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Roles of mTOR signaling in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
A close connection between the mTOR pathway and male fertility has also demonstrated in lower model organisms. In Caenorhabditis elegans (C. elegans), Vellai and colleagues found that depletion of mTOR homolog let-363/CeTor by RNA interference reduces fertility.43 The reproductive defects are also observed in mutants of daf-2 gene, which encodes the C. elegans insulin/IGF-like receptor.44–47 Insights into the regulation of the mTOR pathway on fertility have also been provided by studies in Drosophila. In Drosophila, the release of insulin-like peptides (ILPs) responds to changes in nutritional availability and couples metabolism, longevity, and fertility through a TOR/Raptor-dependent mechanism.48 Loss of function of PRAS40, an inhibitory subunit of TORC1, completely rescues the sterility of insulin receptor substrate (chico) mutant flies.49,50 In contrast, Drosophila mutants of Rictor or Sin1, two members of TORC2, grows normally and are fertile.51 Therefore, the mTORC1 pathway integrates nutrient status in animals to regulate fertility in a manner that is highly conserved from flies to mammals (Table 16.1). More recently, an accumulating body of evidence suggests an essential role of the mTOR pathway in mouse spermatogenesis. Genetic manipulation for inhibition/activation of mTOR signaling in mice is complicated, and both mTORC1 and mTORC2 play important roles in multiple aspects of testicular function as shown in greater detail in Table 16.1.
The Genetic Program of Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Xiufang Wang, Huanling Zhang, Libo Su, Zhanjun Lv
Somatopause, or the age-related decrease of growth hormone and the insulin-like signaling pathway, appears to play roles in regulating life span. Insulin-like signaling activity and the expression of insulin-like peptides are reduced in long-lived nematodes, mice, and humans. Centenarians are generally more sensitive to insulin. Mutations in insulin-like growth factor-1 (IGF-1) receptors are overrepresented in many Ashkenazi Jewish centenarians (Kenyon, 2010; Moskalev et al., 2014). daf-2 is a gene that encodes for a hormone receptor similar to mammalian insulin and IGF-1 in nematodes. In nematodes, mutations that decrease the activity of daf-2 doubled a nematode's life span (Kenyon, 2010). In humans, insulin resistance, changes in body composition, physiologic declines in growth hormone IGF-1, and sex steroids feature the process of aging. The enhanced levels of corticosteroid hormones led to degenerative changes in salmon. The life span of salmon was extended when the gonad was removed from salmon before maturation via prevention of interrenal hyperplasia (Allard and Duan, 2011).
Oxidative Stress and the Aging Brain: From Theory to Prevention
Published in David R. Riddle, Brain Aging, 2007
Carmelina Gemma, Jennifer Vila, Adam Bachstetter, Paula C. Bickford
There are a number of mutated genes that regulate the insulin/insulin growth factor 1 (IGF-1) signaling pathway. Age-1, daf-2, and daf-16 genes in C. elegans are associated with an insulin-like signaling pathway. Age-1 and daf-2 suppress the activity of the downstream target daf-16, a transcription factor that belongs to the Forkhead family of proteases [79]. Hence, loss of function of either of these upstream regulators enhances daf-16 function and leads to increased lifespan. Importantly, loss-of-function mutations in daf-16 not only prevents longevity conferred by the age-1 and daf-2 mutations, but also abolishes stress resistance [80], thereby strengthening the intimate link between longevity and the stress responsiveness associated pathway. These animals are smaller in size, and have a decreased body temperature and a modest increase in antioxidant capacity. Recent studies have shown that knockout mice for the IGF receptor live longer and display greater resistance to oxidative stress [81, 82].
