Abstract
One theory that attempts to explain how and why an organism ages is the developmental hypothesis of aging (DevAge), which describes how developmental programming leads to aging in adults. Interestingly, the developmental origins of health and disease hypothesis (DOHaD) asserts that some aging-associated diseases that occur in adults are closely related to development and to conditions in the intrauterine environment. Thus, both aging and aging-associated diseases can be viewed, at least in part, as the result of a developmental program that is activated early in embryogenesis and persists throughout the lifespan of the organism. We would expect this developmental program to be regulated by a set of interacting protein networks that connect environmental and molecular signals. However, the connection between aging and development is not clear. Thus, a systems biology approach that incorporates different “omic” databases for two mammalian models, Homo sapiens and Mus musculus, was used to evaluate how development and aging are interconnected. Interestingly, three major, evolutionarily conserved processes, namely the immune system, epigenetics, and aerobic metabolism, appear to regulate aging and development in both H. sapiens and M. musculus. Considering that these three processes are essential to embryogenesis, the protein networks within these processes are subjected to strong selective pressure to eliminate gross developmental abnormalities in early embryogenesis. This selective pressure becomes more relaxed in the adult organism, permitting the onset of aging-associated diseases and inflammation-related aging; this concept echoes the antagonistic pleiotropy hypothesis of aging.
Similar content being viewed by others
References
Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, Lane RH (2008) Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41:91–102
Adams PD (2009) Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol Cell 36:1–14
Akam M (1998) Hox genes, homeosis and the evolution of segment identity: no need for hopeless monsters. Int J Dev Biol 42:445–451
Attig L, Gabory A, Junien C (2010) Early nutrition and epigenetic programming: chasing shadows. Curr Opin Clin Nutr Metab Care 13:284–293
Bäckdahl L, Bushell A, Beck S (2009) Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. Int J Biochem Cell Biol 41:176–184
Bader GD, Hogue CW (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform 4:2
Baserga M, Bertolotto C, Maclennan NK, Hsu JL, Pham T, Laksana GS, Lane RH (2004) Uteroplacental insufficiency decreases small intestine growth and alters apoptotic homeostasis in term intrauterine growth retarded rats. Early Hum Dev 79:93–105
Baynes JW (2001) The role of AGEs in aging: causation or correlation. Exp Gerontol 36:1527–1537
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B Stat Methodol 57:289–300
Bibikova M, Laurent LC, Ren B, Loring JF, Fan JB (2008) Unraveling epigenetic regulation in embryonic stem cells. Cell Stem Cell 2:123–134
Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83:876–886
Budovsky A, Muradian KK, Fraifeld VE (2006) From disease-oriented to aging/longevity-oriented studies. Rejuvenation Res 9:207–210
Budovsky A, Tacutu R, Yanai H, Abramovich A, Wolfson M, Fraifeld V (2009) Common gene signature of cancer and longevity. Mech Ageing Dev 130:33–39
Chakravarthy MV, Zhu Y, Wice MB, Coleman T, Pappan KL, Marshall CA, McDaniel ML, Semenkovich CF (2008) Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age. Diabetes 57:2698–2707
Chen JH, Martin-Gronert MS, Tarry-Adkins JL, Ozanne SE (2009) Maternal protein restriction affects postnatal growth and the expression of key proteins involved in lifespan regulation in mice. PLoS ONE 4:e4590
Chen J, Xu H, Shen Q, Guo W, Sun L (2010) Effect of postnatal high-protein diet on kidney function of rats exposed to intrauterine protein restriction. Pediatr Res 68:100–104
Chu GC, Dunn NR, Anderson DC, Oxburgh L, Robertson EJ (2004) Differential requirements for Smad4 in TGFbeta-dependent patterning of the early mouse embryo. Development 131:3501–3512
Chuykin IA, Lianguzova MS, Pospelova TV, Pospelov VA (2008) Activation of DNA damage response signaling in mouse embryonic stem cells. Cell Cycle 7:2922–2928
