SYSTEMIC BIOLOGY OF AGING: MODELING THE MOLECULAR MECHANISMS OF THE DEVELOPMENT OF AGE-RELATED DISEASES. CONCEPTUAL OVERVIEW
DOI:
https://doi.org/10.11603/mie.1996-1960.2019.2.10314Keywords:
systems biology, aging, molecular mechanisms, mathematic modeling.Abstract
Background. The phenomenon of aging includes a group of interrelated processes occurring at the organism, tissue, cellular and molecular genetics levels. It has long been suggested that aging is closely related to the complex dynamics of physiological systems that support homeostasis and, in particular, to the deregulation of regulatory molecular networks. The paper presents evidence of the importance of the dynamics of such complex systems during aging and the fact that physiological deregulation (the gradual destruction of the ability of complex regulatory networks to maintain homeostasis) is an emergent property of these networks that plays an important role in old age.
Purpose. The purpose of this review is to summarize the existing concepts about the main determinants of aging and longevity, as well as to consider the trends in the development of mathematical models of aging processes.
Results. Materials and methods. It is shown that the lack of integrated translational research in the development of systemic medicine and systemic biology is one of the main factors limiting the provision of modern means in solving the problem of anti-aging. Among the main factors of aging, attention is drawn to the fact that exposure to mitochondria is an attractive prospect for achieving improved health and longevity, since the rejuvenation of old, mitochondria can be an important therapeutic strategy for improving the health of older people.
Conclusion. It is also postulated that the speed and ease of integrating modern software systems for modeling biological systems allow researchers to study large models, including their interaction in multidimensional formats with ensembles of small models.
References
Anisimov, V. N. (2003). Molekulyarnyie i fiziologicheskie mehanizmyi stareniya [Molecular and physiological mechanisms of aging]. SPb.: Nauka. [In Russian].
Artyomov, A.V., Burechkovsky, E. S. (2016). Starenie: razlichiya mezhdu smertyu kletki i smertyu organizma s pozitsii matematicheskoy modeli [Aging: the differences between cell death and death of the organism from the standpoint of a mathematical model]. Ukrainskyi zhurnal medytsyny, biolohii ta sportu (Ukrainian Journal of Medicine, Biology and Sports), 3(1), 215-220. [In Russian].
Voitenko, V. P. (1987). Matematicheskoe modelirovanie v gerontologii [Mathematical modeling in gerontology]. Gerontologiya i geriatriya: ezhegodnik. Immunitet i starenie. Sbornik statey (Gerontology and geriatrics: yearbook. Immunity and aging. Digest of articles), Kyiv, 118-130. [In Russian].
Voropaeva, O. F., Shokin, Yu. N., Nepomnyashchikh, L. M. et al. (2014). Matematicheskoe modelirovanie funktsionirovaniya sistemyi belkov p53-MDM2 [Mathematical modeling of the functioning of the p53 - MDM2 protein system]. Byull. ekspr. biol. i med. (Bull. exp. biol. and honey), 2, 261-264. [In Russian].
Galitsky, V. A. (2009). Epigeneticheskaya priroda stareniya [The epigenetic nature of aging]. Tsitologiya (Cytology), 512, 388-397. [In Russian].
Gerasimenko, N. D., Degtyar, N. I., Rasin, M. S. (2016). Sistemnoe vospalenie i starenie: rol yadernyih transkriptsionnyih faktorov terapevticheskoy vozmozhnosti [Systemic inflammation and aging: the role of nuclear transcription factors of therapeutic opportunity]. Problemyi stareniya i dolgoletiya (Problems of aging and longevity), 25:4, 554-561. [In Russian].
Dontsov, V. I. (2006). Metodologiya suschnostnogo modelirovaniya stareniya i rod modeley, postroennyih s eyo pomoschyu [The methodology of the essential modeling of aging and the genus of models built with its help]. Trudyi ISA RAN (Proceedings of ISA RAS), 19, 94-116. [In Russian].
