Search Results (3,894)

Diabetes mellitus severely impairs skeletal muscle regeneration after injury, limiting satellite cell activation and angiogenesis and disrupting barrier integrity while increasing fibrosis. Hypobaric hypoxia has been proposed to improve the regenerative microenvironment through hypoxia-responsive signaling, but its temporal effects and the coordination between vascular and myogenic programs in diabetic muscle remain unclear. To clarify these processes, adult male mice were divided into five groups: diabetes mellitus control (DM), cardiotoxin-injured (CTX) diabetes assessed on days 7 and 14 (CTX7, CTX14), and hypobaric-hypoxia-treated diabetic injury assessed on days 7 and 14 (H+CTX7, H+CTX14). Animals in the hypoxia groups were exposed to a hypobaric hypoxia chamber for 8 h per day for 14 days. Fibrosis, angiogenic and myogenic markers, and endothelial junctional genes were examined using histology, immunofluorescence, immunoblotting, and qRT-PCR (Quantitative Real-Time PCR). Hypobaric hypoxia on day 7 enhanced HIF-1α (hypoxia-inducible factor 1 alpha), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthas), Kdr (kinase insert domain receptor,VEGFR-2), and Angpt2 (angiopoietin-2) expression, accompanied by simultaneous endothelial sprouting and early myogenic stimulation compared to CTX7. Improvements were observed in Angpt1 (angiopoietin-1), Cdh5 (cadherin-5, VE-cadherin), Emcn (endomucin), the Angpt1/Angpt2 ratio, and CD31 density. Myogenin and MyHC (myosin heavy chain) were induced with a reduction in eMyHC (embryonic myosin heavy chain) in accordance with stabilization of endothelium and maturation of fibers, which occurred by day 14. A decrease in fibrosis and an increase in the myofiber cross-sectional area occurred. These findings suggest that hypobaric hypoxia modulates HIF-1α signaling, which in turn induces the VEGF-Kdr-eNOS pathway and the angiopoietin–Tie2–VE-cadherin pathway. Together, these pathways coordinate vascular remodeling and myogenic regeneration, ultimately improving the structural and functional recovery of diabetic muscle. Full article

Sinensetin, a polymethoxylated flavone abundant in citrus fruits, has been recognized for its broad biological activities and wide use in traditional medicine around the world. Emerging clinical evidence from flavonoid-enriched orange juice interventions indicates antioxidant and anti-inflammatory effects, aligning with extensive preclinical data. In this review, we explored in vitro and in vivo findings on the anti-inflammatory and anticancer actions of sinensetin and delineated the underlying cellular pathways, especially in terms of proposed targets for sinensetin. In inflammatory settings, sinensetin attenuates NF-κB activation, lowers pro-inflammatory cytokines (e.g., TNF-α, IL-6), and enhances antioxidant defenses, supporting its reported antioxidant, anti-bacterial, anti-viral, and anti-obesity properties. Across multiple tumor models, sinensetin suppresses oncogenic signaling—including β-catenin, PI3K/AKT, VEGF, NRF2, P53, and MKK6—concomitant with reduced proliferation, migration, and survival signaling. We further discuss emerging immunological effects, including modulation of innate immune cell activation and cytokine production, which may contribute to tumor microenvironment reprogramming and inflammation resolution. Together, these mechanistic insights position sinensetin as a promising lead for chemopreventive and adjunct therapeutic strategies. Our efforts aim to provide insights into the future translational development and clinical evaluation of sinensetin and its derivatives. Full article

