The Complement System, Aging, and Aging-Related Diseases: History
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Contributor:
Runzi Zheng
,
Yanghuan Zhang
,
Ke Zhang
,
Yang Yuan
,
Shuting Jia
,
Jing Liu

The complement system is a part of the immune system and consists of multiple complement components with biological functions such as defense against pathogens and immunomodulation. The complement system has three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Increasing evidence indicates that the complement system plays a role in aging. Complement plays a role in inflammatory processes, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathways. In addition, the complement system plays a significant role in aging-related diseases, including Alzheimer’s disease, age-related macular degeneration, and osteoarthritis. However, the effect of complement on aging and aging-related diseases is still unclear. Thus, a better understanding of the potential relationship between complement, aging, and aging-related diseases will provide molecular targets for treating aging, while focusing on the balance of complement in during treatment. Inhibition of a single component does not result in a good outcome. 

  • complement system
  • C3
  • aging

1. Introduction

The complement system plays a central role in innate immunity. According to the “body fluid theory”, the presence of antiviral and bactericidal substances in bodily fluids is dependent on the presence of two factors. Heat-stable factors include antibodies, while a heat-unstable factor is the complement system [1]. Similar to antibodies, complement plays a crucial role in resisting foreign substances in the immune system. During the recognition process, the complement system produces a membrane attack complex (MAC) to detect and remove foreign pathogens. As scientific research has expanded, researchers have gradually learned that the complement system is closely linked to a number of diseases, including myocardial infarction [2], systemic lupus erythematosus [3], and metabolic syndrome [4].
Currently, population aging is a major public health concern worldwide. There were over 962 million people over the age of 65 in 2017, and this population is growing at a 3% annual rate [5]. Aging itself is a complex and chronic process. In addition, the World Health Organization (WHO) has determined that aging can be treated as a disease under the International Classification of Diseases (ICD-11) [6]. In this “diseased” state, the structures and functions of the cells degrade. The body’s lack of balance eventually leads to a variety of ailments, such as chronic illnesses. People have begun to rely not only on chronological age (CA) to describe aging, but also on biological age (BA) to define aging. According to research, the complement components C3 and C4 are favorably connected with metabolic syndrome and inversely correlated with life expectancy in centenarians [7]. C3 and C4 are associated with daily physical activities in centenarians [4], and abdominal obesity in centenarians was strongly correlated with complement C3 levels [8]. This finding suggests that the complement system and aging are linked through some pathways. The association between complement and aging, on the other hand, is less well understood, and the processes are unclear.

2. The Complement System

2.1. Composition of the Complement System

Complement can be traced back 350 million years to horseshoe crabs. In 1891, Buchner and colleagues discovered that blood was resistant to bacterial heat destabilizers, and in 1899, Paul Ehrlich used the term complement to describe the antibacterial and heat-sensitive compounds found in blood [1][3]. The complement system is composed of more than 40 different proteins, the majority of which are plasma proteins or membrane proteins produced by the liver, as well as other proteins that work together. Complement components were originally named in the order in which they were identified: C1, C2, and C3. Until now, complement components have been named following the order of activation: C1, C4, C2, C3, C5, C6, C7, C8, and C9 [1][9][10].
C1 is a critical component of the initiation of the classical pathway (CP), which is a complex made up of C1q, C1r, and C1s that separates after C1 is activated. C1q has a molecular weight of 400 kDa and can bind and recognize proteins on bacteria and viruses. C1r is a β-globulin that activates C1s by breaking the thioester connection between them. C1s is an alpha globulin and a serine protease that cleaves C4 and C2 after C1r activation [11].
C4 and C2 are also critical components of the complement system, and they play key roles in activating the complement cascade in both the CP and lectin pathway (LP). C4 is a disulfide-bonded three-chain glycoprotein composed of a-chain, b-chain, and g-chain. When the complement system is activated, activated C1s cleave C4 into two parts, C4a and C4b, and the generated C4b binds C2a (small fragment generated by C1s cleavage of C2) to form C4b2a (a C3 convertase). C4b can also cleave C4d (an inactive split product), and its accumulation can be used as a marker of complement activation [12][13]. C4a is an allergenic toxin [14].
C3 is the central point of the three-cascade activation pathway of the complement system and is composed of alpha and beta chains. C3 converting enzyme cleaves C3 into C3a small fragments and C3b large fragments in vivo, and the presence of C3b aids in the formation of C5 converting enzyme, while C3b also produces C3d, which acts as a receptor that inhibits complement factor I [15]. C3a is also an allergenic toxin [16].
C5 is the MAC component carrier. C5 convertase cleaves C5 into two parts: C5a and C5b. C5a is the complement system’s most potent allergenic toxin, and C5b is a hydrophobic molecule that serves as the precursor to MAC formation [11].