Krutko, V. N., Dontsov, V. I. (2008). Sistemnyie mehanizmyi i modeli stareniya [System mechanisms and models of aging]. Moscow: URSS Press. [In Russian].
Mintser, O. P., Zalisky, V. M. (2018). Metodyi sistemnoy biologii v otsenke globalnyih perestroek kletochnogo obmena pri hronicheskih zabolevaniyah obmena veschestv [Role of the system biology in global modifications of cellular metabolism in chronic metabolic disorders]. Medychna informatyka ta inzheneriia (Medical informatics and engineering), 3(43), 36-43. [In Russian].
Novoseltsev, V. N., Novoseltseva, Zh. A., Yashina, I. (2003). Matematicheskoe modelirovanie v gerontologii - strategicheskie perspektivyi [Mathematical modeling in gerontology - strategic perspectives]. Uspehi gerontologii (Successes of gerontology), 12, 149-165. [In Russian].
Khalyavkin, A. V., Krutko, V. N. (2006). Podhod k modelirovaniyu stareniya s pozitsii biofiziki slozhnyih system [An approach to modeling aging from the standpoint of biophysics of complex systems]. Trudyi ISA RAN (Proceedings of ISA RAS), 19, 117-155. [In Russian].
Aschner, Y., Downey, G. P. (2016). Transforming growth factor-beta: master regulator of the respiractory system in health and disease. Am. J. Respir. Cell Mol. Biol., doi: 10.1165/remb.2015-0391TR.
Bar, C., Bernardes de Jesus, B., Serrano, R., et. al. (2014). Telomerase expression confers cardiopratation in the adult mouse heart after acute myocardial infarction. Nat. commun., 5, 5863.
Barja, G. (2014). The mitochondrial free radical theory of aging. Prog. Mol. Biol. Transl. Sci., 127, 1-27. DOI: https://doi.org/10.1016/B978-0-12-394625-6.00001-5
Bitean, B., Karpas, J., Huangbo, D., et. al. (2011). Regulation of Drosophila lifespan by JNK signaling. Exp. Gerontol., 46 (5), З49-З54.
Bitto, A., Wang, A. M., Behnett, C. F., et. al. (2015). Biochemical genetic pathways that modulate aging in multiple species. Cold Harbor Persp. Med.,5 (11). doi: 10.1101!cshpersp.a025114.
Brannmark, C., Nyman, E., Fagerholm, S., et. al. (201З). Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes. J. Biol. Chem., 288 (14), 9867-9880. DOI: https://doi.org/10.1074/jbc.M112.432062
Budanov, A. V., Karin, M. (2008). p53 target genes sestrin 1 and sestrin 2 connect genotoxic stress and mTOR signaling. Cell, 1З4 (З), 451-460. DOI: https://doi.org/10.1016/j.cell.2008.06.028
Carrol, B., Hewitt, G., Korolchuk, V. I. (201З). Autofphagy and ageing: implications for age-related neurodegenerative diseases. Essays Biochem, 55, 119-1З1. DOI: https://doi.org/10.1042/bse0550119
Chen, D., Guarente, L. (2007). SIR 2: a potential target for calorie restriction mimetics. Trends. Mol. Med., 1З (2), 64-71. DOI: https://doi.org/10.1016/j.molmed.2006.12.004
Chelliah, V., Juty, N., Aimera, J., et. al. (2015). BioModels: ten-year anniversary. Nucleic Acids Res., 4З (Database issue), D 542-548. DOI: https://doi.org/10.1093/nar/gku1181
Cheong, J. K., Zhang, F., Chua, P. J., et. al. (2015). Caseinkinase 1alfpha-dependent feedback loop controls autophagy in RAS-driven cancer. J. Clin. Invest., 125 (4), 1401-1418. DOI: https://doi.org/10.1172/JCI78018
Chondrogiani, N., Petropulos, I., Grimm, S., et. al. (2014). Protein damage, repair and proteolysis. Mol. Aspects Med., З5, 1-71. DOI: https://doi.org/10.1016/j.mam.2012.09.001
Cohen, A. A., Milot, E. Li Q., et. al. (2015). Detection of a novel, integrative aging process suggest complex physiological integration. PLoS One, 10(З), e0116489. DOI: https://doi.org/10.1371/journal.pone.0116489
Corper, A., Stucki, M. (2014). Chromatin maintenance and dynamics in senescence: a spotlight on SAHF formation and the epigenome of senescent cells. Chromosoma, 12З (5), 42З-4З6.