Background: The anterior cruciate ligament (ACL) and medial collateral ligament (MCL) display strikingly different healing behaviors, despite their similar structural roles within the knee. The epiligament (EL)—a vascular and cellular envelope surrounding each ligament—has emerged as a critical determinant of repair capacity. The aim of this study was to perform a region-specific, comparative analysis of EL molecular profiles in the ACL and MCL to elucidate the mechanisms underlying their contrasting reparative outcomes. Methods: Human ACL and MCL specimens were obtained from 12 fresh knee joints. Immunohistochemical labeling for CD34, α-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) was performed across proximal, mid-substance, and distal EL regions. Quantitative image analysis using IHC Profiler for ImageJ generated semiquantitative (negative, low-positive, positive) distributions, and inter-ligament comparisons were quantified using t-tests (p  <  0.05). Results: Distinct, region-specific EL signatures were identified. The ACL EL exhibited strong proximal α-SMA expression (0% neg/66.8% low+/33.2%+) and notable distal CD34 positivity (0% neg/83.3% low+/16.7%+), while VEGF expression was confined to the mid-substance (≈55% low+/26%+). In contrast, the MCL EL was largely negative for CD34 and VEGF across all regions, showing a homogeneous but functionally oriented α-SMA profile: proximally negative, sparse mid positivity, and high distal low-positive staining (93.4% low+). Differences in proximal and distal CD34 and α-SMA expression between the ACL and MCL were highly significant (p  <  0.0001–0.001), confirming a mechanistic divergence in EL organization. Conclusions: The ACL EL is regionally heterogeneous, vascularly biased, and enriched in contractile α-SMA+ cells, suggesting localized but poorly coordinated reparative potential. In contrast, the MCL EL is structurally uniform, with distributed α-SMA activity supporting stable wound contraction and tissue continuity, despite limited angiogenic signaling. These findings indicate that the ACL’s failure to heal is not attributable to the absence of progenitor or angiogenic factors, but rather to its fragmented spatial organization and dominant contractile phenotype. Therapeutically, preserving and modulating the EL, particularly its CD34+ and α-SMA+ compartments, could be key to enhancing intrinsic ACL repair and improving outcomes in ligament reconstruction and regeneration. Full article

Objective: Evaluate the efficacy and safety following intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in patients with diabetic macular oedema (DME). Methods: To evaluate retinal microvascular remodelling and photoreceptor metrics using adaptive optics (AO) alongside systemic vascular status assessed by brachial/aortic hemodynamic and carotid ultrasound. We conducted a single-centre longitudinal study including twenty-one patients with DME. The following four diagnostic visits were performed: baseline (V1, no anti-VEGF treatment), 2–3 months (V2), 6–8 months (V3), and 12–14 months (V4). Adaptive optics (rtx1) measured foveal cone number (N) and regularity (Reg) within a standardised 80 × 80 µm window, and superior temporal retinal arteriole morphology after the first bifurcation (vessel diameter [VD], lumen diameter [LD], wall thickness [WT], wall-to-lumen ratio [WLR], and wall cross-sectional area [WCSA]). SphygmoCor provided peripheral (brachial) and central (aortic) pressures, augmentation pressure (AP), augmentation index (AIx), and carotid–femoral pulse wave velocity (PWV and PWVHR heart rate adjusted). Carotid ultrasound assessed intima–media thickness (IMT), carotid lumen diameter (CLD), and IMT/CLD ratio (IMTLR) 2 mm proximal to the bifurcation in diastole. Visual acuity (Visus), intraocular pressure (IOP), and central retinal thickness (CRT) were obtained at each visit. Results: In the treated eye (TE), WLR showed a significant overall change (Friedman p = 0.007), with a modest V4 vs. V1 increase (Wilcoxon p = 0.045); LD also varied across visits (Friedman p = 0.034). Cone metrics improved as follows: Reg increased over time (Friedman p = 0.019), with a significant rise at V4 vs. V1 (p = 0.018), and cone number increased at V3 vs. V1 (p = 0.012). Functional/structural outcomes improved as follows: visual acuity increased at V3 (p = 0.009) and V4 (p = 0.028), while CRT decreased at V3 (p = 0.002) and V4 (p = 0.030); IOP remained stable compared to V1. Systemic hemodynamics was largely unchanged; small fluctuations in DBP and cDBP across V1–V4 were observed (Friedman p = 0.034 and p = 0.022, respectively), whereas AIx, AP, PWV, and PWVHR showed no significant trends. Carotid IMT, CLD, and IMTLR did not change significantly across visits, supporting systemic vascular safety. Conclusions: Intravitreal anti-VEGF therapy in DME was associated with improvements in photoreceptor organisation and macular structure/function, with AO-derived arteriolar remodelling detectable over time, and no adverse changes in large-artery structure. These findings support ocular efficacy and systemic vascular safety; confirmation in larger cohorts is warranted. Full article

