Vaccine responses are impaired in aged mice and older people. A key first step in mounting successful responses to vaccines is for antigens to access the draining lymph node from the site of injection. Here we tested the hypothesis that nanoparticle drainage to the lymph node is impaired in older mice after intramuscular injection. We observed fewer 20 nm nanoparticles in the draining lymph node in aged mice after intramuscular injection. However, there was no significant difference in the abundance of larger 1000 nm particles in the lymph nodes of aged mice, which are typically transported to the lymph node by antigen presenting cells. This impaired nanoparticle access was associated with changes in lymph node stromal cells, and a reduction in lymphatic endothelial cells in aged mice. These data suggest that access of smaller antigens to the lymph node may be impaired in ageing and may have implications for the initiation of T and B cell responses after vaccination.
Centenarians represent a model of exceptional longevity and immune resilience. In young adults, acute exercise typically induces rapid immune cell redistribution and provides a useful paradigm to assess immune adaptability. However, immune cell responses to acute exercise in centenarians remain unknown. To characterise acute exercise-induced changes in circulating immune cell populations and phenotypes in centenarians using high-dimensional spectral flow cytometry. Seven centenarians (100–104 years; six women) participated in a randomised crossover study including an acute exercise session ( 20 min of combined walking, mobility and resistance exercise) and a time-matched seated control condition. Peripheral blood mononuclear cells collected before and after each condition were analysed using spectral flow cytometry and high-dimensional approaches. In this exploratory study, acute exercise was associated with nominally significant condition-by-time interactions in selected immune cell subpopulations, including natural killer (NK) cell subsets and classical monocytes (all nominal p < 0.05). Yet, these findings should be interpreted cautiously given the exploratory nature of the study and the large number of immune outcomes analysed. Furthermore, these effects were modest, occurred alongside baseline differences between study visits, and primarily reflected divergent temporal patterns between conditions rather than pronounced exercise-induced redistribution. No nominally significant changes were observed in phenotypic marker expression or metacluster relative abundance. In centenarians, acute exercise does not induce widespread redistribution or phenotypic changes in circulating immune cells but elicits modest, selective responses, indicating that selected components of immune adaptability may remain detectable even in extreme ageing. These findings support the notion that immune resilience in extreme ageing may be characterised by maintenance of immune homeostasis under physiological stress rather than by pronounced immune reactivity.
Aging is characterized by chronic low-grade inflammation, in which macrophages contribute to the establishment of a senescence-associated inflammatory environment. Interleukin-38 (IL-38), an anti-inflammatory member of the interleukin-1 family, has been implicated in immune regulation; however, its role in macrophage aging remains unclear. This study examined age-associated changes in IL-38 expression and its functional relevance in aged macrophages. Macrophages derived from aged mice exhibited significantly reduced endogenous IL-38 expression, accompanied by enhanced inflammatory activation, increased oxidative stress, accumulation of DNA damage–associated signals, and cell-cycle–associated alterations. Exogenous IL-38 supplementation attenuated inflammatory cytokine expression, reduced p-p65 and nuclear p65 levels, decreased oxidative stress and γH2AX-associated signals, and partially restored cell cycle regulatory molecules. Conversely, IL-38 knockdown enhanced inflammatory and senescence-associated features and increased p-p65 and nuclear p65 levels. Pharmacological inhibition of NF-κB recapitulated several effects observed following IL-38 treatment, supporting a functional association between IL-38 and NF-κB-related signaling. These findings indicate that reduced endogenous IL-38 is associated with age-related inflammatory and senescence-associated phenotypes in macrophages and suggest that IL-38 may modulate age-associated macrophage phenotypes, at least in part, in association with NF-κB-related signaling.