Costacon, T., Zgibor, J. C., Evans, R. W., et. al. (2005). The prospective association between adiponectin and coronary artery disease among individuales with type I diabetes. Diabetology, 48(1), 41-48. DOI: https://doi.org/10.1007/s00125-004-1597-y
Crider, K. S., Yang, T. P., Berry, R. J., et al. (2012). Folate and DNA metylation: areview of woleular mechanism and the eridence for folates role. Adv. Nutr., З(1), 21-З8.
Curtius, K., Wong, C. J., Hazelton, W. B., et al. (2016). A molecular clock inters heterogenere tissue age accusing patients with Barrott's esghagus. Plos. One, 12(5), e1004919.
Cvijowic, M., Almguist, A. J., Hagmar, J., et al. (2014). Bridging the gaps in system biology. Mol. Genet. Genomics, 289(5), 727-7З4.
Dalle Pezze, P., Nelson, G., Otten, E. G., et al. (2014). Dynamic modeling of pattways to cellular senescence reveals strategies for targeted interveution. PloS. Comput. Biol., 10(8), e100З728. doi:10.1371/journal. pcbi.1003728.
Dolan, D., Melson, G., Zupanic, A., et al. (201З). System modeling of NHEJ reveals the importance of ratex regulation of Ku 70/80 in the dynamics of the dna dauge fori. PLoS Eme, 8(2), e55190. DOI: https://doi.org/10.1371/journal.pone.0055190
Dolan, D., Zupanic, A., Nelson, G., et al. (2015). Integrated stohastix model of DNA demage Repair by Non-konofogous End foining and p53/p21-Mediated Early seneseence sugualliy. PloS Compat. Biol., 11(5), e1004246. DOI: https://doi.org/10.1371/journal.pcbi.1004246
Eleyon, A., Zoncu, R., Sabatini, D. H. (2016). Amino acids and mTORC1: from lysosomcs to disease. Trends Mol. Cell Biol. doi:10.1038/nrm. 2016.14.
Fang, E. F., Soheibye-Kuudsen, M., Chem, F., et. al. (2016). Nuclear DNA dauage signaling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. doi:101038/nrm 2016.14.
Garcia-Martinez, J. M., Alessi, D. R. (2008). mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoid-induced protein kinase 1 (SGK 1). Biochem J., 416(З), З75-З85. DOI: https://doi.org/10.1042/BJ20081668
Gauthier, L. D., Greenstein, J. L., O'Rourke, B., et. al. (201З). An integrated mitochondrial ROS production and scavenging model: implications for heart failure. Biophys J., 105(12), 28З2-2842. DOI: https://doi.org/10.1016/j.bpj.2013.11.007
Geva-Zatorsky, N., Rosenfeld, N., Itzkovitz, S., et. al. (2006). Oscillations and variability in the p53 system. Mol. Syst. Biol., 2, 00ЗЗ. DOI: https://doi.org/10.1038/msb4100068
Goetz, R., Ohnishi, M., Ding, X., et. al. (2012). Klotho co receptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol. Cell. Biol., З2(10), 1944-1954. DOI: https://doi.org/10.1128/MCB.06603-11
Goitre, L., Trapani, E., Trabalzini, L., et. al. (2014). The Ras superfamily of small GTP ases: he unlocked secret. Meth. Mol. Biol., 1120, 1-18. DOI: https://doi.org/10.1007/978-1-62703-791-4_1
Govihdarajn, D. R., Pencina, K. M., Raj, D. S., et. al. (2014). A system analysis of age-related changes in some cardiac aging traits. Biogerontology, 15(2), 1З9-152.
