**3. Conclusions**

The aging process remains one of the most intriguing problems of biology and medicine. Recent advances in molecular biology make it possible to achieve an understanding of the fundamental foundations of this complex process. An intensive study of time- and tissuespecific gene expression is a tool that should lead us to a tangible control over age-dependent lesions.

Hypothalamic neurosecretory centers have been an object of deep interest since its role in the regulation of many body functions: adaptation, stress response, food and sexual behavior, emotions, thermoregulation, cognitive processes, and circadian rhythms have been discovered.

WRN and pin1 proteins increases and stimulates the expression of p53. The p21 protein requires for stable low level of apoptosis. The level of p21 protein is high in young FVB/N mice and decreases with aging. In transgenic animals with overexpression of the oncogene HER-2/Neu,

**Figure 12.** The apoptosis regulation in neurons in aging. (A) Signal cascade of apoptosis in physiological aging; (B) signal

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Thus, overexpression of HER2 blocks the signal pathway of p53, affecting both the p53 regu-

In addition, we investigated age-related changes of STAT-signaling pathway. We revealed that in hypothalamus of wild-type mice, the synthesis of STAT1 increases and activates p53-mediated way. The expression of antiapoptotic factors STAT3, 5, 6, and survivin decreases in the studied neurosecretory centers. By contrast, in aged HER-2/Neu mice the expression of these factors

We showed the involvement of cytokine-dependent pathways in the mechanisms of apoptosis during aging. The realization of TNF-dependent apoptosis in hypothalamic neurons during physiological aging shows an increase of Fas receptor expression and expression of adapter proteins associated with the death domain (FADD and TRADD). In older transgenic animals, the expression of HER-2/Neu causes suppression of the extrinsic pathway of apoptosis—the TNF-dependent pathway (**Figure 12**). In other side, in the hypothalamus of young transgenic mice, the high TRADD expression may activate one of the survival ways (NF-kB, MAPK/ERK, or PI3K-AKT). So, HER-2/Neu tyrosine kinase receptor plays an important role in the mechanism of cell resistance to apoptosis in aging, and one of the targets of HER-2/Neu

the synthesis of these proteins is low, and there is no reaction to aging (**Figure 12**).

lating proteins and the targets of p53.

cascade of apoptosis in aged HER-2/Neu transgenic mice.

is TNF-signaling cascade.

increases, and STAT1 synthesis was low (**Figure 12**).

Aging disrupts vital activity, as noted in many cases. The first sign of aging, discovered by those who studied aging in vivo, is a disruption in the regulation of functions in almost all body systems. We know that the regulation of all processes is at least duplicated, so, the cell has not only an internal genome-dependent development program but also a subject to the influence of the nervous and endocrine systems. So, it can be concluded that the agedependent changes are found in the central part of endocrine system, that is, in the hypothalamic neurosecretory centers. Indeed, our preliminary study showed that in old mice there is a significant loss of hypothalamic neurosecretory cells by apoptosis [1]. Obviously, a reduced amount of neurosecretory cells cannot maintain the previous level of functional regulation for a long time. This functional stress in the hypothalamic neurosecretory cells can be the cause of avalanche-like morphofunctional changes in the body caused by aging.

So, the results obtained in our studies allow to propose a possible scheme of apoptosis regulation of the hypothalamus neurons in physiological aging and in aged transgenic mice with HER-2/ Neu overexpression (**Figure 12**). Thus, in the late stages of ontogeny, we observe an increase in the synthesis of proteins involved in the induction of apoptosis, only in a group of wild-type mice. At physiological aging, we observed increased level of hypothalamic neuron apoptosis mediated by the p53- and Fas-dependent pathways, with caspase-8 and -3 activation. As we have shown, the WRN gene also participates in the regulation of physiological aging. The synthesis of The Apoptosis Regulation Mechanisms in Hypothalamic Neurons in Physiological… http://dx.doi.org/10.5772/intechopen.72694 121

one of the reasons for this is a possible suppression of the survival ways (AKT and ERK cascades) or an increased content of proapoptotic factors, for example, FasL in physiological aging. HER-2/Neu expression causes suppression of the extrinsic pathway of apoptosis (TNFdependent). In this case, both the reception of an apoptotic signal (Fas receptor expression) and its further carrying out (FADD and TRADD expression) are suppressed. However, in young transgenic mice, the increased TRADD expression may activate one of the survival ways—NF-kB, MAPK/ERK, or PI3K-AKT cascade (**Figure 11**). Thus, HER-2/Neu tyrosine kinase receptor plays an important role in the mechanism of cell resistance to age-dependent apoptosis, and