The gradual decline in the functionality of the immune system during aging is commonly referred to as immunosenescence. This study aims to investigate changes in the B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire during natural aging and evaluate the dynamics of emergent low-level BCR IGH clonality in the elderly. We conduct a longitudinal study nested within the Doetinchem Cohort study, comprising 98 participants aged between 31 and 59 years old at study entry who had repeated blood samples drawn at 5 year intervals over a 30 year period (n = 548 samples). We sequenced the IGH gene repertoire and evaluated the impact of aging on IGH gene repertoire clonality and diversity using linear mixed effects modeling. Participants older than 60 years exhibited increased BCR IGH clonality and reduced IGH gene repertoire diversity. In a multivariable model, IGH gene repertoire diversity was significantly decreased for individuals with a dominant clonotype ratio greater than 10 (β =-0.57, p < 0.001). Additionally, a trend toward reduced IGH gene repertoire diversity was observed in participants aged 60–70 years (β =-0.19, p = 0.1) and those aged 70 years or older ( β =-0.20, p = 0.13). IGH gene repertoire diversity was determined primarily by the naïve and transitional B-cell pool, while BCR IGH clonality was influenced by switched memory and age-associated B-cell counts. In summary, our study indicates that IGH gene repertoire diversity decreases significantly after age 60, which coincides with an increased incidence of low-level BCR IGH clonality. This clonality may be driven largely by switched memory and age-associated B-cells. By providing deep insights into age-related dynamic changes in the IGH gene repertoire, these findings lay the groundwork for the molecular assessment and monitoring of incident clonality by clinicians and researchers alike.
Advanced age is a recognized risk factor for primary Sjögren’s disease (pSjD), suggesting a role for aging-related mechanisms in its pathogenesis. However, whether cellular senescence directly drives autoimmune inflammation and glandular dysfunction remains unclear. Furthermore, the specific role of senescent fibroblasts within the pSjD microenvironment has not been defined. This study investigates the mechanisms underlying fibroblast senescence and its therapeutic potential in pSjD. The senescence landscape of salivary glands was assessed by immunohistochemistry, multiplex immunofluorescence, and single-cell RNA sequencing, coupled with computational trajectory and gene regulatory network inference. In vitro, primary salivary gland fibroblasts (SGFs) were treated with interferon-gamma (IFN-γ). Senescence-associated β-galactosidase staining, reactive oxygen species detection, siRNA knockdown, co-immunoprecipitation, dual-luciferase reporter, and transwell migration assays were conducted to elucidate the underlying mechanisms. In vivo, a non-obese diabetic (NOD) mouse model was utilized to evaluate the efficacy of a senolytic combination (dasatinib and quercetin) on salivary flow rates and lymphocytic infiltration. Integrative analysis of human clinical samples and scRNA-seq revealed a significant accumulation of senescent fibroblasts in pSjD salivary glands. Pharmacological clearance of senescent cells in NOD mice significantly attenuated lymphocytic infiltration and restored salivary function, supporting a pathogenic contribution of fibroblast senescence. Subsequent computational trajectories and in vitro validations identified a senescence-enriched DNAJB1high fibroblast subpopulation. Mechanistically, IFN-γ upregulated DNAJB1 transcription via JUND, which was in turn associated with p21-mediated senescence and enhanced CD4⁺ T cell recruitment. Furthermore, in vivo evaluations confirmed that the senolytic intervention effectively suppressed the glandular JUND-DNAJB1-p21 axis, corroborating the mechanistic findings. These findings indicate that the JUND-DNAJB1-p21 axis contributes to fibroblast senescence and autoimmune pathogenesis in pSjD. Senolytic clearance of senescent cells may represent a potential therapeutic strategy for mitigating glandular dysfunction.
