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Nutritional and metabolic factors in amyotrophic lateral sclerosis

Nature Reviews Neurology volume 19, pages 511–524 (2023)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.

Key points

  • Clinical and epidemiological evidence links metabolic alterations to amyotrophic lateral sclerosis (ALS) onset and progression; these metabolic defects precede motor symptoms, suggesting a causative role in ALS.

  • Although hypermetabolism is consistently observed in ALS, its causes and clinical relevance remain largely unknown; to address this, a consensus approach to identifying hypermetabolism in ALS is needed.

  • Exploring ALS metabolic dysregulation is key for optimizing patient care and analysing nutritional status, especially fat mass stability, is crucial for understanding energy homeostasis; imbalances might require energy intake interventions, orally or via gastrostomy.

  • Compounds that improve cellular bioenergetics exert neuroprotection in in vivo and in vitro ALS models, but most have failed in clinical trials or have provided modest benefit in people living with ALS.

  • Studies in mouse models and patient trials have demonstrated a potential therapeutic role for high-calorie diets in ALS, but optimal nutritional intervention parameters require further elucidation.

  • A personalized approach of bioenergetic enhancement with nutritional interventions might yield superior outcomes in ALS.

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Fig. 1: Direct and indirect effects of amyotrophic lateral sclerosis-related genes on mitochondrial function.
Fig. 2: Potential interventions in treating bioenergetic failure in amyotrophic lateral sclerosis.

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Acknowledgements

C.McD. is supported by the NIHR Sheffield Biomedical Research Centre and an NIHR Research Professorship Award. S.N. is supported by a FightMND Mid-Career Research Fellowship.

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Authors and Affiliations

  1. Department of Neurology, University of Ulm, Ulm, Germany

    Albert Ludolph

  2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Site Ulm, Ulm, Germany

    Albert Ludolph

  3. Université de Strasbourg, Inserm, Mécanismes Centraux et Périphériques de la Neurodégénérescence, UMR-S1118, Centre de Recherches en Biomédecine, Strasbourg, France

    Luc Dupuis

  4. Department of Neurology, University of Kentucky, Lexington, KY, USA

    Edward Kasarskis

  5. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia

    Frederik Steyn

  6. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia

    Shyuan Ngo

  7. Department of Neuroscience, University of Sheffield, Sheffield, UK

    Christopher McDermott

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Ludolph, A., Dupuis, L., Kasarskis, E. et al. Nutritional and metabolic factors in amyotrophic lateral sclerosis. Nat Rev Neurol 19, 511–524 (2023). https://doi.org/10.1038/s41582-023-00845-8

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