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Ageing and neuronal vulnerability

Nature Reviews Neuroscience volume 7, pages 278–294 (2006)Cite this article

Key Points

  • Ageing affects neurons as much as it does cells in other organ systems. During ageing, neurons experience increased amounts of oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their DNA.

  • Studies of mutations in the genes that cause Huntington's disease or early-onset forms of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis have provided evidence that the defective genes exacerbate age-related processes in neurons, including aggregation of pathogenic proteins, oxidative stress and perturbed cellular ion homeostasis.

  • The physical and molecular characteristics of neurons, their functional properties and their location in neural circuits are all likely to influence their fate during ageing. Examples include differences in relative vulnerabilities to excitotoxicity, metabolic stress and neurotoxins.

  • Neurons have an array of mechanisms that might protect them against the adversities of ageing and neurodegenerative disorders, such as antioxidant defences, protein chaperones that prevent protein aggregation and neurotrophic factors that stabilize ion homeostasis and mitochondrial function.

  • Synapses are regions of neurons that are particularly vulnerable to ageing and neurodegenerative disorders. They are prone to excitotoxic damage, as well as damage by pathogenic proteins such as amyloid-β peptide and mutant huntingtin.

  • Data from studies of animal models and human populations suggest that factors that promote healthy ageing, such as regular exercise and reduced energy diets, might also protect the nervous system against neurodegenerative disorders.

Abstract

Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.

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Figure 1: The who, where and when of neuronal death in age-related neurodegenerative disorders.
Figure 2: The nervous system can respond adaptively, or can succumb, to ageing.
Figure 3: The sensitive synapse.
Figure 4: Once triggered, the death of neurons is programmed.
Figure 5: Counteracting ageing by stimulating beneficial cellular stress responses.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA.

Author information

Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, 21224-6825, Maryland, USA

    Mark P. Mattson & Tim Magnus

  2. Department of Neuroscience and Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205-2196, USA

    Mark P. Mattson

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  1. Mark P. Mattson
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Correspondence to Mark P. Mattson.

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DATABASES

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ALS

Alzheimer's disease

FTDP-17

Huntingtons' disease

Parkinson's disease

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Glossary

Selective neuronal vulnerability

(SNV). The susceptibility of specific populations of neurons that is limited to a region or regions of the nervous system.

Proteasome

A protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

Lipid peroxidation

An autocatalytic process in which free radicals attack double bonds in membrane lipids, resulting in structural damage to membranes and the liberation of toxic aldehydes such as 4-hydroxynonenal.

Autophagy

A process in which damaged organelles are degraded within membrane-bound organelles.

Dietary restriction

A decrease in the amount of food consumed over time (caloric restriction) and/or the frequency of meals (intermittent fasting).

Reactive oxygen species

(ROS). Highly reactive oxygen-based molecules with an unpaired electron in their outer orbital that are capable of damaging proteins, lipids and nucleic acids. Examples include hydrogen peroxide and hydroxyl radicals.

Hormesis

A process in which exposure of a cell or organism to a sublethal level of stress increases the resistance of that cell or organism to a subsequent higher and otherwise lethal level of the same or different stress.

Sirtuins

A family of histone deacetylases that have important roles in cellular stress responses and energy metabolism.

Mitochondrial uncoupling proteins

A family of proteins that reside in the mitochondrial inner membrane and promote a proton leak across the membrane, thereby decreasing oxidative phosphorylation and reactive oxygen species production.

Trans-entorhinal region

An area of the brain — located between association cortices and the hippocampus — that is important in the integration of information and learning and memory processes.

Caspases

A family of cysteine proteases that cleave proteins at specific aspartate residues and have a key role in inflammation and mammalian apoptosis.

BCL2

A protein that promotes the survival of neurons by stabilizing mitochondrial membranes and decreasing oxidative stress.

Calpains

Cysteine proteases activated by calcium that cleave various substrates, including cytoskeletal proteins.

Permeability transition pores

Pores in the mitochondrial membranes that are formed by proteins in response to signals that trigger apoptosis.

Ceramides

Membrane lipids that are incorporated into sphingomyelin and are released in response to the activation of sphingomyelinases.

Ion-motive ATPases

Energy-dependent ion pumps in membranes that are essential for the restoration and maintenance of the Na+ and Ca2+ gradients.

Afterhyperpolarization

The membrane hyperpolarization that follows the occurrence of an action potential.

Glutathione peroxidase

An antioxidant enzyme that converts hydrogen peroxide to water.

Mitochondrial manganese superoxide dismutase

An antioxidant enzyme located in mitochondria that converts superoxide anion radicals to hydrogen peroxide.

Lysosome

A membrane-bound organelle with a low pH that contains high concentrations of enzymes that degrade proteins.

Frontotemporal dementia

A neurodegenerative disorder resulting from the degeneration of neurons in the frontal lobe.

Repeat isoform

An isoform of the microtubule-associated protein tau that contains either three or four microtubule-binding domains.

Cytokines

A large class of intercellular signalling proteins that are important in neural–immune system interactions and inflammatory processes.

Complement factors

Proteins that function in innate immunity, often forming pores in membranes, which results in cell death.

Leukocyte adhesion molecules

Proteins located on the surface of vascular endothelial cells that bind to leukocytes, thereby facilitating the passage of the leukocytes across the blood–brain barrier.

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Mattson, M., Magnus, T. Ageing and neuronal vulnerability. Nat Rev Neurosci 7, 278–294 (2006). https://doi.org/10.1038/nrn1886

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