Host-virus resilience networks and viral inflammaging circuits in aging and long COVID: a CMV-centered perspective

Aging and long COVID are increasingly recognized as states of disrupted host homeostasis characterized by chronic inflammation, immune remodeling, metabolic dysfunction, and impaired stress adaptation. These alterations may compromise the mechanisms that normally maintain viral latency, thereby increasing susceptibility to reactivation of persistent viruses such as Cytomegalovirus (CMV). In this mini-review, we propose a systems-level framework in which latent viral reactivation emerges as a manifestation of declining organismal resilience rather than an isolated virological event. We introduce the concept of host-virus resilience networks, encompassing interconnected immune, metabolic, epigenetic, and cellular stress-response pathways that collectively preserve CMV latency across the lifespan. Age-associated immunosenescence, inflammaging, mitochondrial dysfunction, and epigenetic drift may progressively destabilize these networks, weakening antiviral surveillance and facilitating viral reactivation. We further propose the concept of viral inflammaging circuits, defined as self-reinforcing feedback loops in which chronic inflammation promotes viral reactivation, while viral activity further amplifies immune dysregulation, tissue stress, and inflammatory signaling. Within this framework, CMV is considered both a marker and a potential driver of immune aging through persistent antigenic stimulation, T-cell remodeling, and chronic inflammatory activation. Long COVID may represent a convergent resilience failure state in which persistent immune perturbation and metabolic stress intersect with latent herpesvirus biology. By integrating concepts from geroscience, immunology, and systems virology, this review aims to provide a conceptual model linking CMV persistence to network-level dysregulation in ageing and post-viral syndromes and highlights the importance of resilience-based approaches for understanding chronic inflammatory disease progression across the lifespan.