Background/Objectives: Obesity-associated hyperleptinemia has been linked to breast cancer (BC) progression via mechanisms that remain incompletely understood. This study explores the role of leptin and its receptor (LEPR) in facilitating BC cell proliferation, migration, epithelial–mesenchymal transition (EMT), and STAT3 signaling pathway activation. Methods: We analyzed gene expression and survival data from TCGA BRCA dataset. MCF-7 and MDA-MB-231 BC cells were exposed to leptin at 10 ng/mL (lean-associated levels) and 100 ng/mL (elevated levels linked to obesity). MTT assays, colony formation tests, wound-healing and tumor spheroid dissemination experiments evaluated cell proliferation and migration. Immunofluorescence and Western blot analysis assessed changes in EMT markers and cytoskeletal alterations, while Western blotting and qPCR assessed STAT3 and NCOA1 expression and activation levels. Results: Elevated LEPR expression was linked with unfavorable prognosis in BC patients. Higher doses of leptin (100 ng/mL) significantly enhanced cellular proliferation rates and migratory capabilities, in both cell lines, and promoted EMT characteristics marked by downregulated E-cadherin and cytoskeleton structural changes. Whereas heightened JAK2/STAT3 signaling correlated with elevated leptin dosages, STAT3 inhibition using AG490 reversed leptin-induced migration while reinstating E-cadherin levels to baseline. Furthermore, leptin upregulated NCOA1, an essential STAT3 coactivator, facilitating increased expression of Cyclin D1 and VEGF target genes. Clinical positive relationships were seen between LEP/LEPR expressions and NCOA1 levels and between NCOA1 and various gene signatures related to STAT3/P-STAT3 within BC specimens. Conclusions: Obesity-associated hyperleptinemia enhances aggressiveness in BC through a mechanism involving LEPR-mediated activation pathways encompassing NCOA1/STAT3, which drive proliferation, migration, and EMT. This assigns a potential therapeutic utility for obesity-related advancements found within BC pathology. Full article

Diseases of the pancreas—such as pancreatic ductal adenocarcinoma (PDAC) and pancreatitis—have long been a challenge to treat. The study of lymphatics within the pancreas can provide some additional insights and offer new therapeutic targets. Here, we explore the development of pancreatic lymphatics and their connections to the nervous system and individual disease states, as well as the potential for therapeutic interventions. Lymphangiogenesis pathways in PDAC, driven by VEGF-C and other mediators, have been extensively explored, but specific therapeutic interventions are lacking. Furthermore, due to the emergence of PDAC with pancreatitis, insights could improve treatment in both settings. The role of neuroimmune interactions and control, as in other organ sites, appears as critical to both lymphatic and immune processes. With a better understanding of the lymphatic environment within the pancreas, we can develop more effective treatments for patients. Full article

Background: Submacular hemorrhage (SMH) is a vision-threatening condition most associated with neovascular age-related macular degeneration (nAMD), although it may also arise from polypoidal choroidal vasculopathy, pathological myopia, retinal vascular diseases, trauma, and systemic factors. Rapid management is essential because subretinal blood induces photoreceptor toxicity, clot organization, and fibroglial scarring, leading to irreversible visual loss. The choice and urgency of treatment depend on hemorrhage size, duration, and underlying pathology, and the patient’s surgical risk category, which can influence the invasiveness of the selected procedure. This review aims to provide an updated synthesis of recent advances in the surgical and pharmacological management of SMH, focusing on evidence from the past five years and comparing outcomes across major interventional approaches. Methods: A narrative review of 27 recent clinical and multicentre studies was conducted. The included literature evaluated pneumatic displacement (PD), pars plana vitrectomy (PPV), subretinal or intravitreal recombinant tissue plasminogen activator (rtPA), anti-VEGF therapy, and hybrid techniques. Studies were analyzed about indications, surgical methods, timing of intervention, anatomical and functional outcomes, and complication and patient risk stratification. Results: Outcomes varied depending on the size and duration of hemorrhage, as well as the activity of underlying macular neovascularization. PD with intravitreal rtPA was reported as effective for small and recent SMH. PPV combined with subretinal rtPA, filtered air, and anti-VEGF therapy demonstrated favorable displacement and visual outcomes in medium to large hemorrhages or those associated with active nAMD. Hybrid techniques further improved clot mobilization in selected cases. Across studies, delayed intervention beyond 14 days correlated with reduced visual recovery due to blood organization and photoreceptor loss. Potential risks, including recurrent bleeding and rtPA-associated toxicity, were reported but varied across studies. Conclusions: Management should be individualized, considering hemorrhage characteristics and surgical risk. Laser therapy, including PDT, may serve as an adjunct in the perioperative or postoperative period, particularly in PCV patients. Early, tailored intervention typically yields the best functional outcomes. Full article

