Positive Health Online

I.          Introduction

Stress has considerable effects on the immune function. Recent studies have suggested that the aging of the immune system (or immunosenescence) is, in part, closely linked to psychological stress factors and stress hormones. Chronic stress leads to premature ageing of the essential homeostatic systems, which are central to the adaptation of organisms to environmental changes.[1]

In young individuals, effective immune responses can compensate for the effects of stress. However, as we age, the immune system deteriorates, due to both the ageing of the various components of the immune system and the establishment of a chronic pro-inflammatory state known as “inflammaging”.[2]

The characteristics of immuno-senescence (whether natural or induced by stress) include:

• High levels of oxidative stress (reactive oxygen species; ROS);
• Persistent chronic inflammation;
• Telomere shortening and telomerase inactivation;
• Chronic exposure to endogenous glucocorticoids;
• Decrease in cellular immunity.

Description of the components, objectives and sequential cascade of the treatment
Specific nucleic acid SNA®-HLA II

The Micro-Immunotherapy MISEN formula has a composition and sequential nature rendering it highly suitable for regulating and stabilizing parameters altered by stress and the aging process.

Mechanism of Action

• The MISEN formula alternates sequences for stimulating regeneration, proliferation and effective functioning in diverse cell lines with sequences designed to optimize apoptosis, cell cycle inhibition and the expression of tumour suppressor genes;
• The objective is to promote cellular rejuvenation without increasing the risk of neoplastic proliferation;
• The MISEN formula, thus, aims to equilibrate the factors leading to cellular ageing, such as chronic exposure to endogenous glucocorticoids, thereby compensating for deficiencies resulting from the process of senescence. 

II.        Mode of Action of the MISEN Formula

Composition

Dilutions: Stimulating  - Modulating - Inhibitory

Senescence is a process that generally occurs in response to stress and DNA lesions. This natural response to DNA damage protects the body against cancer,[3] but leads to a large increase in the levels of ROS and other pro-inflammatory factors associated with cell death (or apoptosis), which in turn contributes to tissue ageing. During senescence, inflammation may be observed, due to the secretion of age-linked inflammatory factors (the senescence-associated secretory phenotype or SASP), which aggravates the imbalance. This results in a persistent, chronic inflammation of various degrees of severity.[4]

The triggering, propagation and modulation of the adaptive immune response depend on the precise regulation of MHC class II molecules. Unlike MHC class I molecules, which are widely expressed in different cell types, the expression of MHC class II molecules, such as HLA-DR, is restricted to antigen-presenting cells (professional APCs) including macrophages, dendritic cells and B lymphocytes. By contrast, in inflammatory conditions,[5] such as those occurring during immuno-senescence, HLA-DR expression may be triggered in cells that did not initially present antigens (non-professional APCs), such as epithelial cells and keratinocytes.[6,7,8]

The ‘repeated’ presentation of antigens to T lymphocytes by non-professional APCs is one of the causes of a loss of T-cell effector function, which manifests as a loss of CD28 expression by these cells, particularly in a context of chronic inflammation.[9,10] CD28 is an essential co-stimulation receptor responsible for the activation, proliferation and survival of T cells.[11] CD28 co-stimulation is also necessary for the effective activation of CD4+ T lymphocytes,  because it plays an essential role in the establishment of effector function in these cells.[12]

Immune-Modulating Cells

SNA®-HLA II

Objective:

To inhibit the overexpression of MHC class II molecules in non-professional APCs in inflammatory environments, so as to decrease the immune depletion of CD8+ T lymphocytes and its consequences.

Interleukin 2 (IL-2)

The accumulation of CD28- T lymphocytes, particularly within the CD8+ subpopulation, is one of the most important changes associated with ageing. CD28 co-stimulation favours T-lymphocyte immune responses and the expansion of T-cell populations, by stimulating the production and secretion of IL-2.[13,14]

Immuno-senescence is characterized by specific re-modelling of the immune system, triggered by chronic exposure to antigens and oxidative stress. As the immune system ages, adaptive immunity deteriorates, due to gradual decreases in the numbers of naïve T and B lymphocytes and absolute numbers of T and B lymphocytes.[15] The telomeres play an important role in this process.

Telomeres are specialized structures located at the ends of chromosomes; they gradually shorten over successive cell divisions; this shortening is inversely proportional to age.[16] They protect the ends of the chromosomes from DNA degradation and repair activities. Telomerase is required for telomere repair.[17]

Excessive shortening of the telomeres leads to cell cycle arrest or replicative senescence. The immune system is very sensitive to telomere shortening, because its efficacy is entirely dependent on cellular renewal and the expansion of T and B lymphocyte populations. Immune cells (CD4+ T lymphocytes, CD8+ T lymphocytes, B lymphocytes, granulocytes, monocytes and NK cells) are the only cells capable of increasing telomerase activity, thereby favouring a lengthening of telomeres and limiting their degradation in activated cells.[18]

Interleukin 2 is an essential immuno-regulatory cytokine, because it increases telomerase activity in immune cells, such as lymphocytes and NK cells.[19,20]

IL-2

Objective:

To attenuate the consequences of the continual decrease in CD28 expression by T lymphocytes and to stimulate telomerase activity in immune cells.

