The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

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...

SummaryHuman neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during aging are unknown. Here we show that induction of the repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a universal feature of normal aging in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Chromatin immunoprecipitation with deep sequencing (ChIP-seq) and expression analysis show that REST represses genes that promote cell death and AD pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein (Aβ) toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional ortholog of REST, C. elegans SPR-4, also protects against oxidative stress and Aβ toxicity. During normal aging, REST is induced in part by cell non-autonomous Wnt signaling. However, in AD, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathologic misfolded proteins. Finally, REST levels during aging are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the aging brain.