Ageing as a risk factor for neurodegenerative disease

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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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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.

Correspondence to Vilhelm A. Bohr.

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