The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro–endocrine–immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.

The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR β-chain diversity in young (∼25 years), middle-aged (∼60 years), and elderly adults (∼75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67⁺ cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at ∼2 × 10⁷ different TCR β-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR β-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.

Human aging is a very complex process that occurs in an intricate biological and physiological setting. Many changes occur with aging and among the most important are changes in immune reactivity associated with cell differentiation stages and the phenomenon of inflammaging, understood as subclinical inflammatory readiness, manifested by elevated levels of proinflammatory factors. It was stated for a long time that this tandem occurs in parallel or eventually sequentially. However, recent evidence points to the fact that, as both originate from chronic antigen stimulation, they mutually drive each other. In this context, inflammaging is considered the basis of most age-related diseases (ARD). In this review concerning human inflammaging, we argue that inflammatory diseases develop during whole life as a diverted (excessive) normal immune reaction to specific stressors. Thus, inflammaging may not be the cause of these diseases; however, it can be the trigger of clinical manifestation of ARD. In this context, the best intervention should aim to regulate the balance between pro- and anti-inflammatory signals and the more appropriate reaction to chronic stimulations to avoid/delay the appearance of associated diseases.

The distribution of peripheral T cell subsets in young and healthy old people is markedly different, characterized by decreased numbers of naïve cells and increased numbers and clonal expansions of memory cells, predominantly in the CD8+ MHC class I-