Herskovitz, A. Z., Guarente, L. (2014). SIRT1 in neurodevelopment and brain senescence. Neuron, 81(З), 471-48З. DOI: https://doi.org/10.1016/j.neuron.2014.01.028
Hill, S. M., Hauzen, S., Nystrom, T. (2017). Restricted access: spatial sequestration of damage proteins during stress and aging. EMBO Rep., 18(З), З77-З91. DOI: https://doi.org/10.15252/embr.201643458
Hoftman, J. M., Soltow, Q. A., Li, S., et. al. (2014). Effects of age, sex, and genotype on gene-sensitivity metabolomic profiles in the bruit fry, Drosophila melanogaster. Aging Cell, 1З(4), 596-604. DOI: https://doi.org/10.1111/acel.12215
Khan, M. H., Ligon, M., Hussey, L. R., et. al. (201З). TAF-4 is required for the life extension of isp-1cek-1 and tpk-1 Mit mutants. Aging, 5(10), 741-758. DOI: https://doi.org/10.18632/aging.100604
Kirkwood, T. B. (2005). Undestanding the odd science of aging. Cell, 120(4), 4З7-447.
Kirkwood, T. B. (2011). Systems biology of ageing and longevity. Philos. Trans.R. So. Lond. B. Biol. Sci., З66(1561), 64-70. DOI: https://doi.org/10.1098/rstb.2010.0275
Kirkwood, T. B. L., Proctor, C. J. (200З). Somatic mufations and ageing in silico. Mech. Ageing Dev., 124(1), 85-92. DOI: https://doi.org/10.1016/S0047-6374(02)00177-X
Kirkwood, T. B. L. (2017). Why and how are weliving longer? Exp. Physiol., 102(9), 1067-1074.
Kitano, H. (2007). Towards a theory of biological robustness. Mol. Syst. Biol., З, 1З7. DOI: https://doi.org/10.1038/msb4100179
Kowald, A., Kirkwood, T. B. (1996). A network theory of aging: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the aging process. Mutat. Res., З16(5-6), 209-2З6. DOI: https://doi.org/10.1016/S0921-8734(96)90005-3
Kowald, A., Kirkwood, T. B. (2000). Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells. J. Theor. Biol., 202(2), 145-160. DOI: https://doi.org/10.1006/jtbi.1999.1046
Kowald, A., Klipp, E. (2014). Mathematical models of mitochondrial aging and dynamics. Prog. Mol. Biol. Transl. Sci., 127, 6З-92. DOI: https://doi.org/10.1016/B978-0-12-394625-6.00003-9
Krause, F., Ulendorf, J., Lubitz, T., et. al. (2010). Annotation and merging of SBML models with semantic SBML. Bioinformatic, 26(З), 421-428. DOI: https://doi.org/10.1093/bioinformatics/btp642
Kriete, A., Bost, W. J., Booker, G. (2010). Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses. PLoS Comput. Biol., 6(6), e1000820. DOI: https://doi.org/10.1371/journal.pcbi.1000820
Kriete, A. (201З). Robustness and aging - a systems level perspective. Biosystems, 112(1), З7-48. DOI: https://doi.org/10.1016/j.biosystems.2013.03.014
Labbadia, J., Morimoto, R. I. (2015). The biology of proteostasis in aging and disease. Annu Rev. Biochem., 84, 4З5-464. DOI: https://doi.org/10.1146/annurev-biochem-060614-033955
Lai, X., Wolkenhauer, O., Vera, J. (2012). Modeling miRNA regulation in canor signaling system: miR-34a regulation of the p53/Sirt1 signaling module. Methods Mol. Biol., 880, 87-108. DOI: https://doi.org/10.1007/978-1-61779-833-7_6
Lai, X., Wolkenhauer, O., Vera, J. (2016). Understanding microRNA-mediated gene regulatory networks through mathematical modelling. Nucleic Acids Res., 44(1З), 6019-60З5. DOI: https://doi.org/10.1093/nar/gkw550
Lee, Y. H., Lee, N. H., Bhattarai, G., et al. (2010). PPARy inhbits inflammatory reaction in oxidative stress induced human diploid fibroblast. Cell. Biochem. Funct., 28(6), 490-496. DOI: https://doi.org/10.1002/cbf.1681
Lipsitz, L. A., Goldberger, A. L. (1992). Loss of «complexity» and aging. Potential applications of fractals and chaos theory to senescence. JAMA, 267(1З), 1806-1809. DOI: https://doi.org/10.1001/jama.1992.03480130122036
Mao, Z., Hine, C., Tian, X., et. al. (2011). SIRT6 promotes DNA repair under stress by activating. Science, ЗЗ2(60З6), 144З-1446. DOI: https://doi.org/10.1126/science.1202723
Marin-Garcia, J. (2016). Mitochondrial DNA repair: a novel therapeutic target for heart failure. Hert Fail. Rev. doi:10.1007/S 10741-016-9543-x.
