Estradiol, insulin-like growth factor-I and brain aging

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Summary

The decrease in some hormones with aging, such as insulin-like growth factor-I (IGF-I) and estradiol, may have a negative impact on brain function. Estradiol and IGF-I may antagonize the damaging effects of adrenal steroids and other causes of brain deterioration. The signaling of estradiol and IGF-I interact to promote neuroprotection. Estrogen receptor α, in an estrogen-dependent process, can physically interact with IGF-I receptor and with the downstream signaling molecules of the phosphotidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3 (GSK3) pathway. Estradiol and IGF-I have a synergistic effect on the activation of Akt, which in turn decreases the activity of GSK3. This may be one of the mechanisms used by estradiol to promote neuronal survival, since the inhibition of GSK3 is associated to the activation of surviving signaling pathways in neurons. Furthermore, estradiol may control Tau phosphorylation by modulating the interactions of estrogen receptor α with GSK3 and β-catenin, another molecule involved in the regulation of neuronal survival and the reorganization of the cytoskeleton. All these actions may be involved in the neuroprotective effects of the hormone. Possible aging-associated changes in the expression or activity of these signaling molecules may affect estradiol neuroprotective effects. Therefore, it is important to determine whether aging affects the signaling of estradiol and IGF-I in the brain.

Introduction

The aging process affects all tissues and organs, including the brain. Individual variations in decline of cognitive skills, development of affective disorders and neurodegenerative diseases with aging suggest that brain deterioration is not only the result of age per se and probably represents a failure to adapt to age-associated homeostatic changes (Mattson and Magnus, 2006). Hormones are involved somewhat in the aging process since the levels of many of them change in plasma with aging. Several hormones such as growth hormone, IGF-I, dehydroepiandrosterone and sex hormones decrease with aging in mammals (Lamberts et al., 1997). In humans, their change is associated in time with the progression of neurodegenerative disorders, increased depressive symptoms, and other psychological disturbances (Resnick and Maki, 2001; Azcoitia et al., 2003; Sonntag et al., 2005). This suggests that the modification in hormone levels with aging may have a negative impact on brain function. Alternatively, since the brain is an important center for endocrine control, brain aging may be involved in the hormonal changes. These hormonal changes may represent a positive adaptive response to the aging process, since accumulating evidence suggests that animal lifespan may be subject to endocrine regulation (Holzenberger et al., 2004).

Section snippets

Influence of IGF-I and estradiol on age-related disorders

Even if the hormonal changes are a general positive adaptation to aging, they may have a negative impact on the brain. The decrease in the levels of neuroprotective hormones in aged people may result in a reduced protection against the environmental and genetic factors that promote neurodegeneration. However, not all hormones exert neuroprotective effects. Considerable evidences show a link between stress, hypothalamo–pituitary–adrenal (HPA) axis dysfunction, memory disorders and aging (

Interactions between estradiol and IGF-I signaling pathways

As in other tissues, the effects of estradiol in the nervous system may be exerted by the activation of classical nuclear estrogen receptors α and β (Fig. 2). In addition, estradiol may elicit rapid actions in the nervous system by the interaction with the cytoplasmic and membrane compartments of neurons and glial cells (Kelly et al., 2002; McEwen, 2002b; Beyer et al., 2003; Toran-Allerand, 2004). Estradiol may also act in the nervous system through non-specific receptors, such as

Conclusion

The intricate association of estradiol and IGF-I signaling may be highly relevant for their effects in the aging brain. Aging-associated changes in IGF-I levels, IGF-binding proteins, IGF-I receptors and IGF-I receptor-associated signaling molecules may affect the neuroprotective effects of estradiol in the brain. Therefore, to predict the outcome of hormonal therapies we need first to determine how aging affects the signaling of estradiol and IGF-I in the brain.

Role of the funding source

University of Lille 1, USTL (France) contributed with editorial assistance, reviewed drafts of the manuscript and contributed to the decision to submit the manuscript for publication. The authors retained full editorial control and responsibilities throughout the preparation of the manuscripts.

Conflict of interest

None declared.

Acknowledgments

We acknowledge financial support from Ministerio de Educación y Ciencia, Spain (SAF2005-00272), the European Union (LSHM-CT-2005-518245) and the University of Lille 1. This supplement is based upon the proceedings from Lille Summer School in Neurosciences—Brain Plasticity in Life Span held in France in 2006. The supplement is supported financially by University of Lille 1, USTL (France), Servier (France) and Nestlé (Switzerland).

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