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  • Review Article
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Ageing as a risk factor for neurodegenerative disease

Nature Reviews Neurology volume 15, pages 565–581 (2019)Cite this article

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Abstract

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

Key points

  • Ageing is the main risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD).

  • Tissues composed primarily of postmitotic cells, such as the brain, are especially sensitive to the effects of ageing.

  • Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication — correlate with susceptibility to neurodegenerative disease.

  • NAD+ deficiency is a key biomarker for mitochondrial dysfunction, and agents that elevate intracellular NAD+ have shown promising results against many features of neurodegeneration.

  • Genomic instability, mitophagy, cellular senescence, protein aggregation and inflammation are being explored as therapeutic targets for neurodegenerative disease.

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Fig. 1: Neurodegenerative disease prevalence.
Fig. 2: Hallmarks of ageing.
Fig. 3: NAD+, DNA damage, mitophagy, ageing and neurodegeneration pathways.
Fig. 4
Fig. 5: Cellular senescence and neurodegeneration.

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Acknowledgements

The authors’ research is supported by the Intramural Research Program of the NIH National Institute on Aging. The authors thank B. Yang and N. B. Fakouri for critical reading of the manuscript. The Bohr laboratory receives nicotinamide riboside as a gift from ChromaDex.

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  1. Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA

    Yujun Hou, Xiuli Dan, Mansi Babbar, Yong Wei, Deborah L. Croteau & Vilhelm A. Bohr

  2. Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Steen G. Hasselbalch

  3. Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Vilhelm A. Bohr

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All authors researched data for the article, Y.H., X.D., M.B., Y. W., D.L.C. and V.A.B. contributed substantially to the discussion of content, Y.H., X.D., M.B., Y.W., S.G.H., D.L.C. and V.A.B. wrote the article, and Y.H. and V.A.B reviewed and edited the manuscript before submission.

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Hou, Y., Dan, X., Babbar, M. et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15, 565–581 (2019). https://doi.org/10.1038/s41582-019-0244-7

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