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.

Figure 1. Altered functional activation of brain systems during brain ageing

Functional imaging of brain activation during task performance shows a change in activation patterns as the human brain ages. a, Top: functional magnetic resonance imaging scans show simultaneous activation of the medial prefrontal cortex (mPFC), posterior cingulate (pC) and lateral parietal cortex (LP) in young adults, but this temporal correlation of activity is considerably reduced in aged individuals. (Images reproduced, with permission, from ref. .) Bottom: hypothetical connections between areas of the mPFC, pC and LP may mediate the coordinated activation in young adults, whereas declining function of such connections could underlie the observed disruption in coordinated activity in ageing brains. (Images courtesy of C. Koch, California Institute of Technology, Pasadena.) b, Positron emission tomography shows that young adults performing a memory test exhibit right-lateralized brain activation. Aged adults with poor performance in this test also had right-lateralized PFC activity, but aged adults with good performance showed bilateral activation. Thus, recruitment of additional brain areas may compensate for age-dependent functional decline in the primary areas subserving cognitive abilities (3, 5). (Images reproduced, with permission, from ref. .)

Figure 2. Evolutionary changes in gene regulation in the brain during ageing

A broad regulatory shift in age-related gene expression appears in the primate lineage. Genes that change with ageing in the human and rhesus macaque cortex are predominantly downregulated (pink), in contrast to the mouse cortex, where most age-regulated genes are upregulated (green). This degree of gene repression is not observed in several other non-neural human tissues, including peripheral blood mononuclear cells (T.L. and B.A.Y., unpublished observations), muscle (98) and kidney (99).

Figure 3. Conserved pathways that regulate organismal and brain ageing

Shown are mechanisms that involve mitochondrial function, oxidative stress, autophagy, protein homeostasis, TOR signalling, insulin/IGF-1 signalling (IIS), caloric restriction (CR) and sirtuins. Modest concentrations of ROS generated by mitochondria during normal metabolism may induce stress-resistance pathways that scavenge ROS and repair damage. However, progressive mitochondrial damage may lead to pathological concentrations of ROS production, which, in turn, may contribute to further mitochondrial damage. Damaged mitochondria can be cleared by autophagy, which is promoted by CR and inhibited by TOR signalling. CR improves overall mitochondrial function, in part, by promoting mitochondrial biogenesis and reducing ROS production (100). ROS can damage other crucial macromolecules, such as DNA and proteins. Unrepaired DNA damage may give rise to epigenetic changes and gene silencing and may exacerbate mitochondrial impairment by reducing the expression of nuclear-encoded mitochondrial genes. ROS can also modify proteins, leading to protein unfolding and aggregation. Modified proteins can be removed by a number of degradative pathways, including the ubiquitin proteasome pathway. Inadequate clearance may lead to the accumulation of toxic protein aggregates. The dynamics of protein clearance and aggregate formation may be modulated by the IIS pathway and by SIRT1 and CR. The accumulation of damaged and toxic proteins may also be modified through the regulation of messenger RNA translation by TOR signalling and CR.

Figure 4. The brain as a potential regulator of organismal ageing

The ageing of the brain may be coordinated with the ageing of organ systems through hormonal feedback circuits. The left-hand side of the diagram shows how glucocorticoid hormonal signalling may contribute to brain ageing. Stressors induce hypothalamic production of corticotropin-releasing hormone (CRH), leading to glucocorticoid release from the adrenal glands. The hippocampus, in turn, senses glucocorticoid concentrations through the glucocorticoid receptor (GR), resulting in feedback inhibition of glucocorticoid release through the hypothalamus. Chronically elevated glucocorticoid concentrations during ageing may be detrimental to hippocampal function, blunting the ability of the hippocampus to repress glucocorticoid release and potentially setting up a self-reinforcing process of hormonally mediated hippocampal decline. The right-hand side of the diagram shows how hormonal feedback circuits, similar to the pathways shown on the left-hand side, may be a general mechanism contributing to the decline of other functional systems in the brain. Dashed arrows indicate effects that may be indirect and/or are poorly understood mechanistically.