loss, lower succinate levels, less inflammation, and better-maintained microbial function. These results suggest that SUCNR1 is crucial in influencing aging-related succinate elevation, oral dysbiosis, and inflammation. Analysis of gene families and pathways in the oral microbiome demonstrated distinct aging-related changes between WT and KO mice, with the functional potential being preserved in the KO-aged group. This study underscores the importance of succinate elevation and signaling through SUCNR1 in regulating inflammation, alveolar bone loss, and shifts in the oral microbiome, offering potential targets for therapeutic interventions in age-related oral health issues.
... Aging is accompanied by a wide range of physiological changes, such as chronic inflammation (López-Otín et al, 2023). Ageassociated inflammation in the absence of overt infection has been termed inflammaging (Franceschi et al, 2018). While the origins of inflammaging are mostly unclear, it is typically characterized by high levels of pro-inflammatory cytokines, chemokines, acute phase proteins, and soluble cytokine receptors in the serum (Franceschi et al, 2018;Li et al, 2023). ...
... Ageassociated inflammation in the absence of overt infection has been termed inflammaging (Franceschi et al, 2018). While the origins of inflammaging are mostly unclear, it is typically characterized by high levels of pro-inflammatory cytokines, chemokines, acute phase proteins, and soluble cytokine receptors in the serum (Franceschi et al, 2018;Li et al, 2023). Inflammaging was shown to contribute to the development of age-associated diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer (López-Otín et al, 2023). ...
Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/-tert-/-double-mutant animals and observed a thorough rescue of tert-/-phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/-tert-/-zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telo-merase mutant animals.
... Pathways associated with the altered intercellular communication hallmark include Gap junction, Tight junction, Cell-adhesion molecules, ECM-receptor interaction, and Protein-protein interactions at synapses, underscore that impaired cell-cell communication and structural remodeling accompany aging 23 . ...
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. In this study, we performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). After adjusting for age, sex, and immune cell type proportions, and correcting for batch effects and genomic inflation, we identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with aging in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted immune response, metabolic regulation, and synaptic plasticity, all of which are key biological processes implicated in AD. Moreover, our colocalization analysis revealed 32 genomic regions where shared genetic variants influenced both DNAm and dementia risk. Adjusting for age and other covariate variables, we found roughly one-third of aging-associated CpGs are also associated with AD or AD neuropathology in independent studies external to the ADNI and FHS datasets. Finally, we prioritized 9 aging-associated CpGs, located in promoter regions of PDE1B, ELOVL2, PODXL2, and other genomic regions, that showed strong positive blood-to-brain methylation concordance, as well as association with AD or AD neuropathology in independent studies, after adjusting for age and other covariates. Our findings provided insights into the functional overlap between the aging processes and AD, and nominated promising blood-based biomarkers for future AD research.
... The ability of the immune system to respond to infectious challenges declines with increasing age, leading to increased hospitalization, increased mortality, and chronic repercussions [1,2]. In older individuals, there is a systemic increase in sterile inflammation and expanded dysfunctional immune cell subsets that are hyper-and hypo-responsive depending on the stimuli or cellular context [3][4][5][6]. These major age-associated alterations of the immune system are collectively referred to as immunosenescence. ...
CD8+ T cells exhibit distinct changes with aging, including a diminished naïve cell pool, an expansion of memory and exhausted cells, and altered effector molecule production, altogether leading to increased susceptibility to infection. They have reduced cytotoxicity in vivo, but increased granule content and faster cytotoxic kinetics to target cells in vitro. Whether CD8+ T cells from old mice degranulate when activated in vivo, within the aged environment, is unknown. This study investigates in vitro and in vivo degranulation of CD8+ T cells from young and old mice during supraphysiological aCD3 stimulation and two types of infection. Actively degranulating CD8+ CD44+ T cells were identified by positive labeling after a two-hour exposure to granule-specific fluorescent antibodies (CD107a and CD107b). Surprisingly, CD8+ T cells from old mice challenged with supraphysiological TCR-specific stimulation exhibited higher levels of degranulation as compared to their young counterparts. This effect is more prominent in vitro and can be partially explained by the age-specific increase in CD8+ CD44+ CD62L− cells. However, during microbial exposure or LCMV Armstrong infection, we show that CD8+ CD44+ and antigen-specific T cells from old mice have reduced degranulation, consistent with the diminished cytotoxic capacity. These data highlight the preserved intrinsic cytotoxic capacity of memory CD8+ T cells from old mice and suggest that the aged microenvironment and type of stimulation are contributing factors to the lower degranulation and cytotoxic capacity of these cells. This provides insight into the potential of increasing T cell activation to improve vaccine approaches in the elderly.
