Chronic Low-grade Inflammatory Phenotype (CLIP) and Senescent Immune Dysregulation

Purpose: The aim was to provide an overview of chronic low-grade inflammatory phenotype (CLIP) and evidence for its role in the pathogenesis of frailty and other chronic conditions as well as potential causative factors and interventions. Methods: We reviewed evidence from published clinical and laboratory studies and summarized the opinions of experts from published reviews. Findings: CLIP is a low-grade, systemic, unresolved, and smoldering chronic inflammatory state clearly indicated by a 2- to 4-fold increase in serum levels of inflammatory mediators, such as interleukin-6 and C-reactive protein. It involves many other cellular and molecular inflammatory mediators. CLIP typically occurs during aging, also known as “inflammaging,” and is an integral part of the spectrum of immunosenescence. Causative factors likely include persistent viral infections, particularly chronic cytomegalovirus infection, cellular senescence, failure to eliminate degraded materials and waste products, dysregulated microbiota and gut permeability, obesity, and others. Substantial evidence supports CLIP as a powerful contributing factor to frailty and many other chronic conditions and adverse health outcomes. Many of the inflammatory mediators and their regulatory mechanisms in CLIP may serve as potential targets for therapeutic intervention. However, development of new interventional strategies for CLIP and its associated chronic conditions should take the complexity of the inflammatory network into consideration. Nonpharmacologic interventions, such as caloric restriction and exercise, may have significant impact on CLIP and its causative factors, leading to substantial health benefits. Metformin and resveratrol have anti-inflammatory property and may serve as a promising therapeutic agent for treatment of CLIP and frailty. Implications: CLIP is a chronic inflammatory pathophysiologic process that plays an important role in the pathogenesis of frailty and many other chronic conditions. Improving our understanding of this phenotype may provide opportunities to identify potential targets of effective prevention and therapeutic strategies for frailty and other CLIP-associated conditions.