Table 1.

Summary: the interplay between ageing and ALS

Lower motor unit cell type	Normal ageing	Key references	Amyotrophic lateral sclerosis	Key references
Motor neurons	Reduction in motor neuron number with ageing Loss of synaptic inputs Electrical abnormalities ‘Senescence like’ alterations Lipofuscin accumulation Mitochondrial aberrance Age-dependency in motor phenotypes and MN degeneration	Tomlinson and Irving, 1977 Maxwell et al., 2018 Moldovan et al., 2016 Ohashi et al., 2018 Moreno-Garcia et al., 2018a Rygiel et al., 2014 Azpurua et al., 2018 Srivastava et al., 2012	Loss of MNs in ALS (degeneration) Loss of synaptic inputs Excitotoxicity Cytoskeletal changes RNA metabolism alterations Mitochondrial aberrance Axonal transport defects Ageing risk factor for MN degeneration in ALS	Vaughan et al., 2015 Van Damme et al., 2017 a Azpurua et al., 2018 de Waard et al., 2010
Skeletal muscle	Sarcopenia: age-associated muscle weakness/wasting Satellite cells: loss of regenerative capacity; poor proliferation and self-renewal; senescence Altered skeletal muscle niche/environment NF-κB implications Mitochondrial dysfunction, oxidative stress, autophagy alterations, ER stress FGFBP1 maintains NMJ in ageing	Marzetti et al., 2017 a Blanc et al., 2016 Sousa-Victor et al., 2014b Conboy et al., 2005 Oh et al., 2016 Valentine et al., 2018 Carnio et al., 2014 Baehr et al., 2016 Taetzsch et al., 2017	ALS: early muscle symptoms-weakness; wasting Muscle specific expression of SOD1 → MN degeneration (die-back hypothesis) Satellite cells: loss of regenerative capacity NF-κB implications Mitochondrial dysfunction, oxidative/ER stress and autophagy defects = proposed ALS mechanisms FGFBP1 maintains NMJ in an ALS model	Hobson and McDermott, 2016 a Wong and Martin, 2010 Scaramozza et al., 2014 Frakes et al., 2014 Barber and Shaw, 2010 a Van Damme et al., 2017 a Taetzsch et al., 2017
Astrocytes	Ageing upregulates A1 reactive genes > A2 Aged ACs are vulnerable to oxidative stress Senescence Loss of AC neuronal support functions with ageing (e.g. cholesterol synthesis) Age-associated regional heterogeneity in AC expression Disrupted interaction with microglia-proinflammatory	Clarke et al., 2018 Papadopoulos et al., 1998 Bitto et al., 2010 Boisvert et al., 2018 Soreq et al., 2017 Lana et al., 2019	A1 AC phenotype in ALS Oxidative stress is a proposed ALS mechanism ACs in ALS: evidence for toxic gain-of-function and loss of homeostatic function mechanisms Differential regional vulnerability to neurodegeneration and pathology might relate AC expression changes with ageing Neuroinflammation is a proposed ALS mechanism	Clarke et al., 2018 Barber and Shaw, 2010 a Nagai et al., 2007 Tyzack et al., 2017 Soreq et al., 2017 Van Damme et al., 2017 a
Schwann cells	Disrupted macrophage interaction and phagocytosis Loss of Schwann cell dedifferentiation potential and regenerative capacity with ageing Disrupted Schwann cell structure with ageing Terminal Schwann cell numerical decline with ageing, with remaining TSCs structurally aberrant	Scheib and Hoke, 2016 Painter et al., 2014 Thomas et al., 1980 Snyder-Warwick et al., 2018	TSC morphological, structural and numerical alterations are implicated in ALS Loss of Schwann cell regenerative capacity in ALS	Bruneteau et al., 2015 Carrasco et al., 2016b Carrasco et al., 2016a

Refer to the ‘Discussion’ section for further evidence supporting the interplay between ageing and ALS. AC = astrocyte; MN = motor neuron.

Individual cellular components of the lower motor unit (Fig. 2) undergo an array of changes in both normal ageing and ALS, a number of which are summarized above but discussed in detail in the text. Indeed, careful interrogation of overlapping molecular/cellular phenotypic alterations in ageing and ALS might reveal key insights into the interplay between this ubiquitous physiological phenomenon and the rapidly progressive, universally fatal age-associated neurodegenerative disease. ^aReview articles.