2.2. Activation of the Complement System

Classical pathway, lectin pathway, and alternate pathway are three commonly accepted pathways of complement system activation. The main difference between the three pathways is the initiation process. After initiation, C3 convertase is formed and further cleaves C3. The C3b fragment binds to the preceding complex to form C5 convertase which cleaves C5b and C5a, causing the assembly of the MAC, which lyses cells and stimulates the production of an inflammatory response to remove foreign substances.

3. Complement and Aging

As human beings live longer, they react to external stresses and accumulate harmful substances in the body, and eventually the physiological integrity of tissues and organs is gradually lost and their functions are impaired, which is a process researchers call aging [17]. Common hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, the loss of proteostasis, mitochondrial dysfunction, cellular senescence, and other underlying mechanisms [18][19]. The complexity of the phenomenon makes aging a difficult process to understand, but inflammation is the key to abnormalities associated with the aging process [20][21][22]. This slow and widespread inflammatory process is sensed by C3(H2O) in the AP, which activates the complement system. Elevated complement levels can act as immunomodulatory agents and clear the accumulation of harmful substances from the organism. Complement C3 and C4 levels have been shown to correlate with age [5], and longevity has been shown to have a negative connection with C3/C4 levels, suggesting that high C3 levels are harmful to longevity. Another study demonstrated that low levels of C3 delayed renal senescence [23] and that the use of Radix polygalae saponins to affect C3 expression could also extend the lifespan of C. elegans [24]. It is clear that complement and aging are closely linked, but the relationship between them is unclear. Complement affects inflammation, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathway. Complement may act through these components in the biological process of organismal aging.

3.1. Complement and Inflammation

C3a is the product of the cleavage of C3 by C3 convertase, and is an allergenic toxin that can mediate inflammation. C4a and C5a have similar functions [25]. In guinea pig macrophages [26], C3a could stimulate cellular responses such as the Ca2+ response and O2 release, while in human eosinophils, C3a is an effective activator of transitory Ca2+ alterations and reactive oxygen species formation [27]. Different concentrations of C3a can induce ROS production by human polymorphonuclear neutrophils (PMNs), and C3a is a potential activator of the PMNs respiratory burst [28]. Reactive oxygen species (ROS) mediate the activation of NLRP3 inflammatory vesicles, and the accumulation of ROS is an important cause of pathological aging [29][30]. The C3a/C3aR signaling axis can induce IL-1β secretion from monocytes by enhancing ATP efflux and activating the NLRP3 inflammatory vesicle through extracellular signal-regulated protein 1/2 (ERK1/2) [31]. TNF-α and interleukin IL-1β gene expression and protein synthesis in human peripheral blood mononuclear cells is also affected by C3a and C3a desArg (C3a lacking C-terminal arginine) [32]. Therefore, researchers know that C3a has a proinflammatory effect, but interestingly, C3a has an anti-inflammatory effect under different conditions. C3a can bind C3a receptor (C3aR) in acute intestinal injury to reduce neutrophil mobilization and ameliorate intestinal ischemia-reperfusion pathology in mice [33]. As a result, the role of C3 in inflammation is more complicated than simple magnification.

