Insulin resistance and pathological brain ageing

Sir Harold Himsworth's prescient observations 75 years ago have recently been expanded to include a clear relationship between insulin resistance and central nervous system function. Insulin is a master regulator of corporeal ageing in all known species, determining the rate and expression of ageing in multiple body systems. Thus, it is not surprising that insulin also plays an important role in brain ageing and cognitive decline that is associated with pathological brain ageing. Brain ageing is accompanied by reduced insulin effectiveness, either by an inadequate cellular response to insulin or by insulin deficiency attributable to reduced insulin transport across the blood-brain barrier. Age-associated brain insulin abnormalities may contribute to cognitive decline in ageing, as have been documented in older adults with Type 2 diabetes mellitus and hypertension. With more extreme pathology, brain insulin resistance may be associated with neurogenerative diseases such as Alzheimer's disease, and the condition which precedes Alzheimer's disease, known as amnestic mild cognitive impairment. In the following review, we discuss the mechanisms through which insulin resistance may induce or potentiate pathological brain ageing and thereby create a neurobiological environment that promotes neurodegeneration and associated cognitive decline. This topic is timely, given that insulin resistance-associated conditions such as diabetes and obesity have reached epidemic proportions. The prevalence of such chronic conditions, in combination with a rapidly ageing population, may result in a corresponding increase in the prevalence of Alzheimer's disease and other cognitive disorders. Fortunately, insulin resistance-associated conditions are amenable to both pharmacologic and lifestyle interventions that may reduce the deleterious impact of insulin resistance on the ageing brain.