Martinez Guimera, A., Welsh, C., Dalle Pezze. P., et. al. (2017). Systems modelling ageing: from single senescent cells to simple multi-cellular models. Essays Biochem., 61(3), 369-377. DOI: https://doi.org/10.1042/EBC20160087
Maslov, A. Y., Ganapathi, S., Westerhof, M., et. al. (2013). DNA damage innormally and prematurely aged mice. Agine Cell, 12(3), 467-477. DOI: https://doi.org/10.1111/acel.12071
Mc Auley, M. T., Martinez Guimere, A., Hodson, D., et. al. (2017). Modelling the molecular mechanisms of aging. Biosci. Rep., 37 (1), BSR 20160177.
Mc Govern, A. P., Powell, B. E., Chevassut, T. J. (2012). A dynamic multi-compartmental model of DNA methylation with demonstrable predictive value in hematological malignance. J. Theor. Biol., 310, 14-20. DOI: https://doi.org/10.1016/j.jtbi.2012.06.018
Medvedev, Z. A. (1990). An attempt at a rational classification of theories of ageing. Biol. Rev. Camb. Philos. Soc., 65(3), 375-398. DOI: https://doi.org/10.1111/j.1469-185X.1990.tb01428.x
Mendias, C. L., Bakhurin, K. I., Gumucio, J. P., et. al. (2015). Haploin sufficiency of myostatin protects against aging-related declines in musele function and enhances. Agine Cell, 14(4), 704-706. DOI: https://doi.org/10.1111/acel.12339
Miwa, S., Lawiess, C., von Zglinicki, T. (2008). Mitochondrial turnover in liver is fast in vivo sound is accelerated by dictary restriction: application of a simple dynamic model. Aging Cell, 7(6), 920-923. DOI: https://doi.org/10.1111/j.1474-9726.2008.00426.x
Mooney, K. M., Morgan, A. E., Mc Auley, M. T. (2016). Aging and computational system biology. Wiley Interdiscip. Rev. Syst. Biol. Med., 8(2), 123-139. DOI: https://doi.org/10.1002/wsbm.1328
Murray, P. J., Cornelissen, B., Vallis, K. A., et. al. (2016). DNA Double-strand break repair: a theoretical framework and its aplications. J. R. Soc. Interfase, 13(114), 20150679. DOI: https://doi.org/10.1098/rsif.2015.0679
Pall, M. L., Leine, S. (2015). Nrf 2, a master of detoxification and alsoautioxidant, anti-inflammatory and other cytoprotective mechanisms inraised by health promoting factors. Sheng Li Xue Bao, 67(1), 1-18.