3.2. Complement and Metabolism

Complement C3 is strongly associated with lipid metabolism, cardiovascular disease, metabolic syndrome, and diabetes [4][34]. C3 is largely generated in the liver [35], and studies have shown a substantial linear association between C3 levels and blood lipids, waist circumference, and C-reactive protein (CRP) [36]. However, other tissues of the body, such as adipose tissue, can create C3, and age-related showing of the metabolism combined with the accumulation of calories can easily lead to obesity [37], which could explain why C3 levels increase. Complement C3 affects both steatosis and the inflammatory response in the liver. Even with 60% liver fat, geese do not show inflammatory or pathogenic features, due to C3 representative downstream genes of C3 (FASN and ETNK1) that regulate C3 function [38]. In addition to obesity, a study of 2815 nondiabetic healthy middle-aged men with long follow-up plasma protein analysis showed that complement C3 levels were associated with the risk of developing diabetes [39]. C3 can also be used as a predictor of cardiovascular or coronary events [40]. Complement protein deposition and activation in the arterial wall can be observed in patients with coronary artery disease. Activation of the complement system is hypothesized to play a role in acute coronary crises. In ruptured and fragile plaques, deposits of iC3b (inactivated C3b) are increased, and when the plaque ruptures, the lesion components are discharged into the bloodstream, further activating the complement system in the artery [41].

3.3. Complement and Apoptosis

Apoptosis is a self-directed and orderly form of cell death that is under genetic control, and it is a means to eliminate unwanted cells without triggering an inflammatory response. The activation of apoptotic mechanisms removes senescent cells and allows the body to function normally. Senescent cells are resistant to apoptosis and require assistance to further induce apoptosis [42]. C3 can lead to apoptosis by forming the MAC via the complement-activated pathway. The complement system (which generates significant levels of C3a/C5a/MAC) can be stimulated by lipopolysaccharide (LPS) and cobra venom factor (CVF) to trigger endothelial cell death. In a glaucoma mouse model, the MAC can also trigger apoptosis, which results in the death of retinal ganglion cells [43][44][45]. iC3b, an inactivated form of C3b, can also promote apoptosis through immunomodulatory effects [45]. However, C3 tends to have diverse effects depending on the situation. When C3a was cultured with human macrophages, the macrophage apoptotic rate decreased with increasing complement C3a concentrations, according to one study [46]. Complement C3 can also prevent imiquimod-induced bullous-like skin inflammation by inhibiting apoptosis [47]. Moreover, C3 interacts with the autophagy-associated protein ATG16L1 to regulate autophagy and protect β-cells from cytokine-induced apoptosis [48]. Thus, islet β-cell apoptosis can be increased by C3 inhibition [49]. The amount of complement molecules in our bodies is crucial, and if we want to use these molecules for our benefit, we must first identify a proper state, because complement has varying effects depending on the conditions.

4. Complement and Aging-Related Diseases

Aging is one of the major risk factors for the development of diseases, such as metabolic diseases [50], neurodegenerative diseases [51], and cardiovascular diseases [52], in the human body. Although the complement system affects the body through immune regulation, dysregulation of complement in aging-related diseases is more likely to accompany disease and exacerbate disease onset.