Detrimental effects of fructose on mitochondria in mouse motor neurons and on C. elegans healthspan
Published in Nutritional Neuroscience, 2022
Divya Lodha, Sudarshana Rajasekaran, Tamilselvan Jayavelu, Jamuna R. Subramaniam
Clarity is still sought after for the exact mechanisms by which fructose wreaks havoc. One of the direct mechanisms linked to mitochondria is the reduction of copper transporter, ctr-1, as shown in the stomach leading to Cu deficiency and high iron overload in rats fed on a high fructose diet31. As both Copper and iron are important components of the electron transport chain, it could directly impact the mitochondrial function. Another possibility is the generation of ROS13,14 and the absence of oxidative stress response. In vivo, in C. elegans, a high glucose/fructose diet abrogates all positive effects of the well – established reduced insulin signaling, brought about by mutations in the single exclusive Insulin/IGF-1 like receptor, daf-2, mediated 2 fold increase in lifespan with a proportionate increase in healthspan32. In daf-2 mutants, longevity is elicited through the removal of daf-2 mediated suppression of FOXO transcription factor, daf-16, and its downstream targets through the insulin/IGF-1 signaling cascade. Feeding glucose to daf-2 worms abrogates the longevity through downregulation of daf-16 and one of its targets, aquaporin, a glycerol channel, aqp-133. It needs to be established that fructose could be acting through the same mechanism.
Neuromodulators: an essential part of survival
Published in Journal of Neurogenetics, 2020
ILP signaling has long been associated with survival (see Kenyon, 2010; and references therein). The worm ILP receptor DAF-2, which is a receptor tyrosine kinase (Kimura, Tissenbaum, Liu, & Ruvkun, 1997), promotes reproductive growth and inhibits dauer arrest (Riddle, Swanson, & Albert, 1981). The downregulation of DAF-2 activity doubles C. elegans lifespan (Kenyon, Chang, Gensch, Rudner, & Tabtiang, 1993), a discovery that ushered the birth of a field—the genetics of aging. Like DAF-2 (Gems et al., 1998), at least some of the worm ILPs (Hobert, 2013; Li & Kim, 2008) have pleiotropic functions (Fernandes de Abreu et al., 2014), which might be a consequence of their ILP-to-ILP network organization, where one ILP regulates multiple ILPs (Fernandes de Abreu et al., 2014). Many of the ILP functions typify neuromodulator functions. For example, there are ILPs that sometimes behave like the DAF-2 receptor in one context and opposite from DAF-2 in another context (Fernandes de Abreu et al., 2014). The articles in this collection discuss the roles of ILPs in temperature-sensing (see Takeishi, Takagaki, & Kuhara, 2020), in context-dependent avoidance behaviors (see Cheon, Hwang, & Kim, 2020; Kim & Flavell, 2020), in neuroprotection (see Liang, McKinnon, & Rankin, 2020), the dauer program (see Yang et al., 2020), and longevity (see Kim et al., 2020).
Silica nanoparticles disrupt OPT-2/PEP-2-dependent trafficking of nutrient peptides in the intestinal epithelium
Published in Nanotoxicology, 2019
Annette Piechulek, Lutz C. Berwanger, Anna von Mikecz
DAF-2 represents the exclusive C. elegans insulin/IGF-1 receptor, significantly prolongs life span and protects against a variety of cellular stressors (Kenyon 2010; Tank, Rodgers, and Kenyon 2011). Thus, we investigated whether reduced insulin/IGF-1 signaling suppresses the formation of peptide vesicles and monitored β-Ala-Lys-AMCA in daf-2 mutants exposed to nanosilica. Mutant worms fed with OP50 bacteria, β-Ala-Lys-AMCA and nanosilica showed peptide vesicles suggesting altered peptide trafficking (Figure 3(D′,D″,G)). Notably, the cytoplasmic localization of the nanosilica-induced peptide vesicles differed between different daf-2 mutants. While daf-2(e1368) with a mutation in the ligand-binding domain displayed peptide vesicles randomly distributed throughout the cytoplasm, daf-2(e1370) that has a mutated tyrosine kinase domain specifically showed smaller peptide vesicles located in-line along the apical domain of intestinal cells (Figure 3(D′,D″,G,K,L); Figure S6). The cause for the diverse peptide vesicle patterns in relation to different daf-2 mutations is unknown, but are likely related to interactions between mutation of the tyrosine domain, e.g. respective signaling pathways and apical-specific trafficking defects.