Passos, J. F., Nelson, G., Wang, C., et. al. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol., 6, 347. DOI: https://doi.org/10.1038/msb.2010.5
Pearson, C. A., Zeng, C., Simba, R. (2013). Network class superposition analysis. PLoS One, 8(4), e59046. DOI: https://doi.org/10.1371/journal.pone.0059046
Peng, L., Yuan, Z., Ling, H., et. al. (2011). SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol. Cell Biol., 31(23), 4720-4734. DOI: https://doi.org/10.1128/MCB.06147-11
Perkiomaki, J. S., Makkikalli, T. H., Hyikuri, H. V. (2015). Fractal and complexity measures of heart rate. Clin. Exp., 27(2-3), 149-158.
Picca, A., Pesce, V., Fracasso, F., et. al. (2013). Agine and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. PLoS ONE, 8(9), e74644. DOI: https://doi.org/10.1371/journal.pone.0074644
Proctor, C. J., Kirkwood, T. B. (2003). Modelling cellular senescence as a result of telomere state. Aging Cell, 2(3), 151-157. DOI: https://doi.org/10.1046/j.1474-9728.2003.00050.x
Proctor, C. J., Sotiv, C., Boys, R. J., et. al. (2005). Modelling the actions of chaperones and their rake in ageing. Mech. Ageing Dev., 126(1), 119-131. DOI: https://doi.org/10.1016/j.mad.2004.09.031
Proctor, C. J., Lorimer, I. A. (2011). Modelling the role of the Hsp 70/Hsp 90 system in the maintenance of protein homeostasis. PLoS One, 6(7), e22038. DOI: https://doi.org/10.1371/journal.pone.0022038
Proctor, C. J., Macdonald, C., Milner, J. M., et. al. (2014). A computer simulation approach to assessing therapeutic intervention peints for the prevention of cytokine-induced cartilage breat down. Arthritis Rheumatol., 66(4), 979-989. DOI: https://doi.org/10.1002/art.38297
Przybilla, J., Rohef, T., Loeffeer, J. (2014). Understanding epigenetic changes in aging stem cells - a computational model approach. Aging Cell, 13(2), 320-328. DOI: https://doi.org/10.1111/acel.12177
Junnila, R. K., List, E. O., Berryman, D. E., et. al. (2013). The GH/IGF-1 axis in ageing and longevity. Nat. Rev. Endocrinol., 9(6), 366-376. DOI: https://doi.org/10.1038/nrendo.2013.67
Ramasamy, R., Shekhtman, A., Schmidt, A. M. (2016). The multiple faces of RAGE - opportunities for therapeutic intervention in aging and chronic disease. Expert Opin. Thez. Tarcets., 20(4), 431-446. DOI: https://doi.org/10.1517/14728222.2016.1111873
Rattan, S. I. (2008). Hormesis in aging. Ageing Res. Rev., 7(1), 63-78. DOI: https://doi.org/10.1016/j.arr.2007.03.002
Rubinsztein, D. C., Marifio, G., Kroemer, G. (2011). Autophagy and aging. Cell, 146(5), 682-695. DOI: https://doi.org/10.1016/j.cell.2011.07.030
Schulz, M., Uhlendorf, J., Klipp, E., et. al. (2006). SBML merge, a system for combining biochemical network models. Genome Inform., 17(1), 62-71.
Sighania, R., Sramkoski, R. M., Jacobberger, J. W., et. al. (2011). A hibrid model of mammalian cellcycle regulation. PLoS Comput. Biol., 7(2), e1001077. DOI: https://doi.org/10.1371/journal.pcbi.1001077
Solovyev, I. A., Dobrovolskaya, E. V., Moskalev, A. A. (2016). Genetic control of circadian rhythms and aging. Russ. J. Genet., 52(4), 343-361. DOI: https://doi.org/10.1134/S1022795416040104
Soltow, Q. A., Jones, D. P., Promislow, D. E. (2010). A network perspective on metabolism and aging. Integr. Comp. Biol., 50(5), 844-854. DOI: https://doi.org/10.1093/icb/icq094
Somogyi, E. T., Bouteiller, J. M., Glazier, J. A., et. al. (2015). Lib Road Runner: a high performance SBML simulation and analysis library. Bioinformatics, 31(20), 3315-3321. DOI: https://doi.org/10.1093/bioinformatics/btv363
Song, R., Sarnoski, E. A., Acar, M. (2018). The system biology of single all aging. I Science, 7, 157-169.
