Jul 2026· Innovative Medicines & Omics· pp. 026230035· 0 citations
TL;DR
This review examines the biological foundations of inflammaging, emphasizing immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation, and proposes that inflammaging is best understood as multiscale biological interface failure.
Abstract
The concept of inflammaging—defined as the persistent, low-grade inflammatory state accompanying biological aging—has emerged as a unifying framework for understanding chronic disease in later life. Unlike acute inflammation, which is adaptive, transient, and protective, inflammaging reflects persistent dysregulation of immune signaling, impaired resolution of inflammatory responses, mitochondrial decline, and progressive loss of tissue homeostasis. Evidence increasingly indicates that inflammaging is not merely a consequence of aging but an active systems-level process that reshapes metabolic, vascular, neurological, and musculoskeletal physiology. Sustained inflammatory activation contributes to frailty, cardiovascular disease, neurodegeneration, sarcopenia, metabolic dysfunction, and osteoarthritis through interconnected molecular and cellular mechanisms involving immunosenescence, cellular senescence, oxidative stress, inflammasome activation, and epigenetic remodeling. Recent advances in geroscience have reframed inflammation as a multidirectional biological network integrating immune, endocrine, metabolic, microbiological, and biomechanical signals. This perspective moves beyond reductionist cytokine models by conceptualizing inflammation as a distributed regulatory architecture operating across tissues and organ systems. Accordingly, chronic disease may arise not only from local organ pathology but also from progressive failure of intersystem communication and adaptive resilience. This review examines the biological foundations of inflammaging, emphasizing immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation. We propose that inflammaging is best understood as multiscale biological interface failure, in which persistent inflammatory signaling progressively destabilizes tissue integration across physiological systems. This framework may support the development of more precise biomarkers, systems-oriented therapeutic strategies, and translational interventions designed to extend health span rather than merely prolong survival.
Cardiovascular inflammation is increasingly recognized not merely as a secondary response to hemodynamic or metabolic injury, but as a determinant of disease initiation, progression, and remodeling. In the injured heart and vasculature, danger sensing, inflammatory priming, inflammasome activation, nucleic acid recognition, immunometabolic rewiring, immunothrombosis, adaptive immune remodeling, and defective resolution form interdependent circuits rather than isolated pathways. A key challenge is to understand how these circuits shift from adaptive clearance and repair to persistent immune activation, fibrosis, and functional decline. Here, we synthesize evidence on immune landscapes and core inflammatory networks in cardiovascular diseases, focusing on TLR–NF‐κB signaling, NLRP3 inflammasomes, cGAS–STING‐dependent cytosolic DNA sensing, alternative mitochondrial nucleic acid‐sensing platforms, and redox‐immunometabolic gating. We highlight mitochondrial quality control and mitochondria‐derived DAMPs, including mtDNA, mtROS, ATP, cardiolipin, and oxidized lipids, as an upstream interface linking metabolic stress to sterile immune activation. We further organize disease‐specific inflammatory patterns through a stage‐cell‐threshold perspective across ischemic injury, vascular and metabolic disease, and cardiomyopathic remodeling. Finally, we discuss network‐guided therapeutic strategies, translational limitations, biomarkers, endpoints, and safety considerations. This integrated perspective provides a conceptual basis for moving cardiovascular inflammatory therapy from broad suppression toward more precise network regulation.
Jiaxiang Rong, Zhen Wang, Xiaoxiao Lin et al.· MedComm· 0 citations
It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
Tong Wang, Wei Jiang, Xingxu Chen et al.· Frontiers in Immunology· 0 citations
Biological aging is a gradual, multisystem process characterized by progressive functional decline, diminished physiological resilience, and increased susceptibility to chronic diseases. Growing evidence suggests that persistent exposure to adverse social environments, chronic psychological stress, and socioeconomic disadvantage can accelerate biological aging by altering age-related biomarkers and stress-response pathways. The weathering hypothesis provides a framework to explain how the cumulative burden of psychosocial adversity becomes biologically embedded, resulting in physiological wear and tear that hastens age-related deterioration over time. A central mechanism underlying this process is chronic low-grade inflammation, which contributes to the pathogenesis of numerous age-related conditions, including cancer and neurodegenerative diseases (NDDs). These disorders are highly prevalent among Caribbean Hispanics, a population disproportionately affected by social disadvantages and rapid population aging. Recent advances in the biology of inflammation and cellular senescence have generated interest in therapeutic strategies aimed at modulating fundamental mechanisms of aging. Emerging approaches, including senolytics, anti-inflammatory agents, and non-coding RNA–based interventions, offer promising opportunities for precision medicine; however, RNA-based therapies remain largely experimental, and their clinical translation to address stress-related aging and health disparities has yet to be established. In this review, we examine the interplay between weathering and inflammation in shaping biological aging and discuss the potential of innovative precision medicine approaches to mitigate age-related decline and reduce health disparities in vulnerable populations.
