INSULIN RESISTANT BRAIN STATE AND AGING − Rakyat Biologi

It has been clinically demonstrated that with physiological aging a resistance to the action of insulin develops at the periphery, leading to slightly increased glycemia and insulin levels, as reviewed elsewhere (32). Several causes have been postulated for this insulin resistance with aging, among them also the alteration of peripheral IR signal transduction, such as decrease in IRS-1 protein level and its tyrosine residua phosphorylation (18), decrease in IRS-1 association with PI3 kinase and decrease in insulin-stimulated MAPK activity (33,67). The regulation of neuronal glucose metabolism during aging is diminished in the brain, as a result of complex age-associated alterations, but mainly because of the decreased neuronal insulin signal transduction (31). Namely, insulin and C-peptide concentrations decrease with aging (30%-45%) in all brain regions, while brain IR density decreases (38%-49%) in regionally specific manner, particularly stressed in frontal and parietal cortex, with IR tyrosine kinase activity also being decreased, particularly in the temporal region (31).

Additionally, IR signaling pathway in the brain interacts with signaling pathway of other factors, such as insulin growth factor I (IGF-I) and brain-derived neurotrophic factor (BDNF), the alteration of which may therefore contribute to brain insulin dysfunction. As previously mentioned, insulin plays a significant role in cognitive functions and significant decline in cognitive functions has been found with aging (22). Aging itself appears to be associated with decreased brain signaling of BDNF which is known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain (62). The receptor for BDNF belongs to tyrosine kinase superfamily and exerts its effects on neurones via a signal transduction mechanism similar to the insulin signaling pathway (30). When activated, BDNF receptor involves IRS-1 and -2 signaling pathway and stimulation of PI3 kinase which then activates PKB/Act. Activation of this pathway enhances learning and memory, can promote the survival of neurones in metabolic and oxidative stress, and also an important role in regulating glucose metabolism and possibly lifespan has been suggested (61). Alterations of BDNF and its overlapping with the part of insulin intracellular signaling may contribute to insulin resistant brain state in aging. Aging is also associated with a reduced activity of IGF-I in the CNS (91). In spite of relatively constant levels of mRNA in different brain regions, cortical IGF-I protein levels decrease significantly during aging process in rats (71). IGF-I and insulin share a common signal transduction mechanism involving IRS proteins and subsequent signaling pathway, moreover, IR and IGF-I receptors show relative promiscuity and can bind both IGF-I and insulin. There is ample evidence that IGF-I plays a role in cognitive functions, further supporting involvement of insulin signaling pathway dysfunction in age-related decline in cognitive functions (11,91).

There is a clear evidence that the function of the neuronal insulin/IR signal transduction is of a pivotal significance to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurones no longer in the cell cycle (46). It has become evident that normal metabolism of both APP and tau-protein is a part of interactive processes controlled by the normal insulin/IR signal transduction. In physiological brain aging, the malfunction of this cascade starts, leading to various adverse effects that due to their multifolding and permanency may become severe and may increase the vulnerability of the aging brain, facilitating thus the generation of some age-related disorders, such as dementia and the late-onset sporadic Alzheimer’s disease (46).