Increasing evidence emphasizes the beneficial role of naturally derived compounds from different natural sources for the prevention and/or treatment of human diseases, including ALS [54]. Currently, several compounds with antioxidant activity and neuroprotective effects are potential alternative therapies for neurological complications due to their unique therapeutic properties and considerable safety [55]. In addition, there is a variety of natural compounds known for autophagy-modulating properties as well as for controlling oxidative stress and/or active oxygen [56,57].Trehalose is a natural saccharide that can modify autophagy [58], triggering transient lysosomal damage [59]. Induction of autophagy by trehalose may result in a significant reduction in the number of lysosomes in peripheral blood cells of sporadic ALS, suggesting that trehalose could represent an energetic treatment for ALS patients [60]. Trehalose’s mechanisms of action may involve the inhibition of glucose transporters leading to AMPK activation, which could affect autophagy [61]. Consequently, trehalose could act as a weak inhibitor of the lysosome via the inactivation of mTORC1 [62]. Resveratrol, a natural polyphenolic compound, may indicate many beneficial effects. For example, resveratrol has neuroprotective properties against various neurological disorders [63] through the activation of the AMPK autophagy signaling pathway [64]. Resveratrol could reduce mTORC1 signaling for the activation of autophagy [65]. In addition, resveratrol can induce autophagy in embryonic stem cells by activating the AMPK pathway and the concomitant suppression of the mTORC1 signaling cascade [66]. Spermidine, which has a neuroprotective effect in patients with cerebral ischemia [67,68], can be found in a variety of foods [67,68]. Spermidine may also exert its beneficial effects with enhanced autophagy through the AMPK-mTOR pathway [69] and, thus, autophagy induction [70]. Spermidine could activate autophagy via the inhibition of mTORC1 [71]. Urolithin A is a natural polyphenol made by gut microbiota [72], which could induce autophagy for cell protection against kidney injury [73]. In addition, Urolithin A also protects against Parkinson’s disease by enhancement of neuronal survival [74]. Urolithin A could induce mitophagy, which may be required for its neuroprotective effect [75]. Urolithin A could increase the phosphorylation level of AKT and mTOR [76]. Anthocyanins, common plant pigments, can activate autophagy and protect neuronal cells [77], which could improve the memory and motor performance of patients with neurodegeneration [78]. Anthocyanins could induce autophagy via the AMPK-mTOR signaling pathways [79]. Diallyl trisulfide is found in garlic oil, which has a neuroprotective effect against ALS model mice [80]. Diallyl trisulfide could decrease the PI3 K/mTOR signaling pathway and increase the expression of AMPK/TSC2 in Hep G2 cells [81], which might result in inducing autophagy and/or suppressing the levels of ROS [82]. Ginkgolic acid has an anti-cancer effect on colon cancer, triggering apoptosis and autophagy by controlling ROS production, in which mTORC1, p-mTOR, and p-S6 kinase could be dose-dependently reduced by the ginkgolic acid [83]. In addition, autophagy inhibitors could block ginkgolic acid-dependent clearance of α-synuclein in Parkinson’s disease [84]. Genistein, the primary isoflavone from soy products, enhances antioxidant enzyme activities and could activate AMPK signaling through the downregulation of mTOR [85]. The SIRT1 (Sirtuin1)/AMPK pathway, combined with inhibiting mTOR signaling, has also been involved in accelerating autophagy by genistein [86], suggesting that genistein-dependent autophagy can diminish cellular senescence (Figure 2).

In view of the fact that more and more various phytochemicals could be applied to the treatment of ALS, it is necessary to have a more comprehensive understanding of the effects and/or potential mechanisms of the phytochemicals on autophagy and/or ALS. In addition, more research should focus on the regulatory mechanisms of mitophagy in ALS and further explore the potential of targeting mitophagy with certain phytochemicals for the prevention and/or treatment of ALS. The use of such compounds could be an opening point for the new therapy of ALS.