Recent researches stigmatize that the steady increase in life expectancy in Europe, USA, Canada, Japan and England will allow many of the children born in 2000 to reach 100 years of life [1]. In this perspective, the main objective of the geriatrician is to analyze risk factors for diseases and conditions that can lead to functional limitations for the elderly, in order to avoid people to reach a disability state. In summary, the increase in life expectancy must coincide with an expectation of health, good health and self-sufficiency for the last part of life [2]. Old age is a situation in which a number of factors (molecular, cellular, physiological, immunological and psycho-social events) help to set up a scenario of “exhaustion of reserves”; this consist of a inability to functional adaptations and an accumulation of deficits of many organs [3]. This situation undergoes a dynamic process that oscillates between a “successful” and pathological aging, which establishes a situation of vulnerability that is identified with the fragility state. Undoubtedly, to the fragility state contribute the same factors that have contributed to the increased life expectancy, which is attested at the moment at 80 years of age [4]. Many factors have allowed this “stretching”, i.e. the decrease of infant mortality, antibiotic therapy and prevention of cardiovascular and metabolic diseases, but also, especially in industrialized countries, the improvement of hygienic and nutrition conditions [5]. However, if aging is not accompanied by a healthy condition, the costs related to disabilities or frailty age-related could lead to the overgrowth of the public health expense with a negative impact on social welfare.

“The aging phenotype”, including the immunosenescence is the result of an imbalance between inflammatory and anti-inflammatory mechanisms with the consequence of a state defined by some authors as “inflammaging” [6–8]. The “Inflammaging” is due to chronic antigen stimulation that occurs in the course of life and to the oxidative stress that involves the production of oxygen free radicals and toxic products. Both these factors are able to modify the potential of apoptotic lymphocytes. In fact, the phenomenon of “remodelling” and the “up-regulation” of pro-inflammatory cytokines (including IL-6) are the components most heavily implicated in the processes of longevity and diseases related to senescence [9–12]. As pro-inflammatory and anti-inflammatory chemokines and other signalling molecules, might propagate from already activated cells to adjacent ones and systemically by circulating products and microvesicles, recent studies claimed the possibility of understanding molecular basis of inflammaging by novel omic approaches [13].

In this sense, the state of good health in the elderly is the result not only of low pro inflammatory mechanisms, but also of an efficient network capable of neutralizing anti inflammatory antigenic insults received in the course of life. For this reason, the inflammaging would not only be important for the mechanisms of immunosenescence but also for the problem of longevity. It is reported that fragility is the result of an inflammatory state associated with the overproduction of certain lymphokines, including IL-6, called cytokine of geriatricians [14]. This factor, together with hormonal changes, nutritional deficiencies and physical inactivity would lead to one of the most important component of fragility that is sarcopenia [15, 16], as well as the reduction of bone mass. In this context, immunity appears to play an important role, both in the regulation of the mechanisms of aging as well as in the onset of the diseases typical of aging (i.e. infectious diseases, autoimmunity, cancer, metabolic diseases and neurodegenerative diseases).

Another factor influencing the Immune System, in addition to the antigenic stimulus, is the intervention of metabolites of oxygen (ROS), a consequence of the activation of the respiratory burst; as they can cause significant damage, is plausible to assume that aging is also due to an accumulation of free radicals [17]. The increase in oxygen metabolites and their accumulation causes damage to important cellular components (lipid membranes, the structural and enzymatic proteins and nucleic acids), which are contrasted by enzymatic and non-enzymatic defence systems, reparative enzymes, DNA damage and apoptotic processes damage-induced [18, 19]. These protective mechanisms become less effective as a result of continued exposure to oxidative stress and the accumulation of senescent and mutated cells, leading to an increased risk of cancer. The p53 protein counteracts the development of a neoplasm flaunting how cells respond to injury (DNA repair, or, if it fails, apoptosis). p53 plays an important role in senescence: if it increases, the incidence of neoplasia is reduced, but on the other hand it increases the speed of aging [20]. The result is a delicate balance between reduced p53 that leads to death by cancer and increased p53 leading to death for acceleration of senescence. Furthermore, an over expression of p53 generates reactive oxygen intermediates [21].