Costello I, Biondi CA, Taylor JM, Bikoff EK, Robertson EJ (2009) Smad4-dependent pathways control basement membrane deposition and endodermal cell migration at early stages of mouse development. BMC Dev Biol 9:54
Cox P, Marton T (2009) Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 23:751–764
Curran SP, Ruvkun G (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 3:e56
de Magalhães JP, Church GM (2005) Genomes optimize reproduction: aging as a consequence of the developmental program. Physiology 20:252–259
de Magalhães JP, Toussaint O (2009) GenAge: a genomic and proteomic network map of human ageing. FEBS Lett 571:243–247
Dilman VM (1971) Age-associated elevation of hypothalamic threshold to feedback control and its role in development, aging and disease. Lancet 1:1211–1219
Dilman VM (1994) Development, aging, and disease. A new rationale for an intervention. Harwood Academic Publisher, Chur
Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147
Fraisl P, Mazzone M, Schmidt T, Carmeliet P (2009) Regulation of angiogenesis by oxygen and metabolism. Dev Cell 16:167–179
Garlanda C, Maina V, Martinez de la Torre Y, Nebuloni M, Locati M (2008) Inflammatory reaction and implantation: the new entries PTX3 and D6. Placenta 29:129–134
Girvan M, Newman ME (2002) Community structure in social and biological networks. Proc Natl Acad Sci USA 99:7821–7826
Gluckman PD, Hanson MA (2006) The consequences of being born small—an adaptive perspective. Horm Res 65:5–14
Gluckman PD, Hanson MA, Buklijas T (2010) A conceptual framework for the developmental origins of health and disease. J Dev Orig Health Dis 1:6–18
Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321
Hales CN, Barker DJP (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35:595–601
Hales CN, Barker DJP (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20
Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, Genbecev-Krtolica O, Mavrogianis P, Ferrer K, Kruessel J, Fazleabas AT, Fisher SJ, Giudice LC (2007) Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod 76:102–117
Hou FF, Chertow GM, Kay J, Boyce J, Lazarus JM, Braatz JA, Owen WF Jr (1997) Interaction between beta 2-microglobulin and advanced glycation end products in the development of dialysis related-amyloidosis. Kidney Int 51:1514–1519
Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T (2002) The mononuclear phagocyte system revisited. J Leukoc Biol 72:621–627
Iijima K, Ohara M, Seki R, Tauchi H (2008) Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage. J Radiat Res 49:451–464
Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345:105–120
Jennings BJ, Ozanne SE, Dorling MW, Hales CN (1999) Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett 448:4–8
Jones RH, Ozanne SE (2009) Fetal programming of glucose-insulin metabolism. Mol Cell Endocrinol 297:4–9
Karlsson G, Blank U, Moody JL, Ehinger M, Singbrant S, Deng CX, Karlsson S (2007) Smad4 is critical for self-renewal of hematopoietic stem cells. J Exp Med 204:467–474
Kashyap V, Gudas LJ (2010) Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts. J Biol Chem 285:14534–14548
Kawahito S, Kitahata H, Oshita S (2009) Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol 15:4137–4142
Keen CL, Clegg MS, Hanna LA, Lanoue L, Rogers JM, Daston GP, Oteiza P, Uriu-Adams JY (2003) The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications. J Nutr 133:1597S–1605S
Khaliq A, Dunk C, Jiang J, Shams M, Li XF, Acevedo C, Weich H, Whittle M, Ahmed A (1999) Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for “placental hyperoxia” in intrauterine growth restriction. Lab Investig 79:151–170
Kim SY, Paylor SW, Magnuson T, Schumacher A (2006) Juxtaposed Polycomb complexes co-regulate vertebral identity. Development 133:4957–4968
Lang D, Powell SK, Plummer RS, Young KP, Ruggeri BA (2007) PAX genes: roles in development, pathophysiology, and cancer. Biochem Pharmacol 73:1–14
Langley-Evans SC (2006) Developmental programming of health and disease. Proc Nutr Soc 65:97–105
Leonard S, Murrant C, Tayade C, van den Heuvel M, Watering R, Croy BA (2006) Mechanisms regulating immune cell contributions to spiral artery modification-facts and hypotheses—a review. Placenta 27:S40–S46