Immunosenescence, characterized by telomere shortening, senescence-associated T-cell subsets, and chronic inflammation, is a hallmark of biological aging. Whether these aging-related immune biomarkers can be modulated through short-term intervention and whether responses differ according to individual characteristics remain unclear. This study evaluated the effects of short-term hyperbaric oxygen therapy (HBOT) on senescence-related biomarkers and explored factors associated with individual responsiveness. In a prospective cohort study, participants underwent 30 HBOT sessions (2.5 ATA, 100
The thymus is critical in the pathogenesis of early-onset myasthenia gravis (EOMG), whereas its involvement in late-onset myasthenia gravis (LOMG) remains controversial. Herein, we systematically analyzed thymic computed tomography (CT) images and evaluated thymic output in patients with LOMG. We retrospectively examined the chest CT images and clinical profiles of 59 patients with LOMG, 16 patients with EOMG, and 225 matched controls from our center. These data were acquired at the time of diagnosis and before any immunotherapy. The key CT features, thymic volume, surface area, and density (represented by gray value), were assessed quantitatively and compared between groups. In a separate flow-cytometry cohort, circulating naïve T cells and recent thymic emigrants (RTEs) were analyzed in 20 immunotherapy-naïve LOMG patients and 27 healthy matched controls. Patients with LOMG showed lower thymic gray value and larger thymic volume and surface area compared with controls. Thymic volume was positively correlated with BMI and LOMG patients with diabetes had larger thymus than those without. Multivariate Logistic regression analysis revealed that thymic volume, surface area, and gray value were associated with the risk of LOMG. In the independent flow-cytometry cohort, patients with LOMG also exhibited reduced circulating RTEs, suggesting impaired thymic output. Patients with LOMG showed exaggerated thymic involution and reduced thymic output, supporting thymic involvement in the pathophysiology of LOMG. These findings provide clues for future mechanistic and prospective studies.
Senile osteoporosis (SOP) is an age-related metabolic bone disease characterized by reduced bone quality and increased fracture risk, closely associated with immune senescence. Among immune components in the bone marrow niche, macrophages undergo age-associated phenotypic and functional changes that may impair bone homeostasis; however, whether these changes reflect bona fide senescence, inflammatory activation, or polarization remains unclear. This review summarizes the biological characteristics of senescent macrophages, including alterations in senescence markers, senescence-associated secretory phenotype (SASP), epigenetic modifications, and telomere dynamics. It then outlines their functional changes, focusing on oxidative stress, autophagy, and metabolic dysregulation. Importantly, we discuss how senescent or senescence-like macrophage states may regulate macrophage–bone marrow mesenchymal stem cell (BMSC) crosstalk through SASP-related factors, the grancalcin–plexin-B2 axis, mitochondrial transfer, exosome-mediated signaling, and metabolic reprogramming, while distinguishing direct ageing-related evidence from indirect mechanistic evidence.
Abstract Background Subclinical atherosclerotic plaque (SAP) develops silently in older adults. Biological changes that predict plaque formation are not well defined. We examined whether circulating immunological, metabolic, and functional measures identify vascular vulnerability before clinical disease. Methods In a three-year longitudinal study, 49 healthy older adults (63.8 ± 3.8 years) underwent carotid ultrasound, T cell phenotyping, serum protein profiling, body composition assessment, and fitness testing at baseline and follow-up. At follow-up, participants were classified as no SAP, new SAP or persistent SAP. We analyzed baseline determinants and within-person changes to predict incident plaque formation. Results New SAP occurred in 30.3% of those initially plaque-free. At baseline, lower frequencies of CD8 + effector memory (EM) T cells and higher frequencies of CD8 + effector memory re-expressing CD45RA (EMRA) T cells and regulatory T cells (Tregs) were associated with higher odds of new SAP. Over time, expansion of CD8 + EM T cells was the most consistently associated independent variable of new SAP, accompanied by declines in Tregs and in the Treg/Teff ratio. Vascular cell adhesion molecule-1 (VCAM-1) at baseline was an additional independent predictor. Increases in visceral fat and declines in VO 2 peak were linked to new SAP, but immune markers were more robust than metabolic variables or serum cytokines. Conclusion Adaptive immune remodeling follows a phase-dependent pattern in which CD8 + EM reductions and later CD8 + EM expansion with Treg decline signal emerging vascular vulnerability. These immune signatures, together with VCAM-1, may help characterize vascular vulnerability during the subclinical phase of plaque development.