4.1. Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurological illness that affects elderly individuals. Amyloid plaques and neurofibrillary tangles (NFTs) are extracellular deposits of amyloid β protein (Aβ) that characterize this disease. Neuronal fiber tangles are composed of paired helical filament (PHF) aggregates of hyperphosphorylated tau proteins [53][54]. As early as the last century, studies have shown elevated levels of C1q, C3, and C4 colocalized with Aβ plaques in the brain tissue of AD patients and elevated levels of C3 and C4 mRNA in the temporal lobe of the brain [55][56]. In 2018 an investigator found high complement levels in astrocytes isolated from the brains of AD patients [57]. C1q can bind to neurons that express calreticulin (CRT) and cause neuronal ROS production and damage, whereas the presence of the MAC may also contribute to neuronal loss and degeneration in AD [54][58]. Mice lacking C1q or C3 have persistent synapse elimination abnormalities in the CNS [59]. Crossing a C1q-deficient (APPQ−/−) mouse model with an amyloidosis (APPPS1Q−/−) mouse model resulted in a significant reduction in glial cell activation compared to amyloidosis (APPPS1Q−/−) mice, which has been linked to a variety of neurological diseases [60]. C3 knockout in a mouse model with tau protein lesions (TauP301S) improved neuronal loss and brain atrophy in mice [61]. An anti-pGlu3-A antibody that targets the neurotoxic A peptide was recently developed by a researcher. The antibody also contains a component that hinders C1q binding and complement system activation, reducing microglial activation in Alzheimer’s patients [62]. In another study, mice with amyotrophic lateral sclerosis were administered the C5aR (C5a receptor) antagonist PMX205, which was successful in penetrating the central nervous system, enhancing grip strength, and slowing disease progression in the hind limbs [63].

4.2. Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly populations in Western countries, and both age and genetics are risk factors for AMD [64]. AMD is characterized by the early appearance of extracellular vitreous deposits between the choroid and the retinal pigment epithelium, which trigger inflammation. Late onset choroidal neovascularization (CNV) and retinal pigment epithelial (RPE) cell death are linked to severe vision impairment [65]. One of the main causes of AMD is overactivation of the complement replacement pathway [66]. The C3d/C3 ratio was shown to be considerably higher in AMD patients than in controls, and complement activation was higher during the AMD disease phase [67]. C3a can also cause inflammation by stimulating mast cell degranulation, which can facilitate AMD development [68][69]. Moreover, in the early stages of AMD, C3a and C5a are deposited in the subretinal pigment epithelium, increasing the production of inflammatory proteins. Knockout of the C3a and C5a receptor genes reduced vascular endothelial growth factor (VEGF) expression and CNV following laser injury, and the same effect could be obtained using antibody-mediated inhibition of C3a or C5a receptors [70]. Another study showed that animals injected with adenovirus-based C3 in the subretinal cavity showed a variety of AMD symptoms, including endothelial cell proliferation and migration, or retinal pigment epithelium atrophy, all of which point to a clear link between complement levels and AMD [71][72]. The same effects occurred in a study that used C3−/− mice and WT mice to model AMD, and the C3−/− animals had a more severe response [73], showing that a total loss of C3 was harmful to retinal health and that the balance of complement levels inside the organism is critical. In a phase II clinical trial, the C3 inhibitor APL-2 showed promise in slowing the progression of GA (gyrate atrophy of the choroid and retina). The C5 inhibitor avacincaptad pegol showed preliminary efficacy against AMD in a phase 2 trial [74].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23158689

