Neural mechanisms of ageing and cognitive decline

Abstract

During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.Cognitive frailty is emerging as one of the greatest health threats of the twenty-first century. As the life expectancy of the population has increased, so too has the prevalence of cognitive decline and dementia, largely in the form of Alzheimer's disease, which now affects almost 50% of adults over the age of 85 in the United States (1). This startling figure can only grow as the average age of the population rises, so understanding the basis of cognitive decline during ageing is critical. The greatest risk factor for cognitive decline and Alzheimer's disease in older adults is age itself. Therefore, the development of these pathologies must be understood in the context of the molecular biology of the ageing process.Fortunately, the past 15 years have witnessed a great increase in our knowledge of the basic molecular mechanisms of ageing. Most remarkably, functional genetic analysis has identified signalling pathways that act as master regulators of ageing and lifespan and that are conserved in yeast, nematodes, flies and mammals. Analysis of these model systems suggests that the rate of ageing is not inevitably fixed but is plastic and open to modification. Similarly, cognitive decline associated with mammalian brain ageing also seems to be variable and possibly open to modification (Table 1). An important question is whether agerelated cognitive changes are mediated by any of the master regulators of ageing and lifespan identified in model organisms. Moreover, recent studies have implicated these pathways in the control of age-related brain pathology, raising the possibility that altered regulation of fundamental mechanisms of ageing may contribute to the pathogenesis of neuro degenerative disorders.Two important technical advances have provided new insight into the biology of brain ageing. Microarray technology has made global gene expression analysis possible in humans and model organisms, leading to the identification of evolutionarily conserved changes during ageing. Concurrently, improvements in functional brain imaging have afforded us an unprecedented view of the workings of large-scale cognitive networks in the ageing human brain. An important challenge is to unify these two levels of analysis to obtain a more global view of brain and organismal ageing in humans.In this Review, we explore the basic molecular mechanisms of the ageing p...

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