Chronic inflammatory skin disorders are characterized by persistent skin inflammation, impaired barrier function, and frequent recurrence, all of which substantially reduce patients’ quality of life. Traditional studies attribute the pathogenesis of these diseases to immune dysregulation, whereas new evidence indicates that cellular senescence is a key risk factor and a mechanism underlying disease progression. Cellular senescence, defined by irreversible cell cycle arrest, is accompanied by a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and DNA damage. This review systematically outlines the hallmarks, regulatory mechanisms, and inducers of cellular senescence, elucidates its pathological role in representative inflammatory skin disorders, and evaluates emerging therapeutic strategies that target senescent cells. By elucidating the dynamic crosstalk between cellular senescence and inflammatory skin diseases, this review aims to identify novel therapeutic targets and provide new insights into their diagnosis, treatment, and prevention.
Abstract Background Proximal hip fractures represent a profound acute physiological stress in older adults and are often followed by infections, delayed recovery, and functional decline. These complications occur more frequently in frail individuals with reduced physiological resilience and impaired immune responses. As natural killer (NK) cells are central to early immune defense, we aimed to define how acute fracture, hospitalization and frailty shape NK cell homeostasis and function in older patients. Methods We conducted a prospective study including older patients (> 65 years) with acute fractures (SMART cohort; n = 103) and compared them to matched healthy older people from the RESIST senior individuals (SI) cohort (n = 550). A subset of SMART patients (n = 55) was longitudinally followed-up post-surgery. NK cell frequency, phenotype and function were investigated using multiparametric flow cytometry, and plasma soluble immune mediators (SIMs) were analyzed. Results SMART patients were clinically frailer than matched SI individuals, as indicated by reduced grip strength and lower Barthel scores, and exhibited an inflammatory state with elevated CRP levels and leukocyte counts. NK cell frequencies were significantly reduced in SMART patients and inversely correlated with grip strength and systemic inflammation. Furthermore, NK cells from SMART patients showed a distinct immune phenotype and altered chemokine receptor expression compared with SI individuals. Of note, differences between frail and non-frail patients within the SMART cohort were modest and substantially smaller than those observed between SMART patients and SI individuals. Functionally, frail patients displayed reduced baseline expression of cytotoxic molecules, whereas cytokine-induced NK cell responses were preserved. Furthermore, longitudinal analyses revealed stable NK cell frequencies but surgical intervention remodeled NK cell subset distribution and marker expression. Conclusions In conclusion, our findings indicate that NK cell alterations in older patients with fractures are likely driven by the combined impact of acute injury, hospitalization and surgery rather than by frailty alone.
Long-term care facility (LTCF) residents represent one of the populations most vulnerable to SARS-CoV-2 infection and have experienced repeated vaccination and natural viral exposure since the beginning of the COVID-19 pandemic. The long-term dynamics of humoral and cellular immunity in this population remain incompletely characterized. In this multicenter longitudinal study, SARS-CoV-2-specific antibody responses were monitored in LTCF residents over 12 months. A total of 388 residents from LTCF across five Italian regions were enrolled and stratified according to receipt of the SARS-CoV-2 XBB.1.5 mRNA booster during the 2023–2024 vaccination campaign. In a subgroup of residents, peripheral B-cell phenotypes and Spike-specific memory B cells were characterized by flow cytometry and compared with those of younger healthcare workers vaccinated with the same formulation. Anti-Spike IgG titers peaked in residents who received the XBB.1.5 booster and subsequently declined over time, consistent with contraction of vaccine-induced humoral responses. In contrast, individuals who did not receive the booster maintained lower but stable antibody levels. Anti-nucleocapsid seroconversion and clinically diagnosed intercurrent infections occurred at broadly comparable observed rates in boosted and non-boosted residents, suggesting a comparable incidence of SARS-CoV-2 infection during follow-up. Regarding B-cell-mediated immunity, LTCF residents exhibited age-associated remodeling of the B-cell compartment, with reduced total B-cell frequencies but preserved antigen-experienced memory populations. Despite declining circulating antibodies, Spike-specific memory B-cell frequencies remained stable. A late increase in anti-Spike titers coincided with rising anti-nucleocapsid seropositivity, suggesting reactivation of immune memory following natural viral exposure. These findings indicate that repeated vaccination and natural exposure generate durable immunological memory in LTCF residents. In highly exposed populations, immune maintenance may increasingly rely on reactivation of memory responses rather than persistently high antibody titers.