References

  1. Nesargikar, P.N.; Spiller, B.; Chavez, R. The complement system: History, pathways, cascade and inhibitors. Eur. J. Microbiol. Immunol. 2012, 2, 103–111.
  2. Muscari, A.; Sbano, D.; Bastagli, L.; Poggiopollini, G.; Tomassetti, V.; Forti, P.; Boni, P.; Ravaglia, G.; Zoli, M.; Puddu, P. Effects of weight loss and risk factor treatment in subjects with elevated serum C3, an inflammatory predictor of myocardial infarction. Int. J. Cardiol. 2005, 100, 217–223.
  3. Vignesh, P.; Rawat, A.; Sharma, M.; Singh, S. Complement in autoimmune diseases. Clin. Chim. Acta 2017, 465, 123–130.
  4. Fu, S.; Yao, Y.; Lv, F.; Zhang, F.; Zhao, Y.; Luan, F. Associations of immunological factors with metabolic syndrome and its characteristic elements in Chinese centenarians. J. Transl. Med. 2018, 16, 315.
  5. Cao, W.; Zheng, D.; Wang, G.; Zhang, J.; Ge, S.; Singh, M.; Wang, H.; Song, M.; Li, D.; Wang, W.; et al. Modelling biological age based on plasma peptides in Han Chinese adults. Aging 2020, 12, 10676–10686.
  6. Khaltourina, D.; Matveyev, Y.; Alekseev, A.; Cortese, F.; Iovita, A. Aging Fits the Disease Criteria of the International Classification of Diseases. Mech. Ageing Dev. 2020, 189, 111230.
  7. Fu, S.; Li, Y.; Zhang, F.; Luan, F.; Lv, F.; Deng, J.; Zhao, Y.; Yao, Y. Centenarian longevity is positively correlated with IgE levels but negatively correlated with C3/C4 levels, abdominal obesity and metabolic syndrome. Cell Mol. Immunol. 2020, 17, 1196–1197.
  8. Zhang, C.; Fu, S.; Zhao, M.; Liu, D.; Zhao, Y.; Yao, Y. Associations Between Complement Components and Vitamin D and the Physical Activities of Daily Living Among a Longevous Population in Hainan, China. Front. Immunol. 2020, 11, 1543.
  9. Merle, N.S.; Noe, R.; Halbwachs-Mecarelli, L.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement System Part II: Role in Immunity. Front. Immunol. 2015, 6, 257.
  10. Merle, N.S.; Church, S.E.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement System Part I—Molecular Mechanisms of Activation and Regulation. Front. Immunol. 2015, 6, 262.
  11. McGeer, P.L.; Lee, M.; McGeer, E.G. A review of human diseases caused or exacerbated by aberrant complement activation. Neurobiol. Aging 2017, 52, 12–22.
  12. Chandra, P. C4d in Native Glomerular Diseases. Am. J. Nephrol. 2019, 49, 81–92.
  13. Cohen, D.; Colvin, R.B.; Daha, M.R.; Drachenberg, C.B.; Haas, M.; Nickeleit, V.; Salmon, J.E.; Sis, B.; Zhao, M.H.; Bruijn, J.A.; et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012, 81, 628–639.
  14. Wang, H.; Liu, M. Complement C4, Infections, and Autoimmune Diseases. Front. Immunol. 2021, 12, 694928.
  15. Toapanta, F.R.; Ross, T.M. Complement-mediated activation of the adaptive immune responses: Role of C3d in linking the innate and adaptive immunity. Immunol. Res. 2006, 36, 197–210.
  16. Janssen, B.J.; Huizinga, E.G.; Raaijmakers, H.C.; Roos, A.; Daha, M.R.; Nilsson-Ekdahl, K.; Nilsson, B.; Gros, P. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 2005, 437, 505–511.
  17. Dodig, S.; Cepelak, I.; Pavic, I. Hallmarks of senescence and aging. Biochem. Med. 2019, 29, 030501.
  18. Khan, S.S.; Singer, B.D.; Vaughan, D.E. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 2017, 16, 624–633.
  19. Lopez-Otin, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217.