The aging process remains one of the most intriguing problems of biology and medicine. Recent advances in molecular biology make it possible to achieve an understanding of the fundamental foundations of this complex process. An intensive study of time- and tissuespecific gene expression is a tool that should lead us to a tangible control over age-dependent

Hypothalamic neurosecretory centers have been an object of deep interest since its role in the regulation of many body functions: adaptation, stress response, food and sexual behavior, emotions, thermoregulation, cognitive processes, and circadian rhythms have been

Aging disrupts vital activity, as noted in many cases. The first sign of aging, discovered by those who studied aging in vivo, is a disruption in the regulation of functions in almost all body systems. We know that the regulation of all processes is at least duplicated, so, the cell has not only an internal genome-dependent development program but also a subject to the influence of the nervous and endocrine systems. So, it can be concluded that the agedependent changes are found in the central part of endocrine system, that is, in the hypothalamic neurosecretory centers. Indeed, our preliminary study showed that in old mice there is a significant loss of hypothalamic neurosecretory cells by apoptosis [1]. Obviously, a reduced amount of neurosecretory cells cannot maintain the previous level of functional regulation for a long time. This functional stress in the hypothalamic neurosecretory cells can be the cause of

So, the results obtained in our studies allow to propose a possible scheme of apoptosis regulation of the hypothalamus neurons in physiological aging and in aged transgenic mice with HER-2/ Neu overexpression (**Figure 12**). Thus, in the late stages of ontogeny, we observe an increase in the synthesis of proteins involved in the induction of apoptosis, only in a group of wild-type mice. At physiological aging, we observed increased level of hypothalamic neuron apoptosis mediated by the p53- and Fas-dependent pathways, with caspase-8 and -3 activation. As we have shown, the WRN gene also participates in the regulation of physiological aging. The synthesis of

avalanche-like morphofunctional changes in the body caused by aging.

TNF-signaling pathway is one of the targets of HER-2/Neu.

**3. Conclusions**

120 Hypothalamus in Health and Diseases

lesions.

discovered.

**Figure 12.** The apoptosis regulation in neurons in aging. (A) Signal cascade of apoptosis in physiological aging; (B) signal cascade of apoptosis in aged HER-2/Neu transgenic mice.

WRN and pin1 proteins increases and stimulates the expression of p53. The p21 protein requires for stable low level of apoptosis. The level of p21 protein is high in young FVB/N mice and decreases with aging. In transgenic animals with overexpression of the oncogene HER-2/Neu, the synthesis of these proteins is low, and there is no reaction to aging (**Figure 12**).

Thus, overexpression of HER2 blocks the signal pathway of p53, affecting both the p53 regulating proteins and the targets of p53.

In addition, we investigated age-related changes of STAT-signaling pathway. We revealed that in hypothalamus of wild-type mice, the synthesis of STAT1 increases and activates p53-mediated way. The expression of antiapoptotic factors STAT3, 5, 6, and survivin decreases in the studied neurosecretory centers. By contrast, in aged HER-2/Neu mice the expression of these factors increases, and STAT1 synthesis was low (**Figure 12**).

We showed the involvement of cytokine-dependent pathways in the mechanisms of apoptosis during aging. The realization of TNF-dependent apoptosis in hypothalamic neurons during physiological aging shows an increase of Fas receptor expression and expression of adapter proteins associated with the death domain (FADD and TRADD). In older transgenic animals, the expression of HER-2/Neu causes suppression of the extrinsic pathway of apoptosis—the TNF-dependent pathway (**Figure 12**). In other side, in the hypothalamus of young transgenic mice, the high TRADD expression may activate one of the survival ways (NF-kB, MAPK/ERK, or PI3K-AKT). So, HER-2/Neu tyrosine kinase receptor plays an important role in the mechanism of cell resistance to apoptosis in aging, and one of the targets of HER-2/Neu is TNF-signaling cascade.

The result of such suppression of the apoptotic cascade in transgenic mice is increased carcinogenesis and a half-reduced life expectancy, compared to the control.

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