An important source of oxygen intermediates are the mitochondria. Although the main mitochondrial function is the production of energy, the isolated mitochondria generate oxygen radicals during oxidative phosphorylation. The mitochondrial electron transport chain is imperfect because it generates a superoxide radical by a process of reduction of O₂. The enzymatic dismutation of the superoxide radical produces H₂O₂, another important biological oxidant. Another factor contributing to the senescence is apoptosis, especially the one induced by acid metabolites arising from the paths of lipoxygenase and cyclooxygenase; however it is not clear whether these products induce the production of reactive intermediates or if they act independently as oxidants to induce apoptosis. Another intermediate product of oxygen metabolism is nitric oxide, a free radical known as an important regulator of mitochondrial function, capable of increasing the apoptotic phenomena, but also, at physiological levels, of preventing apoptosis and of interfering with the cascade of capsaicin [22]. In conclusion, high levels of oxidants can change the potential of oxido-reduction, by reducing the levels of ATP and increasing the porosity of the membranes leading to a progressive aging phenomenon of the cells, included the Immune System ones [23].

As a result of ROS accumulation, cells become resistant to apoptosis -induced damage and the number of senescent cells increases, while chronic antigenic stimulation induces increase of activated immune cells and overproduction of pro-inflammatory lymphokines that contribute to the remodelling of the immune system and of the ‘inflammaging’. Senescence is a highly dynamic phenomenon characterised by continuous body adaptation to deteriorative changes [24].

ROS are closely linked to senescence and age-related diseases, in fact, genomic instability, caused by oxidative damage is the primary cause of aging. A caloric restriction can increase the average life-attenuating oxidative stress caused by normal metabolism [25].

As result of both inflammaging and of ROS increase, the modulation of apoptosis mechanisms becomes particularly delicate during senescence. The reduced sensitivity to the damage-induced apoptosis, typical of senescent cells, contributes to the accumulation of dysfunctional cells, clones of CD8+ and memory cells with a reduction of immunological space and an increased risk of infections and neoplastic diseases or degenerative disorders. The increase of the activation-induced apoptosis in response to inflammatory cytokines contributes to: the depletion of cells “naive”, the reduction of the capacity of clonal expansion, the reduction of T cell responses with decreased ability to mount strong immune responses to antigenic stimuli and reduction of the immune repertoire.

The shortening of the telomeric DNA is age specific, and, regardless of the genetic influence, it is the result of the immunological history of each individual, with a close association between telomere length and mortality of individuals older than 65 years [26]. The input of virgin T cells gradually decreases, and, recently, the marker of the lymphocytes of the new generation are the T REC which represent markers of replication of T cells, with a progressive reduction of each subsequent division. Of course, the T REC decay dramatically with age in peripheral T lymphocytes.

Apoptosis, a complex mechanism of programmed cell death, allows the maintenance of a physiological homeostasis mechanisms between survival and removal of damaged cells, allowing also the prevention of many diseases including neoplastic ones. Apoptosis is a strategic mechanism for the manifestation of the clonotypic diversity during lymphocyte selection, permitting to control the clonal expansion after antigenic stimulation. Apoptosis can be induced after a cellular damage (damage-induced cell death), or can be “activated” by a series of signals and anchor ligands to programmed-death receptors (activation-induced cell death). Apoptosis is part of many changes typical of the immunosenescence, such as thymic involution, the alteration of the “repertoire” of T cells and the accumulation of effector memory cells, all events at the basis of autoimmunity. Studies about apoptosis in aging are controversial. In fact, during senescence both the two apoptotic process can be modulated differently, resulting in a variable impact in the process of senescence. A proper modulation of this important function can extend the lifespan and reduce the degenerative processes and inflammatory and neoplastic diseases that are very common during senescence [6, 27].