Brain metastases have a distinctive vascular ecosystem—shaped by sprouting angiogenesis, vessel co-option, vasculogenic mimicry, and tumor cell transdifferentiation—that governs tumor perfusion, drug exposure, and therapeutic responsiveness. These heterogeneous vascularization patterns exhibit characteristic differences in enhancement morphology, perfusion levels, and metabolic uptake on contrast-enhanced MRI, perfusion imaging, and amino acid PET, providing crucial imaging cues for identifying routes of blood supply, inferring the state of the blood–tumor barrier, and guiding individualized therapeutic strategies. Anti-VEGF therapy is primarily used to alleviate cerebral edema and radiation necrosis, yet it confers limited survival benefit, underscoring the spatiotemporal heterogeneity of the blood–tumor barrier and the persistence of non-classical vascularization pathways. Building on the concept of “vascular normalization,” combinations of anti-angiogenic therapy with immunotherapy, radiotherapy, or targeted agents have shown encouraging intracranial activity in selected settings—most robustly in melanoma brain metastases—but remain insufficiently validated in randomized, brain-metastasis-focused trials. By integrating mechanistic, imaging, and therapeutic perspectives, this review outlines how vascular-ecosystem-based stratification and physics-informed drug-delivery strategies may help transition anti-vascular therapy from symptomatic control toward mechanism-driven precision intervention. Full article

Objectives: To evaluate the effects of intravitreal ranibizumab on retinal nerve fiber layer (RNFL) thickness and optic disc parameters in patients treated for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Methods: This retrospective study analyzed the clinical records of 60 patients who received intravitreal ranibizumab injections for macular edema secondary to AMD, DME, or RVO between October 2014 and January 2016. All patients received intravitreal ranibizumab at a dose of 0.5 mg. Best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were recorded at baseline and during follow-up. RNFL thickness and optic disc parameters were assessed using optical coherence tomography (OCT) and Heidelberg Retina Tomograph III (HRT-3). Measurements were obtained before treatment and at 1 week, 1 month, 3 months, and 6 months after injection. Comparisons were performed within and between disease groups. Results: Of the 60 patients, 31 (51.7%) had DME, 20 (33.3%) had AMD, and 9 (15.0%) had RVO. Best-corrected visual acuity improved significantly during the follow-up period. Mean RNFL thickness measured by OCT showed a significant reduction in the DME and RVO groups (p = 0.0001 and p = 0.043, respectively). In contrast, no significant changes in RNFL thickness were detected using HRT-3, and no consistent alterations in other optic disc parameters were observed. Changes in optic disc parameters varied among disease groups. Conclusions: Intravitreal ranibizumab treatment was associated with a reduction in mean RNFL thickness measured by OCT in patients with DME and RVO during a six-month follow-up period, whereas no corresponding RNFL thinning was detected using HRT-3 in any disease group. The observed optic disc parameter changes appeared to be disease specific. Given the absence of untreated control eyes and the exclusion of patients with glaucoma, these findings apply only to non-glaucomatous eyes and should not be extrapolated to patients with glaucoma. Further prospective studies with larger cohorts, appropriate control groups, and longer follow-up durations are warranted to clarify the long-term effects of anti-VEGF therapy on the optic nerve. Full article

Acute respiratory distress syndrome (ARDS) is a fatal inflammatory lung disorder with few effective treatments. Hyaluronan (HA), a major extracellular matrix component, exhibits diverse biological activities depending on its molecular weight. This study aimed to evaluate the therapeutic potential of HA of various molecular weights in a rat model of ARDS. ARDS was induced in rats via the intratracheal instillation of 5 mg of bleomycin. Seven days later, when ARDS symptoms developed, low (LHA), medium (MHA), high (HHA), and mixed (MIX HA) hyaluronan were intratracheally administered seven times from Days 7 to 28. On Day 7, arterial oxygen saturation (SpO₂) and the partial pressure of oxygen (PaO₂) decreased, carbon dioxide levels increased, the respiratory rate increased, and extensive lung cell infiltration was observed, confirming successful ARDS induction. LHA and MIX HA improved the SpO₂ and PaO₂, and the latter increased lung and alveolar volume, reduced infiltration, and normalized breathing. All HA types attenuated collagen deposition and M1 macrophage activity, while MIX HA enhanced M2 polarization and upregulated MMP-2, MMP-9, and TLR-4. LHA increased VEGF and EGF expression. These findings demonstrate that different-weight HAs provide partial ARDS protection via distinct mechanisms. MIX HA shows synergistic effects, restoring and improving lung structure and function, respectively, representing a promising ARDS therapy. Full article