... Immunosenescence describes dysregulated adaptive and innate immune responses that increase the risk of infection and malignancy as people age, while inflammaging refers to the low-grade chronic inflammation throughout the aging process that produces a broad range of tissue damages and chronic conditions. The former may contribute to the decline in acute inflammatory demyelination events while the latter may contribute to the disability accrual and disease progression with aging [18]. Among the cells crucial in MS pathogenesis and progression, Th17 cells also play a significant role in mediating inflammaging [19,20]. ...
Background
Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA.
Methods
We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50 µg/ml of MBP (or heat-killed Candida) for 24 h. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine response drives the association between age and ARR.
Results
Among 669 pwMS (mean age 51.7 ± 12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p < 0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p = 0.04) but not men (β=-0.1, p = 0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.6% in women, 15.3% in men). In exploratory analyses, older pwMS (≥ 50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (< 50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.
Conclusion
Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.
... These systems comprise antioxidant enzymes and molecules with antioxidant capacity (Chung et al. 2009;Lennicke et al. 2015). The term 'inflammaging' is commonly ascribed to the chronic low-grade inflammation that occurs as individuals age, and it has been proposed as a significant factor linking physiological changes during aging to the development of age-related degenerative illnesses (Franceschi et al. 2018). ...
A relatively recently identified type of controlled cell death termed ‘ferroptosis’ is driven by iron and characterized by reactive oxygen species (ROS) buildup and lipid peroxidation. This review explores the complex mechanisms underpinning ferroptosis and its potential effects on the onset and development of neurodegenerative diseases. The impact of lipid peroxides, glutathione/glutathione peroxidase 4 (GSH/GPX4), and iron metabolism‐targeting small molecule inhibitors and the involvement of nucleic acids, proteins, and phytochemicals as inhibitors of ferroptosis will be discussed. Additionally, we explore the potential of ferroptosis as a therapeutic target for managing neurodegenerative disorders and address the challenges faced in clinical translation. The emerging research on novel drug delivery approaches and nanomaterial‐based strategies for efficient ferroptosis inhibition is also described. In conclusion, this review provides a detailed overview of the complex landscape of ferroptosis, providing insights into its molecular mechanisms, inhibitors, and potential therapeutic applications. Understanding the multifaceted role of ferroptosis in disease pathogenesis will pave the way for developing innovative interventions to harness its therapeutic potential in various neurological conditions.
... This chronic, low-grade inflammation that often develops during aging is provoked by a continuous antigenic load and associated with a reduced efficacy of the anti-inflammatory mechanisms and has been termed "inflammaging." Inflammaging progressively weakens the body's ability to adequately respond to external injuries and thus contributes to the pathogenesis of age-related diseases [8]. ...
Frailty is an age-related syndrome commonly associated with different comorbidities, and its occurrence is particularly frequent in patients with Alzheimer’s disease (AD). A persisting low-grade inflammation has been suggested to favor the onset of both AD and frailty. Besides their role in hemostasis and thrombosis, blood platelets are true inflammatory cells, and their direct contribution to the onset and progression of AD has been documented. In this work, we investigated whether platelet hyperreactivity and pro-oxidative functions are implicated in the development of frailty in a mouse model of AD, the APP23 mice. Assessment of 31 specific clinical signs of deterioration in mice at 3, 9, and 18 months of age demonstrated that the development of frailty was significantly more pronounced in the APP23 mice compared to wild-type littermates. In 18-month-old APP23 mice, a significant platelet hyperreactivity was detected as shown by a significantly stronger platelet aggregation in response to submaximal stimulation of both collagen and thrombin receptors. Moreover, the pro-inflammatory function of platelets, evaluated as circulating and agonist-induced platelet-neutrophil aggregate formation, was significantly increased in aged APP23 mice compared to wild-type littermates. Platelet hyperreactivity was partially prevented by prolonged treatment with the anti-oxidant agent Tempol, which reduced both agonist-induced aggregation and platelet-neutrophil aggregate formation. Importantly, prolonged treatment of APP23 mice with Tempol significantly reduced also the frailty index score in 18-month-old animals. These results outline the possible beneficial effect of an anti-oxidant treatment in hampering platelet hyperreactivity and preventing the onset of frailty associated to AD.
