The gut and circulating virome: emerging players in aging and longevity

Gretta Veronica Badillo-Pazmay¹Carlo Fortunato¹Laura Cianfruglia¹Federica Novazzi^2,3Pietro Giorgio Spezia⁴Luigi Rosa⁴Dolores Limongi^5,6Carla Prezioso^5,6Valeria D'Argenio^7,8Olga Scudiero^7,8,9Lisa Bevilacqua¹⁰Marco Malavolta^11,12Patrizia Russo¹³Fabrizio Maggi⁴Marta Balietti^10*Robertina Giacconi^1*

• ¹Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
• ²Laboratory of Microbiology, ASST Sette Laghi, Varese, Italy, Varese, Italy
• ³Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy
• ⁴Laboratory of Virology, National Institute for Infectious Diseases, Lazzaro Spallanzani- IRCCS, Rome, Italy
• ⁵San Raffaele Open University, Department of Human Sciences and Promotion of the Quality of Life, Rome, Italy
• ⁶Laboratory of Microbiology, IRCCS San Raffaele Roma, Rome, Italy
• ⁷CEINGE-Biotecnologie Avanzate “Franco Salvatore”, Napoli, Italy
• ⁸Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Napoli, Italy
• ⁹Task Force on Microbiome Studies, University of Naples Federico II, Napoli, Italy
• ¹⁰Center for Neurobiology of Aging, IRCCS INRCA, Ancona, Italy
• ¹¹INRCA-IRCCS, Ancona, Italy
• ¹²Universita Politecnica delle Marche Dipartimento di Scienze Cliniche e Molecolari, Ancona, Italy
• ¹³Clinical and Molecular Epidemiology, IRCCS San Raffaele Roma, Rome, Italy

A growing body of evidence indicates that the human virome, comprising both the gut and circulating viral communities, plays a critical role in shaping host physiology across the lifespan. In the context of aging, this complex viral ecosystem is increasingly recognized as a key modulator of immune function, inflammation, and metabolic balance, with direct implications for healthspan and longevity. While much attention has traditionally focused on bacterial components of the microbiota, recent advances in metagenomics have uncovered age-related shifts in the composition and function of the virome, including expansion of specific bacteriophage families, reactivation of latent viruses, and the persistence of commensal viral pathobionts. These changes are tightly linked to immunosenescence, chronic inflammation, and neurodegeneration, hallmarks of unhealthy aging. Notably, centenarians appear to harbor a unique virome signature marked by increased viral diversity, enhanced lytic activity, and the enrichment of phage-encoded metabolic functions, suggesting a potential protective role in extreme longevity. Despite these insights, significant challenges remain in virome profiling, including technical biases, database limitations, and the vast proportion of taxonomically unassigned sequences known as "viral dark matter". This review highlights emerging data on the aging virome, underscores its relevance within the Geroscience framework, and discusses current barriers and future directions for translating virome research into clinical aging studies.