Background: Agingis associated with alterations in oxi-inflammatory-immune profile, and endothelial cell dysfunction. Indeed, increased generation of free radicals as well as immunosenescence are hallmarks of the aging process and age-related diseases. In the past 12 years or so, data has been accumulated on fermented papaya preparation (FPP®)(Osato Research Institute, Gifu, Japan), a specific functional food with robust redox and immune regulator nutrigenomics effect. The aim of this 2-year ongoing study of which we report the first-year data, was to test FPP® in redox, endothelial, and immune markers.Methods: Study population. From a total of 106 subjects, we report the analyzed data referring to 78 clinically stable, healthy, community-dwelling males and females, aged 60 to 75 years. The study was conducted using a double-blind method with designated groups A and B to fulfill the two different treatments. The two treatments are as follows: Group A, also known as “FPP Group,” was given one sachet two times per day containing 4.5g FPP®, along with one placebo capsule provided in the morning. Group B, also known as “AA Group,” was given one papaya-flavored sachet two times per day, along with one antioxidant mixture capsule in the morning. Morning blood samples were collected and tested for: Ultra-sensitive c-reactive protein (a highly sensitive ELISA), inducible nitric oxide synthase (iNOS) (by Human Nitric Oxide Synthase kit), asymmetric dimethylarginine, or ADMA, (a competitive enzyme-linked immunosorbent assay), apoptosis of PBMCs (by Annexin V staining) and MOS 36-item short-form health survey (SF-36) to assess quality of life. Screening and blood tests were carried out as follows: Visit I: Day 0 - Baseline, Visit II: Day 60, or 2 months, Visit III: 6 months, Visit IV: 11 months.Results: Plasma iNOS levels were comparable among both groups at the beginning of the study. FPP®-treated subjects showed a significant increased level at Visits II and III (P<0.05 vs baseline and vs AA). ADMA values were not affected by AA supplementation whereas FPP® treatment was associated with a significant decrease beginning with observation during Visit III (P<0.05 vs baseline and vs AA administration). The FPP® intervention was associated with improvements among several domains of quality of life such as physical function, general health, and mental components (P < 0.01 vs baseline and vs AA group). There was also at significant and comparable positive effect for time on vitality shown in both AA and FPP® groups.Conclusion: Unlike with the antioxidant treatment, the FPP® intervention yielded a transient decrease of ADMA, a decrease of iNOS and lower percentage in apoptotic PBMC. These results suggest that FPP®, by a more multifaceted, subcellular mechanism, as well as non-redox modulatory properties, was beneficially effective in regulating aging markers. These mechanisms are associated with a better SF-36 profile in support of FPP® as a candidate interventional functional food for health maintenance, and specifically in middle-age/elderly subjects.Keywords: Fermented Papaya Preparation, Nitric oxide, ADMA, apoptosis, antioxidants, SF-36