Ribonucleic acid (RNA)

Type I interferons (IFN-α and IFN-β) are a family of pro-inflammatory cytokines essential for antiviral immunity.[21] However, their overproduction is associated with various autoimmune diseases.[22] IFN-α is secreted in response to viral RNA during viral infections.

The activity of type I IFNs in the presence of low-level inflammation or a pro-inflammatory environment linked to senescence[2] favours the production of CD28- cells. For this reason, during ageing, persistent viral infections, episodes of viral reactivation or repeated infections provoking the continuous activation of the TCR (the T-cell antigen receptor) and, thus, increasing the secretion of IFN-α, favour the accumulation of T cells with a senescent CD8+ CD28- phenotype.[23]

IFN-α inhibits telomerase activity, thereby accelerating the differentiation of CD8+ T lymphocytes.[23] In addition to its effects on T lymphocytes,[24] this cytokine also inhibits telomerase activity in cells of other lineages, such as hematopoietic cells,[25,26] by diverse mechanisms.

The stimulation of Toll-like receptors (TLR) and their signalling pathways triggers the secretion of type I IFNs. The TLR7, TLR8 and TLR9 receptors in plasmacytoid dendritic cells (pDCs) trigger the production of IFN-α in response to viruses and the binding of their ligands.[27,28,29,30]

Synthetic and viral single-stranded RNA molecules are the ligands of the TLR7 and TLR8 receptors.[31,32,33]

RNA

Objective:

To modulate the secretion of type I IFNs and their negative effects on CD28 expression and telomerase activity, without losing the defensive capacities provided by these molecules.

Specific Nucleic Acid SNA®-MISEN

Their genes, the environment and chance factors influence the longevity of animals.[34] All genetic mutations affecting endocrine pathway signaling, stress responses, metabolism or telomere length may influence the longevity of organisms.[35]

Diverse factors regulating gene expression can modify the ageing process, by modulating tissue deterioration or cell senescence.[36]

SNA®-MISEN

Objective:

To inhibit genes with stress- or ageing-specific expression.

Epidermal Growth Factor (EGF)

Cell senescence is a safety response, protecting against cancerous transformation.[37] Senescence occurs when cells display a critical shortening of telomeres, due to DNA replication mechanisms. Gradual shortening of the telomeres, in the absence of telomerase, has no effect on the cell cycle. By contrast ‘critical’ telomere shortening plays a key role in senescence.[38] Telomere shortening is one of the fundamental mechanisms of ageing and of lifespan limitation.

Telomerase is a highly regulated enzyme: its activity is closely associated with cell proliferation. In the absence of telomere shortening, as in tumor cells in which telomerase is active, ageing is slowed and the transformed cells do not undergo senescence.[39]

Epidermal growth factor (EGF) activates telomerase by directly activating the telomerase reverse transcriptase (TERT).[40,41]

During senescence, low levels of EGF are observed. In addition to activating telomerase, EGF stimulates neurogenesis[42] and plays an important role in wound healing and the regeneration of tissues such as those of the skin, cornea and gastrointestinal tract.[43]

In summary, activation of the EGF receptor leads to an increase in maximum life expectancy, whereas decreases in the activity of the EGF pathway lead to an acceleration of ageing[44] and degeneration.[45]

EGF

Objective:

To modulate decreases in telomerase activity so as to prevent the critical shortening of telomeres, thereby favouring rejuvenation.

Dimethylsulfoxide (DMSO)

TERT[46] expression leads to telomerase activity and, thus, to an increase in the longevity of normal human cells, by decreasing their senescence.[47,48] As explained above, telomerase can reverse the degeneration of tissues provoked by ageing, in diverse organs, including the nervous system.[49]

However, it should not be forgotten that telomere dysfunction and telomerase activity are considered to be linked to the development of cancer.[50] On the one hand, gradual telomere shortening limits cell viability by favouring senescence,[51] but, on the other, the genomic instability triggered by telomere dysfunction is associated with a high risk of mutation, favouring tumour development.[52]  Similarly, telomerase activity slows cell ageing, by favouring the regeneration of tissues, but it also contributes to the immortalization of transformed cells.[53,54]

Nerve Cells

Thus, for an anti-age intervention to be effective, it is essential to achieve a balance between these two age-related elements: ageing and tumour development. Various studies have highlighted the therapeutic value of a combination of TERT overexpression and tumour suppressor genes, notably p53 and p16, to stimulate anti-ageing activity whilst limiting cancer development.[55,56]

The p53 tumor suppressor gene, which has been described as “the guardian of the genome”,[57] encodes a transcription factor involved in control of the cell cycle, DNA repair, apoptosis and the response of the cell to stress. It can trigger cell growth arrest through direct activation of the cell cycle inhibitor p21 (inhibitor of the cyclin-dependent kinase, CDK).[58] The predominance of mutations inactivating the p53 tumour suppressor gene in most human cancers highlights the importance of this gene in the prevention of this disease.[59] However, by triggering cell growth arrest and apoptosis, p53 activates cell senescence and the ageing of the body.[60,61]

