Therapeutic Targeting of Inflammaging and Emerging Strategies for Managing Age-Related Multimorbidity: A Narrative...

The global aging population faces an increasing burden of chronic multimorbidity, much of which is driven by inflammaging. Inflammaging is defined as a persistent, low-grade inflammatory state recognized as a hallmark of biological aging. This narrative review examines therapeutic strategies targeting key mechanisms of inflammaging, with particular focus on cellular senescence and the senescence-associated secretory phenotype (SASP), nicotinamide adenine dinucleotide (NAD+) decline, and inflammasome activation. Senolytic therapies designed to eliminate senescent cells have progressed into early-phase clinical trials. Combinations such as dasatinib plus quercetin and the flavonoid fisetin have reduced circulating SASP factors in early studies. Senomorphic agents, including rapamycin and Janus kinase (JAK) inhibitors, represent an alternative strategy by suppressing SASP production while preserving cell viability. Another therapeutic approach focuses on restoring intracellular NAD⁺ levels. Supplementation with precursors such as nicotinamide riboside and nicotinamide mononucleotide has shown beneficial effects on vascular function and metabolic health in early human studies. In addition, inhibition of the NAD⁺-consuming enzyme CD38 represents a complementary strategy aimed at preserving NAD⁺ availability. Targeted anti-inflammatory biologics directed against cytokines such as IL-1β, IL-6, and TNF-α have demonstrated clinical benefits in cardiovascular disease, supporting inflammation-targeted therapy. Repurposed metabolic medications including metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists also exhibit anti-inflammatory effects. In addition, evidence-based lifestyle interventions including caloric restriction, regular exercise, and Mediterranean dietary patterns remain important complementary strategies for mitigating inflammaging. Despite progress, translating these findings into clinical practice remains challenging because validated biomarkers are limited, trial designs are complex, and long-term safety data are still needed. Future collaborative research will help evaluate combination strategies and precision approaches targeting biological aging mechanisms.