  20. Borodkina, A.V.; Deryabin, P.I.; Giukova, A.A.; Nikolsky, N.N. “Social Life” of Senescent Cells: What Is SASP and Why Study It? Acta Nat. 2018, 10, 4–14.
  21. Faget, D.V.; Ren, Q.; Stewart, S.A. Unmasking senescence: Context-dependent effects of SASP in cancer. Nat. Rev. Cancer 2019, 19, 439–453.
  22. Franceschi, C.; Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69 (Suppl. S1), S4–S9.
  23. Wu, X.; Lin, L.; Cui, J.; Chen, Y.; Yang, L.; Wan, J. Complement C3 deficiency ameliorates aging related changes in the kidney. Life Sci. 2020, 260, 118370.
  24. Zeng, W.; Wu, A.G.; Zhou, X.G.; Khan, I.; Zhang, R.L.; Lo, H.H.; Qu, L.Q.; Song, L.L.; Yun, X.Y.; Wang, H.M.; et al. Saponins isolated from Radix polygalae extent lifespan by modulating complement C3 and gut microbiota. Pharmacol. Res. 2021, 170, 105697.
  25. McGeer, E.G.; Klegeris, A.; McGeer, P.L. Inflammation, the complement system and the diseases of aging. Neurobiol. Aging 2005, 26 (Suppl. S1), 94–97.
  26. Murakami, Y.; Imamichi, T.; Nagasawa, S. Characterization of C3a anaphylatoxin receptor on guinea-pig macrophages. Immunology 1993, 79, 633–638.
  27. Elsner, J.; Oppermann, M.; Czech, W.; Dobos, G.; Schopf, E.; Norgauer, J.; Kapp, A. C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils. Eur. J. Immunol. 1994, 24, 518–522.
  28. Elsner, J.; Oppermann, M.; Czech, W.; Kapp, A. C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins. Blood 1994, 83, 3324–3331.
  29. Davalli, P.; Mitic, T.; Caporali, A.; Lauriola, A.; D’Arca, D. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid. Med. Cell Longev. 2016, 2016, 3565127.
  30. Sho, T.; Xu, J. Role and mechanism of ROS scavengers in alleviating NLRP3-mediated inflammation. Biotechnol. Appl. Biochem. 2019, 66, 4–13.
  31. Asgari, E.; Le Friec, G.; Yamamoto, H.; Perucha, E.; Sacks, S.S.; Kohl, J.; Cook, H.T.; Kemper, C. C3a modulates IL-1beta secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 2013, 122, 3473–3481.
  32. Takabayashi, T.; Vannier, E.; Clark, B.D.; Margolis, N.H.; Dinarello, C.A.; Burke, J.F.; Gelfand, J.A. A new biologic role for C3a and C3a desArg: Regulation of TNF-alpha and IL-1 beta synthesis. J. Immunol. 1996, 156, 3455–3460.
  33. Wu, M.C.; Brennan, F.H.; Lynch, J.P.; Mantovani, S.; Phipps, S.; Wetsel, R.A.; Ruitenberg, M.J.; Taylor, S.M.; Woodruff, T.M. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proc. Natl. Acad. Sci. USA 2013, 110, 9439–9444.
  34. Barbu, A.; Hamad, O.A.; Lind, L.; Ekdahl, K.N.; Nilsson, B. The role of complement factor C3 in lipid metabolism. Mol. Immunol. 2015, 67, 101–107.
  35. Delanghe, J.R.; Speeckaert, R.; Speeckaert, M.M. Complement C3 and its polymorphism: Biological and clinical consequences. Pathology 2014, 46, 1–10.
  36. Onat, A.; Hergenc, G.; Can, G.; Kaya, Z.; Yuksel, H. Serum complement C3: A determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism 2010, 59, 628–634.
  37. Jura, M.; Kozak, L.P. Obesity and related consequences to ageing. Age 2016, 38, 23.
  38. Xing, Y.; Xu, C.; Lin, X.; Zhao, M.; Gong, D.; Liu, L.; Geng, T. Complement C3 participates in the development of goose fatty liver potentially by regulating the expression of FASN and ETNK1. Anim. Sci. J. 2021, 92, e13527.
  39. Engstrom, G.; Hedblad, B.; Eriksson, K.F.; Janzon, L.; Lindgarde, F. Complement C3 is a risk factor for the development of diabetes: A population-based cohort study. Diabetes 2005, 54, 570–575.
