Type 2 diabetes (T2D) is a global metabolic epidemic driven by insulin resistance (IR), chronic inflammation, and β-cell failure. This review synthesizes evidence establishing immune aging—characterized by thymic involution, inflammaging, and immunosenescence—as a critical accelerator of T2D pathogenesis, particularly in aging populations. Central to this nexus is the "ominous octet" framework, which delineates eight interdependent organ dysfunctions perpetuating hyperglycemia. Here, we elucidate how immune aging intersects with cellular stress pathways to disrupt this network, offering novel targets for intervention.
Key Mechanisms Linking Immune Aging and T2D
Inflammaging and Metabolic Dysregulation:
Aging triggers chronic low-grade inflammation via senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines (IL-6, TNF-α). This "inflammaging" impairs insulin signaling, exacerbates IR, and induces β-cell apoptosis through oxidative stress and ER dysfunction. Macrophage polarization shifts from anti-inflammatory (M2) to pro-inflammatory (M1) phenotypes, further disrupting metabolic homeostasis.
Hyperinsulinemia-Inflammation Axis:
Compensatory hyperinsulinemia—initially adaptive—evolves into a pathological driver. Elevated insulin activates stress kinases (JNK, NF-κB), promoting serine phosphorylation of insulin receptor substrates (IRS) and impairing glucose uptake. This fuels a self-propagating cycle: hyperinsulinemia begets inflammation, which worsens IR and β-cell exhaustion.
Organelle Dysfunction as a Unifying Pathway:
Mitochondrial Dysfunction (MD): Reduces ATP synthesis, elevates ROS, and disrupts calcium signaling, impairing insulin secretion and promoting hepatocyte gluconeogenesis.
ER Stress: Misfolded proteins activate the unfolded protein response (UPR), inhibiting insulin receptor trafficking and GLUT4 translocation. Persistent ER stress triggers β-cell apoptosis via JNK/NF-κB pathways.
These dysfunctions amplify all components of the ominous octet, creating a metabolic-inflammatory vortex.
Impact on the "Ominous Octet"
The review details how immune aging and organelle stress exacerbate each element of the octet:
β-Cell Failure: AGE-RAGE axis and SASP induce inflammasome activation (NLRP3), accelerating β-cell senescence.
Hepatic Glucose Overproduction: Inflammation and MD dysregulate PEPCK/G6Pase, increasing gluconeogenesis.
Adipose Tissue (AT) Lipolysis: FFAs from inflamed AT promote ceramide accumulation, activating TLRs and NF-κB.
Muscle Glucose Uptake: ROS and ER stress inhibit GLUT4 translocation.
Renal Glucose Reabsorption: ER stress upregulates SGLT2 expression.
Incretin Deficiency: GLP-1 secretion is impaired by β-cell ER stress.
Neurotransmitter Dysregulation: Hypothalamic mitochondrial-ER crosstalk disruption alters appetite control.
Therapeutic Implications and Future Directions
The review advocates multi-targeted strategies to break the immune-metabolic cycle:
Immunomodulation: Senolytics (e.g., dasatinib/quercetin) clear senescent cells; SPMs (e.g., Resolvin D1) resolve inflammation; GLP-1 RAs promote M2 polarization.
Organelle Protection: Enhancing mitophagy (e.g., spermidine), UPR regulators (e.g., 4-phenylbutyrate), and MAM stabilizers (e.g., mitofusin-2 agonists) restore cellular homeostasis.
Personalized Approaches: Biomarkers like CRP, IL-6, and serine-phosphorylated IRS-1 could guide therapies targeting specific immune-metabolic nodes.
Future research must address clinical heterogeneity (age, ethnicity) and explore emerging areas: gut-microbiome-immune crosstalk, circadian disruption, and α-to-β cell transdifferentiation.
Conclusion
Immune aging is not merely a bystander but a catalytic force in T2D progression. By integrating the ominous octet with immunometabolic stress pathways, this review provides a roadmap for mechanism-based therapeutics aimed at preserving β-cell function and immune resilience in aging populations.
Full text:
https://www.xiahepublishing.com/2472-0712/ERHM-2025-00018
The study was recently published in the Exploratory Research and Hypothesis in Medicine .
Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.