As the largest and most externally exposed organ, the skin is particularly vulnerable to aging, rendering skin aging a widespread clinical and aesthetic concern. Driven by both intrinsic and extrinsic factors, skin aging is characterized by progressive functional decline and structural remodeling that compromise barrier integrity, disrupt dermal homeostasis, and ultimately diminish quality of life. At the upstream regulatory level, skin aging-associated epigenetic modifications drive epigenetic drift that compromises transcriptional fidelity and primes cells toward senescence. At the cellular level, regulatory mechanisms converge on cellular senescence and profound mitochondrial remodeling. At the microenvironmental level, the failure of senescent cell clearance (immunosenescence) and the emergence of a chronic pro-inflammatory milieu (inflammaging) create a self-reinforcing immune–inflammatory axis. This axis exacerbates cytokine production, extracellular matrix remodeling, and progressive tissue degeneration. We further highlight emerging mechanism-targeted interventions, including epigenetic and mitochondrial modulators, senotherapeutics, biologics, immunotherapies, regenerative and device-based therapies. A deeper understanding of these interconnected molecular mechanisms and targeted therapies may offer a roadmap for future therapeutic innovation and translational research in skin aging.
The use of mitochondrial wide association studies (MiWAS) to link mitochondrial DNA variants (mtSNPs) to phenotypes of interest has uncovered important connections between mitochondrial genes and human health. The recent introduction of a re-annotated mitochondrial genome that accounts for small open reading frames (sORFs) with protein coding potential suggests the existence of mitochondrial-derived microproteins, many of which remain uncharacterized. Thus, considering the re-annotated mitochondrial genome when conducting genomic analyses such as MiWAS facilitates the mapping of mtSNPs back to microprotein-encoding sORFs and uncovers interactions between mitochondrial microproteins and biological systems. Here, we employ MiWAS of venous blood samples from the Health and Retirement Study (HRS) and identify a mtSNP associated with sex-specific changes to immune composition. After accounting for re-annotation, we map the identified mtSNP back to a sORF that encodes a novel microprotein, termed MASL (Mitochondrial Associated Small d-Loop peptide). Complementary phenome-wide association studies (PheWAS) in HRS and and UK Biobank confirm interactions between this mtSNP and immune phenotypes of interest, and our targeted RNA-Seq method (mitoSNP-seq) elucidates sex-differences in gene expression and functional pathways potentially altered by this mtSNP that may be relevant to the associated microprotein. Early characterization of the MASL microprotein shows sex-differences in circulating MASL levels in human plasma, and sex-specific interactions when comparing male and female mice treated with synthesized MASL. Together, the results of this study not only contribute to our understanding of mitochondrial dynamics in immunity, but also provide early characterization of a novel mitochondrial-derived microprotein with sex-specific modulatory effects.