The immune system cells are constantly renewed from hematopoietic stem cells (HSC), but this ability declines during senescence and the total amount of hematopoietic tissue decreases. This event also seems to correlate with telomere shortening [28]. The changes affect also the myeloid and erythroid progenitors as B cells, with the consequence of a reduction in mature B cells. The precursors of T cells seem to suffer less; the changes that occur with age to the thymus gland, also lead to changes in the T cell compartment. The thymus undergoes a process of physiological involution, with volume reduction and replacement with adipose tissue in the functional part of both cortex and medulla, contraction of soluble factors and hormonal cytokines production. This process begins early in life and is almost complete at the age of 40–50 years [29].

Moreover, the immune system has the important function to protect the body from any form of damaging agent (chemical, traumatic or infectious). There are two kind of immunity working together in a cooperative manner: the natural immunity (innate) immunity and adaptive (acquired). The natural immunity is the first line of defence because it provides a fast protection, but unspecific and incomplete, consisting mostly of monocytes, natural killer cells and dendritic cells, which acts until the adaptive immune response is established; this immune response is slower, but highly specific and permanent, with a cellular substrate consisting of T and B lymphocytes.

Alterations in innate immunity have a crucial role and the amount of related studies have identified a trend in the chapter of immunogerontology starting with the reduction of barriers in the epithelial layer of the skin and gastrointestinal and respiratory mucosa [49] with a consequent changes in local immunoglobulin ratio. Moreover, even some physiological events, such as the reduction of the thymic mass, seems to support the hypothesis that the immune system plays an important role in the phenomenon of aging, thus justifying a theory to explain some of the immunological diseases typical of this age such as autoimmune diseases, malignancies and infections. The high incidence of infectious events in old age can, however, be secondary to alterations in the phagocyte system [50].

With regard to the skin, immunosenescence is characterized by an impairment of all the structures with loss of the “barrier” function, reduction of the number and the volume of hairs, reduction of the number of sebaceous glands, loss of skin elasticity, impairment of the immunological defence of the skin [51].

Dendritic cells, responsible for the very first recognition of pathogens in the skin, show mitochondrial dysfunctions that interfere with their protective role [52].

In particular there is an impairment of the antigen uptake and of the apoptotic function [53].

Comparing the elderly plasmocytoid dendritic cell (PCD) capacity of antigen uptake with the one of the PCD of the young it is possible to observe a reduced ability of the elderly PCD to induce proliferation and stimulate secretion of INF gamma in CD4+ and CD8+ cells [54].

According to recent studies, the IRP is predictive of the development of cognitive deficits and, as outlined by some authors, [35] is a prelude for a mortality rate over the next 4 years in 58% of cases. The IRP is defined, in the studies of this group of Swedish researchers carried out on elderly octogenarians and nonagenarians, by identifying some characteristic “markers” of this phenotype, including the inversion of the CD4/CD8 ratio, the increase in CD8 * CD28-memory/effector cells, the increase of proinflammatory cytokines such as IL-6, the reduction of B lymphocytes and a marked seropositivity for cytomegalovirus [68].

The pro-inflammatory profile resulting from an interaction between the genotype and environmental factors, becomes strategic trough the years; the increase of cytokine secretion also correlated with the impact of cytomegalovirus infection is responsible for an unsuccessful aging [69]. CMV-specific cells, both CD4+ and CD8+ cells have short telomeres and this leads to chromosomal instability and DNA damage repair processes in growth arrest and/or apoptosis. The consequence is that not all T memory cells differ in the same way and that can happen an expansion of this cell pool, whose clinical consequences consist in an increase in infectious diseases and neoplasms [70].

A shown above, immunosenescence is an unavoidable process typical of life being. Many immune system cells undergoes this process; however, the senescence process differ from one subject to the other. The development of a pro-inflammatory cytokines phenotype together with the counterbalance of an anti-inflammatory profile could let people reach an old age without disability. A correct modulation of immune responses and of apoptotic phenomena, in fact, can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases in order to reach a successful aging.