Aging
Although genetic mutations are present throughout life, ALS most commonly develops in mid-adulthood (50–60 years), implying that the normal aging process renders MNs vulnerable to degeneration. However, there is considerable variability in disease progression amongst mutation carriers, even within the same families. Hence, this implies that there is no simple correlation between genetics and disease phenotypes, suggesting that environmental factors and the normal aging process are relevant to understand neuronal vulnerability in ALS/FTD.
Aging results in the accumulation of detrimental biological changes over time. The reduction of muscle mass and strength (sarcopenia) is one of the major causes of disability in older persons (Enoka et al., 2003; Lauretani et al., 2003; Delmonico et al., 2009; Clark and Manini, 2012), which affects gait speed, balance, and the command of fine motor skills (Fried et al., 2004; Sorond et al., 2015). The deterioration of motor functions with advancing age therefore increases the risk of injury and age-associated diseases such as ALS/FTD (Spiller et al., 2016b; Niccoli et al., 2017).
Aging-associated muscle weakness also results from impairment of the activity of MNs contacting skeletal muscles (Fiatarone and Evans, 1993; Manini et al., 2013). High resolution structural MRI imaging reveals prominent atrophy in the primary motor cortex (Salat et al., 2004), as early as middle life in humans. Age-related decreases in white matter mass and myelinated nerve fiber length also correlate with reductions in the size of the motor cortex (Marner et al., 2003). However, loss of neurons during normal human aging is restricted to specific regions of the CNS only, and the number of cells lost is only slight, contrary to previous convictions that significant loss of neurons occur in the human cortex (Pannese, 2011). Instead, age-related changes observed in aged rhesus monkeys and mice appear to involve loss of dendrites and axons, and demyelination, resulting in significant loss of synapses without loss of the neuronal soma (Pannese, 2011). Similarly, there are fewer cholinergic and glutamatergic synaptic inputs directly abutting α-MNs in aged animals, indicating that aging causes α-MNs to shed synaptic inputs. Thus, both impairment of axon function and substantial loss of synaptic inputs may contribute to age-related dysfunction of α-MNs, without loss of the soma (Maxwell et al., 2018). As a consequence, motor units are gradually lost over the first six decades of life, and this accelerates thereafter (Deschenes, 2011). These studies together indicate that neuronal atrophy and axonal impairment, with reduced neuromuscular activity in the absence of MN loss, occur with normal aging.
A major component of aging-related muscle weakness is breakdown in communication between the brain and NMJ. This is related to increased neural noise which reduces the accuracy of neural transmission (Manini et al., 2013). This can result in activation of the motor unit, so that it becomes erratic, and together with diminished glutamate uptake into MNs, leads to an inability to exert muscle force and motor control (Manini et al., 2013). Furthermore, susceptibility of neurons to cellular stress, due to impairment of proteostasis and/or increased oxidative or metabolic stress during normal aging, may render MNs vulnerable to degeneration. Hence, genetic and environmental factors may combine to determine whether a MN can withstand an age-related disease such as ALS or not (Mattson and Magnus, 2006).

Age-Related Proteostasis Disturbance
During the aging process, a decline in the normal cellular ability to maintain proteostasis is observed and, as a result, damaged proteins accumulate (Kikis et al., 2010). Thus the normal aging process in MNs that are already weakened by ALS-associated insults, such as the presence of misfolded proteins or environmental factors, may combine to induce neurodegeneration. MN populations that are more susceptible in ALS may therefore be less able to tolerate disturbances in proteostasis than the more resistant populations (Neumann et al., 2006; Kikis et al., 2010).
Mitochondria play a crucial role in neuronal aging. Normal features observed in the aging brain include the accumulation of mutations in mitochondrial DNA, the production of ROS, mitochondrial metabolic abnormalities and altered Ca2+ storage (Sun et al., 2016). Remarkably, mitochondria in different regions of the CNS are not equally affected during aging. The sensitivity of the mitochondrial permeability transition pore to Ca2+ in the cortex and hippocampus is greater than that of the striatum and the cerebellum in aged rats (LaFrance et al., 2005; Brown et al., 2006). The cellular location of mitochondria is also relevant to the aging processes. Synaptic mitochondria are more prone to oxidative stress-induced damage than mitochondria located in the soma (Brown et al., 2006; Reddy and Beal, 2008). In addition, synaptic mitochondria display a limited capacity to accumulate Ca2+, unlike those located in the soma (Brown et al., 2006). Furthermore, marked differences have been described between mitochondria located in the spinal cord and those found in distal axons of MNs from aged rats. In the axon termini at the NMJ, mitochondria swelling, fusion and an abundance of megamitochondria (giant mitochondria) during aging have been reported (García et al., 2013). These studies therefore imply that mitochondria become dysfunctional in aged MNs, which might sensitize vulnerable MN populations to ALS/FTD. Mitochondria located at the synapse may also be particularly vulnerable to these age-related processes.

Age-Related DNA Damage
The mammalian genome is under constant attack from both endogenous and exogenous sources. This can result in DNA damage, mutations and impaired cellular viability if not repaired correctly (Madabhushi et al., 2014). There is a significant increase in DNA damage during aging due to reduced capacity of DNA repair. Moreover, erroneous repair of DNA lesions can result in further mutations in the aged brain (Vijg and Suh, 2013). DNA damage is increasingly implicated in neurodegenerative disorders, including ALS, where it is induced by the C9orf72 repeat expansion (Farg et al., 2017; Walker et al., 2017). Interestingly, there is also evidence that both FUS and TDP-43 function in the DNA damage response, in either prevention of damage or repair of R loop-associated DNA damage (Hill et al., 2016). In addition, impairment of the DNA damage response due to the presence of ALS/FTD-associated FUS mutations induces neurodegeneration (Higelin et al., 2016; Naumann et al., 2018). It is therefore possible that the normal aging process results in an impaired ability to repair DNA in MNs. This may be an important source of cellular stress that precipitates neurodegeneration in cells already exposed to pathological events throughout life. However, recent work suggests that mutant SOD1G93A does not impact on DNA strand integrity, implying that DNA damage is not present in all forms of ALS (Penndorf et al., 2017).