Older adults are at increased risk of pneumonia and invasive pneumococcal disease, yet vaccine-induced immunity varies substantially within this population. We evaluated antibody responses to the 23-valent pneumococcal polysaccharide vaccine (PPV23) in 188 Dutch adults aged 72–79 years (trial number: NL74843.041.20; EudraCT: 2020–003620-16), with follow-up extending to two years post-vaccination. Serotype-specific IgG and IgM concentrations increased significantly for all 23 serotypes and remained elevated after two years, compared to baseline. Opsonophagocytic activity, measured for serotypes 1, 3, 8 and 19A, correlated with IgG but not with IgM concentrations. Using AAAAI guidelines for evaluating pneumococcal vaccine responses in adults, 46.2
Abstract Background Community-acquired pneumonia (CAP) has been associated with poor long-term outcomes in older adults. In most pre-pandemic studies, long-term mortality was assessed with a focus on comorbidity burden. Although immunosenescence is a key determinant of CAP, post-acute immune patterns have been little explored. Objective To assess 18-month mortality after CAP hospitalisation and the prognostic value of the Immune Risk Phenotype (IRP). Methods Prospective, observational study of adults ≥ age 65 years discharged after CAP (2019—21). We performed comprehensive geriatric and nutritional assessments, including laboratory tests at 30–60 days post diagnosis. IRP was defined as cytomegalovirus seropositivity with inverted CD4:CD8 ratio, elevated CD8 + T cell count, or expansion of CD8CD28-T cells. The main outcome measure was 18-month mortality. Multivariate logistic with ROC curves and Cox regression analyses were performed. (ClinicalTrials.gov, NCT0462799). Results The sample included 143 patients (55.2% males), with a mean age of 77.6 ± 7.9 years. IRP was found in 46.8% of patients. Elevated lymphocyte count and female sex were predictors of IRP. At 18 months post-CAP, 27 patients (18%) had died, mainly due to infections ( n = 13, 48%) and fractures ( n = 2, 7.4%). Predictors of 18-month mortality included IRP (HR 2.58 [95% CI 1.11–5.99]; p = 0.027), severe chronic kidney disease (6.16 [2.53–14.99]; p <0.001), poor functional status (3.69 [1.53–8.90] p = 0.004), and hypoalbuminemia (3.35; [1.34–8.41]; p = 0.010). Conclusions This study underscores the role of infectious complications in long-term outcomes after CAP. These findings highlight the need for comprehensive geriatric assessment to identify multidimensional risk factors, including immunosenescence as a potentially modifiable domain warranting further investigation and integration into care.
Heart failure (HF) is characterized by systemic inflammation and adverse myocardial remodeling involving immune cell activation. Nonetheless, effective immunomodulatory therapies remain lacking. We aimed to characterize the composition and effector function of immune cells in patients with non-ischemic HF. Peripheral blood mononuclear cells were isolated from patients with non-ischemic HF (n = 19) and controls without HF (n = 19). Using multiparametric flow cytometry, immune cell populations—including monocyte subsets, dendritic cells (DCs), and T-cell subsets—were characterized alongside expression of pattern recognition receptors and immune checkpoint molecules. Monocyte effector functions were assessed via intracellular cytokine staining after lipopolysaccharide (LPS) stimulation. In HF patients, circulating monocytes were increased, whereas the proportion of non-classical (CD14⁻CD16⁺) monocytes was reduced. Monocytes showed higher PD-L1 expression, and intermediate/non-classical subsets had increased TLR4. Following LPS stimulation, monocyte cytokine production (IL-1β, IL-6, TNF-α) was unchanged. Lower frequencies of non-classical monocytes correlated with reduced left ventricular ejection fraction but not with NT-proBNP. Circulating DCs were elevated. T-cell analysis revealed increased CD4⁺ effector Th and IL-17-producing (Th17) cells and fewer regulatory T-cells. To explore whether systemic immune alterations are reflected in cardiac infiltration, myocardial tissue from a subset of HF patients (n = 7) and non-failing controls (n = 4) was analyzed by immunohistochemistry. Despite the systemic immune alterations, large myocardial immune cell infiltrates were not readily apparent in end-stage HF tissue. Non-ischemic end-stage HF is associated with systemic immune alterations indicative of chronic activation with features suggestive of immunosenescence. Without overt corresponding myocardial immune cell infiltrates, these findings emphasize the relevance of systemic immune alterations in non-ischemic end-stage HF.