Sosou, P. D., Kirkwood, T. B. L. (2001). A stochastic model of cell replicative senescence based on telomere shortening oxidative stress, a somatic mutations in nuclear and mitochondrial DNA. J. Theor. Biol., 213(4), 573-586. DOI: https://doi.org/10.1006/jtbi.2001.2432
Sutterlin, T., Kolb, C., Dickhaus, H., et. al. (2013). Bridging the scale: semantic integration of quantitable SBML in graphical multi-cellular models and simulation with EPISM and COPASI. Bioinformatics, 29(2), 223-229. DOI: https://doi.org/10.1093/bioinformatics/bts659
Tan, Z. (1999). Telomere shortening and the population size-dependency of life span of human cell culture. Exp. Gerontol., 34(7), 831-842. DOI: https://doi.org/10.1016/S0531-5565(99)00056-X
Tan, V. P., Miyamoto, S. (2016). Nutrient sensing mTORC1: integration of metabolic and autophagic signals. J. Mol. Cell Cardiol. doi:10.1016/j. yjmcc.2016.01.005.
Tavassoly, I., Parmar, J., Shajahan-Hag, A. N., et. al. (2015). Dynamic modeling of the interaction between autophagy and apoptosis in mammalian cells. CPT Pharmacometrics Drug Pharmacol., 4(4), 26З-272. DOI: https://doi.org/10.1002/psp4.29
Tilstra, J. S., Clanson, C. L., Niedernhofer, L. J., et. al. (2011). NF-Kb in aging and disease. Agine Dis., 2(6), 449-465.
Tomaru, U., Takahashi, S., Ishiru, A., et. al. (2012). Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. Am. J. Pathol., 180(З), 96З-972. DOI: https://doi.org/10.1016/j.ajpath.2011.11.012
Van Denrsen, J. M. (2014). The role of senescent cells in aging. Nature, 509(7501), 4З9-446.
Xue, X., Xia, W., Wenzhong, H. (201З). A modeled dynamic regulatory network of HF-kB and IL-6 mediated by mi RNA. Biosystems, 114(З), 214-218. DOI: https://doi.org/10.1016/j.biosystems.2013.09.001
Wensink, M. J., Wrycza, T. F., Bandisch, A. (2014). No senescence despite declining selection pressure:
Hammilton's result in broader perspective. J. Theor. Biol., З47, 176-181.
West, G. B., Bergman, A. (2009). Toward a system biology frame work for understanding aging and health span. J. Gerontol. A. Biol. Sci. Med. Sci., 64(2), 205-208. DOI: https://doi.org/10.1093/gerona/gln066
Zhang, R., Chen, H. Z., Lu, D.-P. (2015). The four layers of aging. Cell Systems, 1(З), 180-186. DOI: https://doi.org/10.1016/j.cels.2015.09.002
Cuellar, A. A., Lloyd, C. M., Nielsen, P. F., et. al. (200З). An overview of CellML 1.1, a biological model description language. Simulation, 79(12), 740- 747. doi:10.1177/0037549703040939. DOI: https://doi.org/10.1177/0037549703040939
Kiri, C., Smith, L. P., Medley, J. K., Sauro, H. M. (2016). phraSED-ML: A paraphrased, human-readable adaptation of SED-ML. Journal of Bioinformatics and Computational Biology, 14:06, 16500З5. doi:10.1142/ S0219720016500359.
Theurey P. (2018). The Aging Mitochondria. Genes, 9(1), 22. doi:10.3390/genes9010022. DOI: https://doi.org/10.3390/genes9010022
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The majority of Medical Informatics and Engineering Open Access journals publish open access articles under the terms of the Creative Commons Attribution (CC BY) License which permits use, distribution and reproduction in any medium, provided the original work is properly cited. The remaining journals offer a choice of licenses.
This journal is available through Creative Commons (CC) License CC-BY 4.0