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Table 1 Pathways regulating longevity, stress, and disease responses

From: Genetic variation in neurodegenerative diseases and its accessibility in the model organism Caenorhabditis elegans

Insulin/Insulin-like growth factor (IIS) signaling pathway. The insulin-like receptor DAF-2 is one of the main molecular components of IIS pathway in C. elegans, which is activated by binding insulin-like peptides (IPs) [44]. DAF-2 activation by IPs results in recruitment and activation of AKT and SGK-1 (which are activated by phosphorylation of PDK-1 at the plasma membrane) to phosphorylate and sequester DAF-16 in the cytosol [95]. When activated by stresses, dephosphorylated DAF-16 enter the nucleus and regulates the transcription of a large number of genes involved in resistance to abiotic and biotic stresses, dauer larvae formation, metabolism, and longevity [63, 98]. DAF-16 can become dephosphorylated by the absence of the IP ligand(s), by inhibition from upstream pathway members—e.g., DAF-18 opposes the activity of PDK-1 and AKT-1 via inhibition of AGE-1—or by mutations in upstream genes, leading to lifespan extension [28, 56, 62, 72]. Strikingly, downregulation of IIS via daf-2 or age-1 mutations in C. elegans delays the formation of small aggregates in nematode models of NGDs and also slows the onset and decreases the severity of associated pathologies in a daf-16-dependent manner [17].
Mechanistic target of rapamycin (mTOR) pathway. The kinase mTOR integrates nutrient and anabolic signals to promote growth [52, 106, 112]. The TSC1/TSC2 complex acts as a negative regulator of mTORCs upstream, RHEB, but can be activated by AKT kinase (which belongs to IIS pathway) [36]. The mTORC signaling regulates a large number of developmental processes. TORC1 signaling transactivates/represses PH4-4 that induces pro-survival factors expression for life extension under nutrient restriction [85]. Moreover, TORC1 can increase protein synthesis and extends lifespan by both activating the ribosomal subunit S6 kinase (S6K) and inhibiting 4E-BP1 (a negative regulator of translation) [81, 97]. Meanwhile, investigations in C. elegans as well as other organisms have shown that autophagy is induced by inhibition of TORC1 [46]. An inadequate level of autophagy has been implicated in physiological responses to exercise and aging as well as in pathophysiological processes, such as cancer and metabolic and neurodegenerative disorders [47]. Although mammalian TORC2 (mTORC2) signaling shows insensitivity to nutrients in comparison to mTORC1, it does respond to growth factors like insulin through a poorly defined mechanism that requires PI3K (the C. elegans homolog is AGE-1) [111]. Moreover, mTORC2 directly activates AKT and SCK-1 which regulate cellular processes such as metabolism, survival, apoptosis, growth, and proliferation through the phosphorylation of several effectors [47]. In addition, TORC2 controls the cell cycle-dependent polarization of the actin cytoskeleton, which is involved in complex liposome mechanism, inducing several processes required for cancer cell growth, survival, and proliferation. Functioning as a nutrient sensor—detecting nutrients and amino acids—mTOR has a complex influence on several crucial cellular functions and shows clear effects on aging, protein synthesis and autophagy, and the homeostasis pathways that play a key role in the mechanisms that affect NGDs.
Mitochondrial signaling pathway. Mitochondria play important roles in aging and disease through apoptotic/programmed cell death (PCD), aberrant autophagic regulation, endoplasmic reticulum dysfunction, and intracellular calcium (see review [108]). The intrinsic apoptosis machinery of C. elegans comprises CED-9, CED-4, and CED-3, which is conserved from nematode to vertebrates and stimulates a protective response to mitochondrial dysfunction. JNK-1 promotes the expression of EGL-1 and CED-13. EGL-1 is required for all apoptosis, but CED-13 is required for pro-longevity signaling through the intrinsic pathway, i.e., mitochondrial reactive oxygen species (mROS) signaling pathway [80, 107]. Several stress factors, such as low IIS, heat stress, mitochondrial stress, and oxidative stress, among others, have been found to simulate the autophagic degradation of mitochondria (mitophagy). Besides sharing crucial regulatory factors with the general autophagy pathways, stressful conditions, specific components are also recruited for mitochondrial degradation. Outer mitochondrial membrane kinase PINK1 and its recruitment the cytosolic E3 ubiquitin ligase PARK2/parkin (also on the organelle) as well as their downstream signaling mediator, DCT-1, participate in mitophagy induction, mitochondrial homoeostasis protection, and survival promotion under stress conditions [65]. Mutations in PINK1 and PARK2 result in recessive familial forms of human Parkinson’s disease and correlate with mitochondrial dysfunction in mouse models [13, 58]. Similar to DAF-16, the transcription of SKN-1, which plays a key regulator in mitochondrial signaling pathway, has an influence on longevity and stress responses as well as NGDs [12, 107]. SKN-1 activation can be triggered by increased numbers of damaged mitochondria as well as increased cytoplasmic calcium levels upon mitophagy inhibition [65]. However, phosphorylation of SKN-1 by GSK-3 and kinases downstream from the DAF-2 insulin-like pathway (AKT-1, AKT-2, and SGK-1) negatively regulate SKN-1 nuclear accumulation and activation [12, 98]. Prohibitin PHB complex, PHB1/PHB2, affect mitochondrial metabolism by sensing free radicals and/or mediating ROS production to influence longevity [3]. Interestingly, another negative regulator of SNK-1, WDR-23, has been found to interact with and regulate nuclear accumulation of SKN-1 but function independently of DAF-16 [12, 89].
Furthermore, Ca2+ released from the endoplasmic reticulum (ER) can also lead to ROS accumulation. The perturbation of ER Ca2+ homeostasis causes mitochondrial dysfunction, activating the mitochondrial-mediated apoptotic pathway, which has also been implicated in neuronal death in AD mouse model [59, 65]. Additionally, protein-folding stress at the ER stimulates the unfolded protein response (UPR), which is involved in the pathogenesis of many human diseases. For example, the basal activity of the UPR is beneficial under normal conditions but accelerates the pathology caused by toxic Ab protein in a C. elegans model of AD [74].