NF-kappa B is a direct antagonist of p53 that triggers cell survival, proliferation, migration and invasion.[62] During ageing, increases in NF-kappa B levels[63] are associated with cardiovascular diseases[64] and could result in oxidative stress[65] or a persistent inflammatory state, because inflammatory stimuli can induce the production of NF-kappa B.[66,67]

Dimethylsulfoxide (DMSO) has antioxidant,[68] cytoprotective[69] and anti-inflammatory properties.[70] In particular, DMSO has anti-tumour functions: it triggers the expression of the p53 tumor suppressor gene.[71,72] It also decreases levels of the c-myc proto-oncogene,[73] which is deregulated in most human tumors and contributes to malignant transformation by triggering uncontrolled cell proliferation and genomic instability.[74]

DMSO

Objective:

To activate tumour suppressor genes, such as p53, and to decrease the expression of proto-oncogenes, such as c-myc.

Specific Nucleic Acid SNA®-HLA I

NK cells can distinguish between normal cells and cells that have lost MHC class I molecule expression following viral infection or tumor transformation.[75] The p53 tumour suppressor gene activates cell senescence and prevents carcinogenesis. However, the NK cells must then eliminate the senescent tumours. p53 induces the secretion of chemokines by tumour cells; these molecules serve as signals for the recruitment of NK cells to the tumour environment.[76] However, the restoration of p53 does not increase the sensitivity of tumour cells to lysis by NK cells.[77] The cell lysis mediated by NK cells is more effective in the absence of MHC class I antigens. HLA-I antigens “complicate” the recognition of transformed cells for lysis by NK cells and interfere with various molecules involved in the lysis mediated by these cells.[78]

In conditions of stress, NK cell activity is down-regulated by glucocorticoids. Both lysis and fusion with cells sensitive to lysis are affected by glucocorticoids.[79]

SNA®-HLA I

Objective:

To inhibit the formation of HLA-I molecules, to favour the lytic response of NK cells.

Dehydroepiandrosterone (DHEA)

DHEA, which is secreted by the adrenal glands, is one of the most abundant steroids circulating in the human body. DHEA levels progressively decrease with age, suggesting a possible role in the ageing process. According to the neuroendocrine hypothesis of immuno-senescence, ageing and stress cause an imbalance in the cortisol/DHEA ratio, the principal determinant of the immunological changes observed in the elderly.[80] The decrease in DHEA secretion, together with an increase in cortisol secretion, results in greater exposure of the lymphoid cells to the deleterious effects of glucocorticoids.[1]

DHEA has immunostimulatory potential, and favours an increase in bone mineral density and cardiovascular and neurological protection.[81]

It also plays a major role in cell cycle control. DHEA prevents tumour progression by triggering cell senescence, inhibiting cell proliferation and increasing cell death by apoptosis. The effects of DHEA on cells are associated with an increase in the expression of the cell cycle inhibitor genes p16 and p21.[82] The p21 protein (which inhibits CDK, also known as p21WAF1 / Cip1) favours cell cycle arrest in response to numerous stimuli.[83] The p16 gene is also a major tumour suppressor gene. The high frequency of p16 deletions in primary tumour cell lines suggests an important role for p16 in carcinogenesis; indeed, p16 loss is frequently reported to be an early and often critical event in tumour progression.[84]

DHEA

Objective:

To restore the balance in glucocorticoid levels (altered cortisol/DHEA ratio) and to stimulate the expression of cell cycle inhibitor genes (such as the p21 and p16 genes), to prevent tumorigenic cell proliferation.

The MISEN Formula: Action at Several Different Levels

• Hormonal balance and immune defence;
• Cell regeneration and rejuvenation;
• Antitumour capacity;
• DHEA - Restoring the balance of glucocorticoid levels;
• SNA-HLAII - Preventing immune depletion;
• IL-2 / RNA - Modulating the decrease in CD28 expression by T lymphocytes;
• SNAH-MISEN / EGF - Modulating telomerase activity;
• CMSO - Activating tumour suppressor genes (p53) / decreasing the expression of proto-oncogenes (c-myc);
• SNA-HLAI - Activating NK cells;
• DHEA - Stimulating cell cycle inhibitors (p21, p16).

III.       Conclusion

The MISEN formula is designed to act on several different physio-pathological mechanisms linked to chronic stress and ageing, with the following objectives:

• To prevent the immune depletion occurring during senescence (whether natural or induced by chronic stress) and to increase immune defence capacity;
• To counteract the pro-inflammatory effects of diverse factors;
• To favour cell regeneration and rejuvenation, by preventing decreases in the activity of telomerase and associated factors;
• To increase, in parallel, the antitumour and antiproliferative capacities of the body.

In summary, the MISEN formula aims to confer a better response of the immune system and a balance between the processes of senescence and cell proliferation.

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