Ageing and the Brain


Anatomical, neurochemical and functional properties of the mammalian brain change with age, and the trajectories of ageing are modified by many genetic and environmental risk factors, including lifestyle variables. Age‐related changes do not reflect a specific cellular program, but fundamental changes precipitating intracellular accumulation of reactive oxygen species and diminishing energy production may underlie age‐related deterioration of the brain structure and information processing properties. The latter has been hypothesised to bring about differential declines in cognitive functions that rely on processing of information of high novelty and low redundancy. These hypotheses are summarised in a Free‐Radical‐Induced Energetic and Neural Declines in Senescence (FRIENDS) model, some components of which have been demonstrated in longitudinal studies, while others can be inferred from cross‐sectional and postmortem investigations. The major obstacle to understanding brain ageing and its role in cognitive change remains the dearth of multi‐occasion longitudinal studies of the relevant constructs.

Key Concepts

  • Brain is a disproportional consumer of energy, which is necessary for maintaining its information processing machinery.
  • Energy crisis originating in mitochondrial dysfunction and causing further deterioration of the cellular machinery unfolds in time and thus promotes brain ageing.
  • Decline in metabolic, and vascular properties of the brain is precipitated by energy deficit and drives declines in multiple brain properties.
  • Brain shrinks with age, with key regions implicated in cognitive processing evidencing faster declines in comparison to sensory cortices.
  • Energy intensive functions, such as myelin maintenance and synaptogenesis, may be particularly vulnerable to ageing.
  • Age‐related declines are accelerated by genetic variants linked to vascular disease and inflammation as well as environmental pollution, stress and sedentary lifestyle.
  • Changes in iron homeostasis may precipitate structural brain changes.
  • When individual differences in age‐related cognitive changes are observed, they are coupled with alterations in brain structure and function.
  • Age‐related brain deterioration appears less pronounced in persons with high baseline cognitive performance.
  • Boosting cognitive performance and promoting active lifestyle as well as combatting pro‐inflammatory and metabolic risk factors may help to improve brain maintenance and mitigate age‐related declines.

Keywords: MRI; longitudinal studies; mitochondria; iron; cognition

Figure 1. Free‐Radicals‐Induced Energetic and Neural Decline in Senescence (FRIENDS) model of cognitive ageing. Random mutations accumulating over time in the mitochondrial DNA drive mitochondrial function declines with age. The gradual reduction of cellular energy substrates ensues and affects energy‐dependent cellular process, including sequestration and transport of iron, which is vital for mitochondrial energy production. The accumulation of iron, in turn, exacerbates mitochondrial dysfunction and energy deficit. Random events, genetic predisposition and cumulative effects of environmental stress and particulate pollution intensify the inflammation, which worsens age‐related endothelial and metabolic dysfunction. The latter impair the delivery of glucose and oxygen to the brain and heighten energy crisis. Reduced availability of energy slow chemical reactions and result in accumulation of reactive oxygen, nitrogen and carbon species (RONCS), which in turn exaggerates mitochondrial dysfunction. Energy deficit stunts the regeneration of myelin and maintenance of the cellular membranes. Myelin and neuropil are gradually lost, and structural connectivity among the brain regions is impaired. That loss reduces the fidelity and the dynamic range of neural communication, and the information‐processing capabilities of the brain networks are degraded; the system becomes progressively noisier. Noise in the information‐processing system affects all cognitive operations, with the more complex and more energy‐dependent among them being differentially affected.
Figure 2. Age‐related differences in gross neuroanatomy observed in vivo, in asymptomatic adults. (A) A 25‐year old. (B) An 82‐year old. (C) A 79‐year old. In this mode of image acquisition (T2 weighted), the white matter appears dark and the fluid‐filled spaces white. (D) A 24‐year old. (E) An 80‐year old. In this mode of imaging (T1 weighted), the fluid is dark. Note in addition to age‐related differences, individual variability in the brains of older adults. Arrows point to enlarged ventricles (a) and (g), ventricular “caps” around the occipital horns of the ventricles (b), white matter lesions (c), hippocampal shrinkage (e) vs (d), and sulcal expansion (f).


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Raz, Naftali(Oct 2019) Ageing and the Brain. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003375.pub3]