Frances Marín‐Maldonado, Mitzy J. Santiago-Rosario, Wilfred Fonseca-Ferrer et al.· Frontiers in Aging· 0 citations
Considered a global public health priority, sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. Its heterogeneous clinical presentation arises, in part, from pre-existing chronic conditions such as hypertension, metabolic syndrome, diabetes, alcohol exposure, psychosocial stress, and periodontitis, which induce persistent systemic changes even before the infectious event. This narrative review synthesizes evidence from experimental models and clinical studies to clarify the molecular and immunological mechanisms by which chronic conditions influence the septic state. We discuss how these conditions converge on common pathophysiological mechanisms, including low-grade chronic inflammation, oxidative stress, endothelial and mitochondrial dysfunction, and changes in the microbiota and neuroimmune regulation. Pathways such as TLR-NF-κB signaling and the NLRP3 inflammasome are maintained in a basal state of activation, lowering the threshold for hyperinflammatory responses and increasing the risk of multiple organ dysfunction syndrome. In conclusion, understanding these phenotypes can guide the identification of biomarkers and the development of personalized therapeutic strategies, thereby moving beyond one-size-fits-all approaches to the management of sepsis and septic shock.
Maria Vitória Oliveira Miguel, Rayssa Menon Santos, Matheus Marques de Oliveira et al.· International Journal of Mol...· 0 citations
Cardiovascular diseases remain the primary driver of global mortality, with advanced age serving the most significant risk factor for their development and progression. Emerging evidence suggests that chronic infections can act as potent catalysts for cardiac decline by prematurely inducing aging phenotypes. Pathogens, including viruses, bacteria, and parasites, that evade host clearance establish a state of permanent inflammaging: a chronic, low-grade inflammatory milieu characterized by persistent cytokine signaling and leukocyte infiltration. This environment directly mirrors the sterile inflammation that drives natural senescence. Mechanistically, chronic infection subverts the heart's homeostatic pathways, triggering cardiomyocyte senescence through the dysregulation of mTOR signaling and the impairment of autophagy. These infections further drive mitochondrial dysfunction and the overproduction of reactive oxygen species (ROS), leading to oxidative DNA damage and metabolic exhaustion within the myocardium. On a structural level, immune subversion, via macrophage polarization and the induction of autoimmunity, accelerates left ventricular hypertrophy, myocardial remodeling, and interstitial fibrosis. By characterizing chronic infection as a modifiable driver of biological aging, we can prioritize anti-infective strategies as essential components of cardiovascular longevity and geriatric care.
Noah Walsh, Sophia DeCesare, Kavisha Patel et al.· Cellular Physiology and Bioc...· 0 citations
Accumulating evidence suggests that outcomes are shaped not only by age and comorbidities, but also by preexisting biological states. A key determinant is immune resilience-the capacity to restore immune function and organ homeostasis. Aging-or accelerated biological aging-promotes accumulation of senescent cells and the senescence-associated secretory phenotype (SASP), driving chronic low-grade inflammation ("inflammaging"), impairing immune function, and reducing host resilience. SASP may also prime the immune system for exaggerated inflammatory responses in sepsis, contributing to cytokine storm. Notably, hyperinflammatory and immunosuppressive responses often emerge concurrently rather than sequentially. Immune cell death pathways help explain this apparent contradiction, as highlighted in the review featured in this issue of the Journal. These pathways provide a mechanistic bridge between these seemingly opposing states. They are not merely consequences of sepsis but active determinants of immune trajectory. Loss of SCFA- producing microbiota may impair immune regulation and promote dysregulated cell death, sustaining both hyperinflammatory and immunosuppressive states. This framework provides a testable model and supports interventional studies to determine whether restoration of SCFA signaling-such as through early administration of butyrate-producing microbes or tributyrin (a stable butyrate triglyceride)-can favorably alter immune trajectories and improve clinical outcomes.
Y. Yip, K. Ho· Journal of critical care· 0 citations