Molecular hallmarks of ageing in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.

Keywords: ALS; Ageing; Molecular hallmarks; Neurodegenerative diseases.

Fig. 1

Molecular hallmarks of ageing in ALS. The molecular hallmarks of ageing denote a collection of inter-connected molecular and cellular features that are widely linked to the ageing process in diverse tissues and organisms. These mechanisms offer a framework for comprehending the intricacies of ageing. Strikingly, the molecular hallmarks of ageing exhibit notable similarities and substantially overlap with the pathophysiological mechanisms described in ALS

Fig. 2

Primary drivers of ageing and ALS. Ageing and neurodegeneration in ALS are complex processes influenced by a combination of genetic, environmental, and cellular factors. Whilst the precise causes of both ageing and ALS are not fully understood, genomic instability, telomere attrition, epigenetic alterations, proteostasis dysfunction, dysregulated autophagy and mitochondrial dysfunction are thought to be primary drivers