Blood from elderly individuals exhibits a reduced "rejuvenating" effect compared to that of young donors, and plasma from older subjects used as a supplement in cell culture media is less effective than plasma from younger individuals. A mass spectrometry-based proteomic analysis of plasma samples from 229 blood donors—including a prepubertal group, a healthy young adult group, and a cohort of individuals over 75 years old—revealed a chronic inflammatory state in the elderly population, along with complement activation and negative regulation of blood coagulation. This inflammatory condition was confirmed by elevated levels of classical pro-inflammatory cytokines in the plasma of older individuals, as measured by microarray and Milliplex Luminex assays. Moreover, the elderly group showed a reduced production of antibody light chains, suggesting concurrent immunosenescence. We identified 25 proteins whose increased abundance, together with acquired immune aging, may constitute a plasma proteomic signature of aging. The degree of upregulation of these proteins varied among elderly subgroups with different lifestyles. An evaluation of the expression patterns of the 25 consistently elevated proteins revealed distinct protein clusters with differential expression across three lifestyle-based subgroups. Notably, a lifestyle aimed at preserving good physical and/or cognitive function appeared to attenuate the intensity of the aging-related proteomic signature. To explore potential gender-related differences in plasma protein expression, we compared samples from male and female donors. Among elderly individuals, no major differences were observed, except for an increased level of Pregnancy Zone Protein (PZP) in females. In contrast, several gender-specific differences were identified in the plasma profiles of young donors.