  40. Onat, A.; Can, G.; Rezvani, R.; Cianflone, K. Complement C3 and cleavage products in cardiometabolic risk. Clin. Chim. Acta 2011, 412, 1171–1179.
  41. Wunder, G.C. Things your most satisfied patients won’t tell you. J. Am. Dent. Assoc. 1992, 123, 129–132.
  42. Salminen, A.; Ojala, J.; Kaarniranta, K. Apoptosis and aging: Increased resistance to apoptosis enhances the aging process. Cell Mol. Life Sci. 2011, 68, 1021–1031.
  43. Jha, P.; Banda, H.; Tytarenko, R.; Bora, P.S.; Bora, N.S. Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma. Mol. Immunol. 2011, 48, 2151–2158.
  44. Liang, X.S.; Ming, L.; Qian, Y.S.; Jing, S.S. Lipopolysaccharide activated complement induces endothelial cell release of adhesion molecules and apoptosis. J. Chin. Bull. Pharmacol. 2011, 27, 1245–1249.
  45. Amarilyo, G.; Verbovetski, I.; Atallah, M.; Grau, A.; Wiser, G.; Gil, O.; Ben-Neriah, Y.; Mevorach, D. iC3b-opsonized apoptotic cells mediate a distinct anti-inflammatory response and transcriptional NF-kappaB-dependent blockade. Eur. J. Immunol. 2010, 40, 699–709.
  46. Hai, J.Z.; Wan, J.Z.; Fan, W.; Ping, W. Experimental study on the effect of complement C3a on human macrophage apoptosis. J. Chin. J. Mod. Med. 2010, 20, 548–551.
  47. Zheng, Q.Y.; Liang, S.J.; Xu, F.; Yang, Y.; Feng, J.L.; Shen, F.; Zhong, Y.; Wu, S.; Shu, Y.; Sun, D.D.; et al. Complement component 3 prevents imiquimod-induced psoriatic skin inflammation by inhibiting apoptosis in mice. Int. Immunopharmacol. 2020, 85, 106692.
  48. King, B.C.; Renstrom, E.; Blom, A.M. Intracellular cytosolic complement component C3 regulates cytoprotective autophagy in pancreatic beta cells by interaction with ATG16L1. Autophagy 2019, 15, 919–921.
  49. Dos Santos, R.S.; Marroqui, L.; Grieco, F.A.; Marselli, L.; Suleiman, M.; Henz, S.R.; Marchetti, P.; Wernersson, R.; Eizirik, D.L. Protective Role of Complement C3 Against Cytokine-Mediated beta-Cell Apoptosis. Endocrinology 2017, 158, 2503–2521.
  50. Al-Sofiani, M.E.; Ganji, S.S.; Kalyani, R.R. Body composition changes in diabetes and aging. J. Diabetes Complicat. 2019, 33, 451–459.
  51. Hou, Y.; Dan, X.; Babbar, M.; Wei, Y.; Hasselbalch, S.G.; Croteau, D.L.; Bohr, V.A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 2019, 15, 565–581.
  52. Izzo, C.; Carrizzo, A.; Alfano, A.; Virtuoso, N.; Capunzo, M.; Calabrese, M.; De Simone, E.; Sciarretta, S.; Frati, G.; Oliveti, M.; et al. The Impact of Aging on Cardio and Cerebrovascular Diseases. Int. J. Mol. Sci. 2018, 19, 481.
  53. Tenner, A.J. Complement-Mediated Events in Alzheimer’s Disease: Mechanisms and Potential Therapeutic Targets. J. Immunol. 2020, 204, 306–315.
  54. Shah, A.; Kishore, U.; Shastri, A. Complement System in Alzheimer’s Disease. Int. J. Mol. Sci. 2021, 22, 3647.
  55. Rogers, J.; Cooper, N.R.; Webster, S.; Schultz, J.; McGeer, P.L.; Styren, S.D.; Civin, W.H.; Brachova, L.; Bradt, B.; Ward, P.; et al. Complement activation by beta-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1992, 89, 10016–10020.
  56. Walker, D.G.; McGeer, P.L. Complement gene expression in human brain: Comparison between normal and Alzheimer disease cases. Brain Res. Mol. Brain Res. 1992, 14, 109–116.
  57. Goetzl, E.J.; Schwartz, J.B.; Abner, E.L.; Jicha, G.A.; Kapogiannis, D. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann. Neurol. 2018, 83, 544–552.
  58. Veerhuis, R. Histological and direct evidence for the role of complement in the neuroinflammation of AD. Curr. Alzheimer Res. 2011, 8, 34–58.
