Ageing gender-specific "Biomarkers of Homeostasis", to protect ourselves against the diseases of the old age

Abstract

Low-grade inflammatory state causes the development of the principal chronic-degenerative pathologies related with ageing. Consequently, it is required a better comprehension of the physiologic origins and the consequences of the low-grade inflammatory state for the identification of 1) the basic mechanisms that lead to the chronic inflammatory state and, after that, to the progression toward the pathologies and 2) the parallel identification of the prognostic biomarkers typical of these passages. These biomarkers could bring to several improvements in the health quality, allowing an early diagnosis and more effective treatments for: a) the prevention strategies on the healthy population, to assure a healthy longevity and b) the identification of personalized treatment in patients, to assure the benefit of the therapy. For the identification of these biomarkers it is necessary to consider that the ageing processes produce alterations of the physiologic systems and that these modifications compromise the communications between these networks: this state constitutes an obstacle for an appropriate physiologic homeostasis, that plays a fundamental role for the safeguard of the health. It is also to be considered that immune senescence affects both men and women, but it does it in different ways: a sexual dimorphism of immune pathways in the setting of immune response homeostasis is normally present, as we previously underlined. Therefore we hypothesize that, in order to prevent the development of the chronic-degenerative pathologies related with ageing, it is important to identify "Biomarkers of Homeostasis " specific for each gender: these are biologic molecules that should be measurable in a practical and no-invasive way and whose variations can quantify the male and female risk of losing the physiologic system homeostatic capacity. This competence is not only critical in the control of inflammation, but it is also prognostic for the passages from low-grade inflammatory state to the chronic inflammation and to the progression toward the degenerative pathologies. Beginning from the actual results, our intent is 1) to discuss and underline the importance of these new research perspectives in the definition of ageing gender-specific clinical "Biomarkers of Homeostasis" and 2) to propose homeostasis biomarkers, already present in the research results.

Figure 1

Progressive increase of the elderly population: parallel increase of the subjects with chronic inflammation and chronic-degenerative diseases. The mean age and the lifespan are progressively growing and this increase of the elderly population is related with a parallel increase of the subjects with chronic inflammation and chronic-degenerative diseases as neoplastic, autoimmune and neurodegenerative pathologies.

Figure 2

Prognostic biomarkers could be suitable as risk indicator of pathologies and of the clinic/therapeutic trend. The recent developments in the research, in particular in genetic, in proteomic and in informatics areas, are leading to the discovery of prognostic biomarkers that could be suitable as risk indicator of pathologies and of the clinic/therapeutic trend. The transport in the clinical practice of these biomarkers allows the early diagnosis and personalized therapeutic intervention, contributing, then, not only to the improvement in the health quality but also to a better administration of the sanitary system.

Figure 3

Ageing research data identify the incapacity to preserve health in the loss of homeostasis. Changes of the physiologic functions related with the ageing process obstacle an appropriate physiologic homeostasis, impeding health safeguard: they affect all the cells and in particular the nervous, endocrine, immune ones, compromising the functioning of these fundamental regulatory system and their mutual communication.

Figure 4

It is in the physio-pathological pathways that lead to chronic inflammation that it is to be researched the scientific ratio for the definition of clinical biomarkers of homeostasis for the prevention and the treatment of chronic-degenerative diseases. The procedure consists in the individuation of biologic molecules, whose variations could quantify the risk of losing the physiologic system homeostatic capacity in the control of the inflammation. These molecules have to be measurable in a practical and no-invasive way, in all the following stages: a) in the normal state of health, in which we identify biomarkers of a type that are in this case indices of no-risk of disease; b) in the transient inflammatory state, where we define biomarkers of b type that are indices of low-risk of pathology; c) in the chronic inflammatory state, in which it is possible to select biomarkers of c type that are indices of high-risk of disease. The scientific rational is that prognostic biomarkers have to be predictive for the following passages to be efficient in the prevention of chronic-degenerative diseases: 1) from the health physiologic condition (typical for the a type biomarkers), in which there is a homeostatic balance in the inflammation control, 2) to the transient inflammation (b type) where the restoration of this balance is still very probable, 3) and/or to the chronic inflammation (c type) in which this recovery is physiologically very improbable, while it is high the risk of progression toward degenerative pathologies.

Figure 5

Biomarkers of homeostasis allow an early diagnosis and personalized therapeutic interventions, permitting a promising change in the clinical practice and in the sanitary system administration. They open to a large class of prevention programs for these pathologies on the healthy population, that are not yet available, because they are suitable for the identification of subjects that are still healthy, but with a high risk to develop this kind of pathologies. On these individuals it is justified the application of preventive sanitary procedures, saving the actuation where they are not motivated.

Figure 6

The identification of molecules that have the function of homeostatic biomarkers. The study of the relationships between ageing and a healthy longevity, in the healthy population comparing the age subgroups, could be useful in the definition of 1) a type biomarkers (prognostic for the homeostatic state and of no-risk of pathology) and 2) b type biomarkers (prognostic for the transient inflammatory state, then of the restoration possibility of the homeostatic condition and of low-risk of pathology). These biomarkers are usable in prevention intervention on the healthy population and in the evaluation of the risk/benefit for the therapeutic selection of patients. On patients with chronic-degenerative pathologies the procedure is to select the biologic molecules with homeostatic biomarker capacity in association with the losing of the inflammation control, comparing the patient groups and the healthy individuals in internally homogeneous layers for gender and age, as upper described. The intent is to define the significant molecules to select the c type of homeostatic biomarkers, indices of high-risk of disease, prognostic for the degeneration toward pathology.