Immune reconstitution following combined antiretroviral therapy (cART) varies across populations and remains suboptimal in certain subgroups. This study assessed the trajectory and predictors of CD4+ T cell recovery among heterosexual (HET) and men who have sex with men (MSM) living with HIV-1 in Guangxi, China. A prospective cohort of 458 newly diagnosed HIV-1 positive individuals (244 HET and 214 MSM) was followed from 2015 to 2024. Generalized additive models (GAM) were applied to evaluate CD4+ T cell trends. A Bayesian Markov Chain Monte Carlo (MCMC) generalized linear model (glm) estimated the posterior probability of immune recovery (Complete immune recovery (CIR), defined as two consecutive CD4+ T cell counts > 500 cells/µL after cART initiation.). Multivariable logistic regression identified risk factors for immune non-responsiveness. Median CD4+ T cell counts increased from 346 to 700 cells/µL in the HET group and from 404 to 778 cells/µL in the MSM group. However, CD4+ T cells declined during the first year among HET, and counts remained below 500 cells/µL after four years, while MSM surpassed this threshold earlier. Those with baseline CD4+ T cell counts < 150 cells/µL failed to achieve complete immune reconstitution even after six years. The risk of immune non-response among those with CD4+ T cell percentage ≤ 20
Protein lactylation has emerged as a crucial regulator in the pathogenesis of Alzheimer’s disease (AD). Although the Klotho gene (KL) has been clinically linked to AD, its role in lactylation remains unclear. Here, we investigated the influence of Klotho genotype on lactylation and related inflammatory responses. Wild-type KL and the KL F352V variant were transfected into microglia and BV-2 cells of an AD model to assess effects on protein lactylation and cytokine release, followed by transcriptome sequencing to identify downstream mediators. Functional validation using qPCR, ELISA, Western blotting, and immunohistochemistry confirmed that KL expression markedly reduced lactylated protein levels and pro-inflammatory factors, while ameliorating pathological features in AD model mice. Transcriptomic analysis highlighted oncostatin M (OSM) as a key gene suppressed by KL, and OSM knockdown decreased both protein lactylation and inflammation, improving AD pathology in vivo. These findings demonstrate that KL protects against AD progression by inhibiting OSM-mediated signaling, thereby attenuating lactylation and neuroinflammation, and provide novel mechanistic insight into the genetic regulation of lactylation in neurodegeneration.
Background Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a progressive degenerative disease leading to irreversible vision loss in elderly individuals.The complement system, including the alternative pathway (AP) forms an essential part of the innate immune system. Since dysregulation of the complement system has been strongly associated with the development and progression of GA, we sought to investigate the expression of specific regulators of the complement system, known as complement regulatory proteins (Cregs), in relation to progression rate (PR) of disease in patients with GA. Results Using flow cytometry, we determined the proportion of Cregs on peripheral blood leukocytes drawn from patients with GA. Patients were genotyped for risk-associated SNP (CFH rs1061170, ARMS2 rs10490924) and serial fundus autofluorescence images were used to determine the PR of atrophic lesions. Patients with fast GA progression had a lower proportion of CD59 on CD8 + T cells compared to patients with slow progression of disease (p = 0.025), suggesting that dysregulated CD59 could be involved in progression of GA. Patients with high-risk CFH genotypes had a higher proportion of CD59 on classical monocytes compared to patients carrying the low-risk genotype (p = 0.044). Conclusion Our findings indicate that GA progression is associated with dysregulation of complement regulators, and Cregs could serve as a novel target for treatment of GA. However, further studies are needed to elucidate their role in GA pathogenesis and to evaluate their potential as future complement-targeting drugs.