... Aging: The aging process is associated with a decline in mitochondrial efficiency and antioxidant capacity, resulting in cumulative oxidative damage and the emergence of a pro-inflammatory state known as "inflammaging" [111]. Redox imbalance during aging contributes to tissue degeneration, neuroinflammation, and increased risk of chronic diseases such as Alzheimer's and atherosclerosis [112]; 6. ...
Redox imbalance plays a pivotal role in the regulation of inflammation, influencing both the onset and progression of various inflammatory conditions. While the pro-inflammatory role of oxidative stress (OS) is well established, the impact of reductive stress (RS)—a condition marked by excessive reducing equivalents such as NADH, NADPH, and reduced glutathione (GSH)—remains underappreciated. This review offers a novel integrative perspective by analyzing how OS and RS act not merely in opposition, but as interconnected modulators of immune function. We explore the mechanisms through which OS activates inflammatory pathways, and how RS, when sustained, can paradoxically impair immune defense, alter redox-sensitive signaling, and contribute to disease progression. Emphasis is placed on the dynamic interplay between these redox extremes and their combined contribution to the pathogenesis of chronic inflammatory diseases, including autoimmune, cardiovascular, and neuroinflammatory disorders. Additionally, we evaluate therapeutic strategies that target redox homeostasis, arguing for a shift from antioxidant-centric treatments to approaches that consider the bidirectional nature of redox dysregulation. This framework may inform the development of more precise interventions for inflammation-related diseases.
... Community-acquired pneumonia (CAP) remains a significant cause of morbidity and mortality in the elderly population. Due to age-related changes in immune function, often referred to as immunosenescence or"inflammaging,"older adults exhibit heightened susceptibility to infections [1,2]. Furthermore, elderly patients with CAP frequently present with atypical symptoms, complicating accurate diagnosis and risk assessment [3]. ...
... The pathophysiology of CAP in elderly patients is particularly complex, exhibiting distinct inflammatory response characteristics. Older individuals with pneumonia often display abnormal immune response patterns, characterized by elevated levels of certain pro-inflammatory cytokines but relatively blunted overall inflammatory responses, such as lower C-reactive protein (CRP) levels [1,2,7]. This attenuated systemic inflammatory response not only increases susceptibility to infections but also adversely impacts prognosis [7]. ...
Current severity scoring systems (PSI and CURB-65) have limitations in risk stratification for elderly patients with community-acquired pneumonia (CAP). Given the complex immune responses in elderly populations, dynamic biomarker monitoring may provide additional prognostic value. This study evaluates whether integrating early cytokine dynamics with traditional severity scores improves mortality prediction in elderly CAP patients. This prospective observational study included 81 CAP patients aged ≥ 65 years. Multiple cytokines were measured at admission and within 48 h. Traditional severity scores (PSI and CURB-65) were calculated at baseline. Patients were categorized into survival (n = 67) and mortality (n = 14) groups. The predictive value of cytokine dynamics alone and in combination with severity scores was assessed using ROC curve analysis. Among measured cytokines, IL-6 demonstrated significant prognostic value. The mortality group showed an 88% increase in IL-6 levels within 48 h, contrasting with a 49% decrease in survivors (p = 0.040). While individual PSI (AUC = 0.6631) and CURB-65 (AUC = 0.6231) showed modest discrimination, integration with IL-6 dynamics significantly improved predictive accuracy (PSI + IL-6: AUC = 0.7676, p = 0.0017; CURB-65 + IL-6: AUC = 0.7564, p = 0.0027). Early dynamic monitoring of cytokines, particularly IL-6, significantly enhances the prognostic accuracy of traditional severity scores in elderly CAP patients. This pilot study suggests that this integrated approach provides a more precise risk stratification tool, potentially enabling more personalized clinical decision-making. Larger multicenter studies are warranted to validate these findings and establish standardized cutoff values for clinical implementation.
