Perspective Chapter: Zhuxiang Syndrome – A Novel Mechanism Linking Chronic Fungal Infections to Systemic Inflammatory Diseases in Aging

Aging is a complex biological process characterized by progressive physiological changes that elevate the risk of various diseases. One of the most notable consequences of aging is “inflammaging,” a chronic, low-grade inflammatory state linked to the development of several age-related diseases, including cardiovascular and musculoskeletal disorders, as well as skin conditions. Chronic fungal infections, particularly those caused by Aspergillus sydowii, have emerged as significant contributors to exacerbating systemic inflammation in aging populations. This study focuses on a 58-year-old male with a 43-year history of onychomycosis and tinea pedis, who developed recurrent fungal infections leading to systemic inflammation manifesting as arthritis, dermatitis, and cardiovascular abnormalities. Over a 3-year period, we examined the impact of environmental factors, fungal-secreted proteins, and antifungal therapies on his condition. Our findings suggest that Aspergillus sydowii can form composite fungal-human cells, termed “zombie cells,” within the foot skin. These cells, which integrate fungal components with anucleated human keratinocytes, are not dormant but exhibit fungal-like characteristics that trigger systemic inflammatory responses. This phenomenon is proposed to underlie the newly identified Zhuxiang syndrome, which highlights a novel mechanism linking chronic fungal infections to systemic inflammatory diseases in the elderly. By shedding light on the role of chronic fungal infections in the pathogenesis of systemic diseases, this study offers insights into the interplay between aging, inflammation, and fungal pathogenesis, while suggesting potential therapeutic avenues for the management of fungal-related inflammatory conditions in older adults.