Insulin andor IGFI Resistance with Aging

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In general, aging is associated with insulin resistance. Is it possible that neurons also become resistant (or somewhat diabetic) and that their uptake of glucose is not as efficient to satisfy energy demand? In the periphery, previous studies showed age-related alterations in tyrosine kinase activity (Ruiz et al., 1992). Moreover, despite normal levels of insulin receptors in 20-month-old Wistar rats, it was shown that receptor autophosphorylation was reduced by 25%, in addition to decreased IRS-1 levels. Moreover, insulin-stimulated IRS-1 association with phosphatidyl-inositol 3-kinase (PI3-kinase) was decreased by 70% in the liver and 98% in muscles of 20- versus 2-month-old rats, with no change in PI3-kinase level; the phosphorylation of IRS-2 followed a similar pattern (Carvalho et al., 1996). Interestingly, insulin could not induce sodium/potassium-ATPase activation and plasma membrane hyperpolarization of certain cell types in aged Wistar rats (Frolkis, 1995). It was also demonstrated that peripheral insulin resistance in 24-month-old Wistar rats was accompanied by an impairment in insulin-sensitive, glycosyl-phosphatidylinositol-dependent cellular signaling (Sanchez-Arias et al., 1993). One study divided 24- to 27-month-old Wistar rats into three groups having mild, moderate, and severe reduction in maximal insulin-related kinase activity and found that deficits in the mild and moderate subgroups could be reversed by extensive autophosphorylation (Nadiv, Cohen, & Zick, 1992). It remains to be established whether in aged rats differential alterations in these markers could be correlated with cognitive performance and comparable changes in the IGF-I receptor signaling pathway.

A study was also designed to assess whether cognitive deficits in aging could be partially overcome by increasing the availability of IGF-I in the brain (Markowska, Mooney, & Sonntag, 1998). Male rats of two ages (4 and 32 months) were preoperatively trained in behavioral tasks and subsequently implanted with minipumps to infuse IGF-I or a vehicle into the cerebral ventricles. Animals were retested at 2 and 4 weeks. IGF-I improved working memory in the repeated acquisition and object recognition tasks. An improvement was also observed in the place discrimination task, which assesses reference memory. Moreover, injection of IGF-I antisense oligonucleotides in the inferior olive region elicited a complete inhibition of conditioned eye-blink learning in freely moving rats (Castro-Alamancos & Torres-Aleman, 1994). Furthermore, insulin treatment prevents deficits in water maze learning and long-term potentiation (LTP) in streptozotocin-diabetic rats (Biessels et al., 1998). Taken together, these data indicate a potentially important role for IGF-I (and insulin) in the reversal of age-related behavioral impairments in rodents.

The growth hormone (GH)/IGF-I axis is known to be involved in aging of physiological functions. Recent studies indicate that the GH/IGF-I axis may also be associated with cognitive functioning. For example, Aleman et al. (1999) determined whether age-related decline in circulating IGF-I levels were correlated with cognitive performances. Twenty-five healthy older men with well-preserved functional ability participated in the study. Neuropsychological tests of general knowledge, vocabulary, basic visual perception, reading ability, visuoconstructive ability, perceptual-motor speed, mental tracking, and verbal long-term memory were administered. Performance on the last four tests declined with age, whereas the first four were not as sensitive to aging. Interestingly, the authors found that plasma IGF-I levels were significantly correlated with performances (controlled for education) on the Digit Symbol Substitution test and the Concept Shifting Task, two tests measuring perceptual-motor and mental processing speed. Subjects with higher IGF-I levels performed better on these tests. These data support the hypothesis that circulating IGF-I may play a role in the age-related decline of certain cognitive functions, especially those related to the speed of information processing (Aleman et al., 1999). In another study, Rollero et al. (1998) reported that plasma IGF-I levels were directly correlated with cognitive function as assessed using the Mini Mental State Examination; scores and IGF-I levels were lower in patients with the most advanced cognitive deterioration.

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