Pathways involved in inflammaging and frailty: the paradigm of visfatin in inflammation and metabolic diseases and the factors influencing the response to COVID-19 vaccines.

Inflammaging and frailty converge on the immune system and contribute to the increased risk of aging-related diseases, serious infections, and reduced response to vaccines. There have been numerous candidate factors contributing to the frail phenotype. The NAMPT/visfatin pathway appears promising for identifying the molecular mechanisms underlying inflammaging, as intracellular NAMPT mediates the production of NAD+, essential for redox homeostasis and for activation of protective and anti-inflammatory transcriptional factors as Sirt-1; on the other hand, the extracellular form visfatin is pro-inflammatory. Based on recent data we addressed two major paradigms of inflammaging and frailty in which the NAMPT/visfatin pathway may represent a link. In the first part of the present project, we focused on osteoarthritis (OA) as a typical manifestation of inflammaging and frailty and studied 106 elderly (>50 years old) patients with OA and 80 elderly and 97 young (<30 years old) healthy subjects as controls. We report that visfatin pathway was unbalanced in both OA and healthy elderly compared with young subjects, with increased plasmatic visfatin and reduced intracellular NAMPT and pSirt-1 in circulating monocytes, although only Sirt-1 gene expression was reduced. Consistently, circulating mononuclear cell intracellular NAD+ levels were lower in both groups of elders. Increased plasmatic C-reactive protein, chemerin and leptin characterized OA patients regardless of age, sex, and BMI. Secondly, the observations that chronological and biological age do not always correspond became evident during the COVID-19 pandemic, in which some patients showed an altered immune response to the SARS-CoV-2 infection and to vaccination, related to immune conditions and immunosuppressive treatments. We studied 287 patients affected by immune-rheumatic diseases and 67 controls vaccinated with two doses of Moderna-1273 mRNA vaccine, evaluating humoral response, neutralizing activity, cytotoxic response, and cytokine production. Seroconversion was observed in 96% of patients compared to 100% of controls. Non-seroconverted patients were all on mycophenolate mofetil at significantly higher doses compared to seroconverted patients and a daily dose ≥1g was a significant risk factor for lack of seroconversion. Mycophenolate was also associated with significantly lower antibody titers than other immunosuppressants and slightly reduced serum neutralizing activity, while cytotoxic activity was impaired in non-seroconverted patients. Three cases of COVID-19 were observed after the first dose; vaccine side effects were not relevant. Our data cumulatively support the importance of the common theme of immune dysfunctions in determining frailty in OA and the response to vaccines. More specifically, a reduced cellular homeostatic capacity in elderly, associated with both inflammatory and metabolic factors, contributes to the inflammatory milieu associated with aging-related OA, while immunosuppressants are the dominant factor in the response to vaccination regardless of age. We may hypothesize that the NAMPT/visfatin pathway is a candidate target in future approaches to aging- and treatment-related immunological driven frail syndrome.