Diabetic wounds remain chronically non-healing due to impaired angiogenesis, persistent inflammation, and defective extracellular matrix remodelling. In recent years, stem cell-derived exosomes have emerged as a potent cell-free regenerative strategy capable of recapitulating the therapeutic benefits of mesenchymal stem cells while avoiding risks associated with direct cell transplantation. This review critically evaluates the preclinical evidence supporting the use of exosomes derived from adipose tissue, bone marrow, umbilical cord, and induced pluripotent stem cells for diabetic wound repair. These exosomes deliver bioactive cargos such as microRNAs, proteins, lipids, and cytokines that modulate key signalling pathways, including Phosphatidylinositol 3-kinase/Protein kinase (PI3K/Akt), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK), Transforming growth factor-beta (TGF-β/Smad), and Hypoxia inducible factor-1α/Vascular endothelial growth factor (HIF-1α/VEGF), thereby promoting angiogenesis, accelerating fibroblast and keratinocyte proliferation, facilitating re-epithelialization, and restoring immune balance through M2 macrophage polarization. A central focus of this review is the recent advances in exosome-based delivery systems, including hydrogels, microneedles, 3D scaffolds, and decellularized extracellular matrix composites, which significantly enhance exosome stability, retention, and targeted release at wound sites. Comparative insights between stem cell therapy and exosome therapy highlight the superior safety, scalability, and regulatory advantages of exosome-based approaches. We also summarize progress in exosome engineering, manufacturing, quality control, and ongoing clinical investigations, along with challenges related to standardization, dosage, and translational readiness. Collectively, this review provides a comprehensive mechanistic and translational framework that positions stem cell-derived exosomes as a next-generation, cell-free regenerative strategy with the potential to overcome current therapeutic limitations and redefine clinical management of diabetic wound healing. Full article

Objectives: This study aims to analyze the association between systemic inflammation and clinical outcomes in patients with macular edema secondary to retinal vein occlusion (RVO). Methods: A retrospective analysis of 68 patients with acute RVO, in whom cardiovascular risk factors were assessed, was conducted. Laboratory determinations included levels of C-reactive protein (CRP) and homocysteine to explore the systemic inflammatory status. Optical coherence tomography (OCT) parameters and visual acuity (LogMAR) were collected at baseline. Follow-up visual acuity was determined after 12 months. The number of intravitreal anti-VEGF injections and the performed laser treatment were assessed after 12 and 24 months. Associations of inflammatory markers with clinical outcomes were analyzed by correlation analysis, and patients with or without evidence for inflammation were compared. Results: At baseline, the mean foveal retinal thickness (FRT) was 591 ± 277 µm, the mean average central retinal thickness (CRT) was 580 ± 227 µm, and the mean average central retinal volume (CRV) was 12 ± 3 mm³. The level of CRP at baseline was significantly associated with increased FRT, average CRT, and average CRV (p = 0.024; p = 0.027; p = 0.003). CRP levels were also associated with a lower BCVA at baseline and after 12 months (p = 0.018; p = 0.006). In patients with elevated homocysteine levels, a trend towards a higher number of required laser treatments was observed. No association between increased inflammatory parameters and the number of required intravitreal injections was detected. Conclusions: Systemic inflammation is associated with the severity of macular edema secondary to RVO. CRP concentrations could represent a prognostic marker for the course of the patient’s visual acuity. Full article