Figure 7

The Importance of the evaluation of the both gender, men and women, as independent groups: men and women follow different strategies to reach longevity. Clinical and experimental data show that, when the immune system is involved, men and women could not be evaluated in only one group, because the results would be not real, since in the immune response there is a natural gender dimorphism. It has been proved that the immunosenescence affects both men and women, but it afflicts them differently. Furthermore, it has been demonstrated that female and male hormones act affecting in opposite ways the immune system. The research has shown that the gender, male or female, is associated with relevant incidence and prevalence of different types of age related diseases and it also is an important variable in the genetic of longevity, indicating an important observation: men and women follow different strategies to reach longevity.

Figure 8

Homeostasis is preserved and there are no differences between men and women in the outcome of the immune response when the pathways of the gender specific cytokines (IFNγ and IL6) still normally work. The relevance of the gender specific differences in the regulation of the immune response is underlined by the evidence that homeostasis is preserved and there are no differences between men and women in the outcome of this response when the pathways of the gender specific cytokines (IFNγ and IL6) still normally work. It has been shown that the variations between pro- and anti-inflammatory cytokines could influence the success of the immune response. The most relevant discover, however, for the definition of suitable prognostic biomarkers, is the identification of “double prognostic biomarkers”: they are constituted by couple of pro- and anti- inflammatory cytokines that differ between men and women and assure the success of the immune response varying in appropriate relationship each other and following different pathways in each gender.

Figure 9

When alterations occur in the pathways of the gender-specific cytokines, the consequences for men and women are different, in terms of disease development. This event is related to the impairment of the immune system homeostasis, because the alterations of gender-specific cytokine pathways cause a pathologic polarization of specific T cell types, different for each gender. The reason of this fact is related to the different effects generated by IFNγ and IL6 cytokines, that are present in the cellular environment, on the generation of Th cell subtypes during the immune response.

Figure 10

The variations between pro- and anti-inflammatory cytokines could influence the success of the immune response. The most relevant discover, however, for the definition of suitable prognostic biomarkers, is the identification of “double prognostic biomarkers”: they are constituted by couple of pro- and anti- inflammatory cytokines that differ between men and women and assure the success of the immune response varying in appropriate relationship each other and following different pathways in each gender. The early evolution of the immune response is influenced by the positive correlation between the production of IFNγ-IL10 and IL6-IL4 in men, and the negative one between IL6-IL10 in women. The evolution of the late response is also influenced by the positive correlation between the production of IFNγ-IL4 in men and IL6-IFNγ in women. More specifically the “double prognostic biomarkers” for men are related by direct proportionality (they both increase or decrease together with the same trend, both positive or negative) between the IFNγ―IL10, IL6―IL4 and IFNγ―IL4 cytokine levels; while they are interconnected in women by an inverse proportionality (an increase of the first correspond to a decrease of the second and vice versa) between the IL6―IL10 cytokine levels, and with a direct proportionality between the IL6―IFNγ cytokines. These variations between the couple of inflammatory and anti-inflammatory cytokines, specific for each gender, are to be considered “double biomarkers” gender-specific, in the valuation of relationships between ageing and a healthy longevity.

Figure 11

The functional link between Trx1 and CD30 is a very important step in the physiologic homeostasis and it underlines the big potentiality of these elements as clinical diagnostic and therapeutic targets. The results of the research explained that in addition to Trx1, sCD30 is also able to influence the CD30R capacity to mediate the activation of intracellular signals for immune system homeostasis and healthy longevity, thanks to the inhibition of the binding between CD30L and RCD30: Trx1 makes this function catalytically, modifying the stoichiometric structure of RCD30; sCD30 makes the same function binding and blocking the binding site of CD30L, with which it has a strong affinity. For these reasons they have both to be considered for the use of the RCD30 as immunological and therapeutic biomarkers, because Trx1 and sCD30 could both influence the capacity of CD30R to mediate the activation of intracellular signals.

Figure 12

Double biomarkers of homeostasis to evaluate the ability of our physiological system to control the inflammation and preserve the state of health: "Evaluation System". The double biomarkers are of: 1) a type if the levels of Trx1—sCD30 molecules in both gender are within the normal physiological ranges and the levels of IFNy—IL10, IL6—IL4 and IFNy—IL4 for men are in the physiological ranges and they are related by a direct proportionality: their amounts may be equal, above or under the mean and they both increase or decrease in the same sense, positive or negative; the levels of IL6—IFNy and IL6—IL10 for women are in the physiological ranges, and they are respectively related by direct and inverse proportionality: their quantities are equal, above or under the mean, they both increase or decrease with the same verse, positive or negative, in case of direct proportionality, and in inverse verse, positive the first and negative the second or vice versa, in case of inverse proportionality; 2) b type if the levels of Trx1—sCD30 molecules in both gender are or are not in the normal physiological ranges and the levels of IFNy—IL10, IL6—IL4 and IFNy—L4 in men are not in the physiologic ranges, but they are still related by the same direct proportionality, corresponding to the homeostatic condition; the levels of IL6—IL10 and IL6—FNy in women are not in the physiological ranges, but they are still related by the same proportionalities, inverse and direct, corresponding to the homeostatic condition; 3) c type if levels of Trx1—sCD30 molecules in both gender are not in the normal physiological ranges and the levels of IFNy—IL10, IL6—IL4 and IFNy—IL4 in men are not in the physiological ranges and they are not related with the same direct proportionality of the homeostatic state, but they are characterized by an inverse proportionality; the levels of IL6—IFNy and IL6—IL10 in women are not in the physiological ranges and they are not related by the same inverse and direct proportionality of the homeostatic state, but the first couple by an inverse proportionality and the second by a direct one.