  59. Stevens, B.; Allen, N.J.; Vazquez, L.E.; Howell, G.R.; Christopherson, K.S.; Nouri, N.; Micheva, K.D.; Mehalow, A.K.; Huberman, A.D.; Stafford, B.; et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007, 131, 1164–1178.
  60. Fonseca, M.I.; Zhou, J.; Botto, M.; Tenner, A.J. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 2004, 24, 6457–6465.
  61. Wu, T.; Dejanovic, B.; Gandham, V.D.; Gogineni, A.; Edmonds, R.; Schauer, S.; Srinivasan, K.; Huntley, M.A.; Wang, Y.; Wang, T.M.; et al. Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy. Cell Rep. 2019, 28, 2111–2123.
  62. Hettmann, T.; Gillies, S.D.; Kleinschmidt, M.; Piechotta, A.; Makioka, K.; Lemere, C.A.; Schilling, S.; Rahfeld, J.U.; Lues, I. Development of the clinical candidate PBD-C06, a humanized pGlu3-Abeta-specific antibody against Alzheimer’s disease with reduced complement activation. Sci. Rep. 2020, 10, 3294.
  63. Lee, J.D.; Kumar, V.; Fung, J.N.; Ruitenberg, M.J.; Noakes, P.G.; Woodruff, T.M. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1(G93A) mouse model of amyotrophic lateral sclerosis. Br. J. Pharmacol. 2017, 174, 689–699.
  64. Smith, W.; Assink, J.; Klein, R.; Mitchell, P.; Klaver, C.C.; Klein, B.E.; Hofman, A.; Jensen, S.; Wang, J.J.; de Jong, P.T. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001, 108, 697–704.
  65. Tan, P.L.; Bowes Rickman, C.; Katsanis, N. AMD and the alternative complement pathway: Genetics and functional implications. Hum. Genom. 2016, 10, 23.
  66. Armento, A.; Ueffing, M.; Clark, S.J. The complement system in age-related macular degeneration. Cell Mol. Life Sci. 2021, 78, 4487–4505.
  67. Heesterbeek, T.J.; Lechanteur, Y.T.E.; Lores-Motta, L.; Schick, T.; Daha, M.R.; Altay, L.; Liakopoulos, S.; Smailhodzic, D.; den Hollander, A.I.; Hoyng, C.B.; et al. Complement Activation Levels Are Related to Disease Stage in AMD. Investig. Ophthalmol. Vis. Sci. 2020, 61, 18.
  68. Lohman, R.J.; Hamidon, J.K.; Reid, R.C.; Rowley, J.A.; Yau, M.K.; Halili, M.A.; Nielsen, D.S.; Lim, J.; Wu, K.C.; Loh, Z.; et al. Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a. Nat. Commun. 2017, 8, 351.
  69. Bhutto, I.A.; McLeod, D.S.; Jing, T.; Sunness, J.S.; Seddon, J.M.; Lutty, G.A. Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br. J. Ophthalmol. 2016, 100, 720–726.
  70. Nozaki, M.; Raisler, B.J.; Sakurai, E.; Sarma, J.V.; Barnum, S.R.; Lambris, J.D.; Chen, Y.; Zhang, K.; Ambati, B.K.; Baffi, J.Z.; et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl. Acad. Sci. USA 2006, 103, 2328–2333.
  71. Cashman, S.M.; Desai, A.; Ramo, K.; Kumar-Singh, R. Expression of complement component 3 (C3) from an adenovirus leads to pathology in the murine retina. Investig. Ophthalmol. Vis. Sci. 2011, 52, 3436–3445.
  72. Khandhadia, S.; Cipriani, V.; Yates, J.R.; Lotery, A.J. Age-related macular degeneration and the complement system. Immunobiology 2012, 217, 127–146.
  73. Hoh Kam, J.; Lenassi, E.; Malik, T.H.; Pickering, M.C.; Jeffery, G. Complement component C3 plays a critical role in protecting the aging retina in a murine model of age-related macular degeneration. Am. J. Pathol. 2013, 183, 480–492.
  74. Kassa, E.; Ciulla, T.A.; Hussain, R.M.; Dugel, P.U. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol. Ther 2019, 19, 335–342.
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