The increasing prevalence of obesity-related primary arterial hypertension (PAH) in the pediatric population emphasizes the need to develop new biomarkers that can aid in clinical practice for prevention or early diagnosis of the cardiovascular disease. The objective of the present study was to evaluate the relationship between selected adipokines, cytokines, and blood pressure (BP) values in children with obesity. A total of 78 children participated in the study: 60 children with obesity (study group) and 18 children with normal weight (control group). Blood pressure was measured according to guidelines. Serum levels of metabolic and inflammatory markers, including leptin, adiponectin, resistin, ghrelin, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α (TNF-α), vascular endothelial growth factor (VEGF), and insulin were determined using multiplex immunoassays. Statistical analysis included correlation and ROC tests to identify potential predictors of PAH. The study group had significantly higher systolic and diastolic BP compared to the control group (p < 0.0001). Serum levels of leptin, IL-6, VEGF, insulin, and resistin were increased in the study group. Leptin, IL-6 and resistin correlated positively with BP values (p < 0.05), while ghrelin and adiponectin correlated negatively. ROC analysis identified leptin, IL-6, and VEGF as the most promising biomarkers for predicting PAH. The results confirm the role of adipokines and cytokines in the pathogenesis of PAH. The assessment of adipokine and cytokine profiles complements traditional anthropometric parameters such as BMI in assessing cardiovascular risk. Leptin, IL-6, and VEGF presented the strongest correlation with hypertension, suggesting their potential in future diagnostic and preventive strategies. Full article

More than 30% of diabetic patients develop dermatopathies linked to inflammation and increased vascular permeability. Considering the role of the renin–angiotensin–aldosterone system (RAAS) in diabetic complications, this study examined whether aldosterone (ALDO) and the mineralocorticoid receptor (MR) contribute to diabetes-related skin microangiopathy. Vascular permeability was measured in normoglycemic rats and insulin-dependent (streptozotocin-induced) diabetic rats. The expression of MR, 11β-hydroxysteroid dehydrogenase type 2 (HSD11β2), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and the tight junction protein ZO-1 was determined by PCR and immunohistochemistry. Diabetic rats received the MR antagonist eplerenone (EPL, 100 mg/kg) for 10 days. Additionally, the effects of ALDO and EPL on endothelial permeability were evaluated in human dermal microvascular endothelial cells (HMEC-1) using a Transwell system. Diabetic rats showed skin atrophy, collagen damage, elevated ALDO levels, reduced MR and HSD11β2 expression, and increased vascular permeability, along with upregulation of VEGF and vWF. EPL markedly reduced these abnormalities. In vitro, ALDO increased endothelial permeability under hyperglycemia, and EPL counteracted this effect. These findings indicate that activation of the ALDO/MR pathway promotes skin vascular permeability in diabetes through VEGF- and vWF-dependent mechanisms. MR blockade limits these changes, suggesting therapeutic potential in preventing diabetes-associated skin complications. Full article

Background: Aging is traditionally characterized by progressive structural and cognitive decline; however, increasing evidence shows that the aging brain retains a remarkable capacity for reorganization. This adaptive neuroplasticity supports cognitive resilience—defined as the ability to maintain efficient cognitive performance despite age-related neural vulnerability. Objective: To synthesize current molecular, cellular, neuroimaging, and electrophysiological neuromarkers that characterize adaptive neuroplasticity and to examine how these mechanisms contribute to cognitive resilience across aging. Methods: This narrative review integrates findings from molecular neuroscience, multimodal neuroimaging (fMRI, DTI, PET), electrophysiology (EEG, MEG, TMS), and behavioral research to outline multiscale biomarkers associated with compensatory and efficient neural reorganization in older adults. Results: Adaptive neuroplasticity emerges from the coordinated interaction of neurotrophic signaling (BDNF, CREB, IGF-1), glial modulation (astrocytic lactate metabolism, regulated microglial activity), synaptic remodeling, and neurovascular support (VEGF, nitric oxide). Multimodal neuromarkers—including preserved frontoparietal connectivity, DMN–FPCN coupling, synaptic density (SV2A-PET), theta–gamma coherence, and LTP-like excitability—consistently correlate with resilience in executive functions, memory, and processing speed. Behavioral enrichment, physical activity, and cognitive training further enhance these biomarkers, creating a bidirectional loop between experience and neural adaptability. Conclusions: Adaptive neuroplasticity represents a fundamental mechanism through which older adults maintain cognitive function despite biological aging. Integrating molecular, imaging, electrophysiological, and behavioral neuromarkers provides a comprehensive framework to identify resilience trajectories and to guide personalized interventions aimed at preserving cognition. Understanding these multilevel adaptive mechanisms reframes aging not as passive decline but as a dynamic continuum of biological compensation and cognitive preservation. Full article