Leroi A, Bartke A, de Benedictis G, Franceschi C, Gartner A, Gonos ES, Fedei ME, Kivisild T, Lee S, Kartaf-Ozer N, Schumacher M, Sikora E, Slagboom E, Tatar M, Yashin AI, Vijg J, Zwaan B (2005) What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? Mech Ageing Dev 126:421–429
Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21:605–631
Luo G, Yao MS, Bender CF, Mills M, Bladl AR, Bradley A, Petrini JH (1999) Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96:7376–7381
Maere S, Heymans K, Kuiper M (2005) BiNGO: a cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21:3448–3449
Magnani L, Cabot RA (2009) Manipulation of SMARCA2 and SMARCA4 transcript levels in porcine embryos differentially alters development and expression of SMARCA1, SOX2, NANOG, and EIF1. Reproduction 137:23–33
McMillen IC, Robinson JS (2005) Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85:571–633
Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1:135–145
Muñoz-Najar U, Sedivy JM (2011) Epigenetic control of aging. Antioxid Redox Signal 14:241–259
Murohashi M, Nakamura T, Tanaka S, Ichise T, Yoshida N, Yamamoto T, Shibuya M, Schlessinger J, Gotoh N (2010) An FGF4-FRS2α-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos. Stem Cells 28:113–121
Newman MEJ (2005) A measure of betweenness centrality based on random walks. Soc Netw 27:39–54
O’Neill LA (2002) Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal? Trends Immunol 23:296–300
Okazaki K, Maltepe E (2006) Oxygen, epigenetics and stem cell fate. Regen Med 1:71–83
Olovnikov IA, Kravchenko JE, Chumakov PM (2009) Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense. Semin Cancer Biol 19:32–41
Ovchinnikov DA (2008) Macrophages in the embryo and beyond: much more than just giant phagocytes. Genesis 46:447–462
Plaza S, Prince F, Adachi Y, Punzo C, Cribbs DL, Gehring WJ (2008) Cross-regulatory protein–protein interactions between Hox and Pax transcription factors. Proc Natl Acad Sci USA 105:13439–13444
Rando TA (2006) Stem cells, ageing and the quest for immortality. Nature 441:1080–1086
Rappolee DA, Werb Z (1988) Secretory products of phagocytes. Curr Opin Immunol 1:47–55
Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594
Richardson MK (1999) Vertebrate evolution: the developmental origins of adult variation. Bioessays 21:604–613
Rinaudo PF, Giritharan G, Talbi S, Dobson AT, Schultz RM (2006) Effects of oxygen tension on gene expression in preimplantation mouse embryos. Fertil Steril 86:1252–1265
Ringrose L, Paro R (2004) Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38:413–443
Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979
Sadoul K, Boyault C, Pabion M, Khochbin S (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90:306–312
Scardoni G, Petterlini M, Laudanna C (2009) Analyzing biological network parameters with CentiScaPe. Bioinformatics 25:2857–2859
Schumann A, Nutten S, Donnicola D, Comelli EM, Mansourian R, Cherbut C, Corthesy-Theulaz I, Garcia-Rodenas C (2005) Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome. Physiol Genomics 23:235–245
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504
Stoppera H, Schinzelb R, Sebekovac K, Heidlandd A (2003) Genotoxicity of advanced glycation end products in mammalian cells. Cancer Lett 190:151–156
Su D, Zhu S, Han X, Feng Y, Huang H, Ren G, Pan L, Zhang Y, Lu J, Huang B (2009) BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells. J Biol Chem 284:12153–12164
Suh E, Traber PG (1996) An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 16:619–625
Sun M, Yokoyama M, Ishiwata T, Asano G (1998) Deposition of advanced glycation end products (AGE) and expression of the receptor for AGE in cardiovascular tissue of the diabetic rat. Int J Exp Pathol 79:207–222
Tacutu R, Budovsky A, Fraifeld VE (2010) The NetAge database: a compendium of networks for longevity, age-related diseases and associated processes. Biogerontology 11:513–522
Thompson RF, Fazzari MJ, Niu H, Barzilai N, Simmons RA, Greally JM (2010) Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. J Biol Chem 285:15111–15118
Ungewitter E, Scrable H (2009) Antagonistic pleiotropy and p53. Mech Ageing Dev 130:10–17
Vaiserman AM (2008) Epigenetic engineering and its possible role in anti-aging intervention. Rejuvenation Res 11:39–42
Veereman-Wauters G (1996) Neonatal gut development and postnatal adaptation. Eur J Pediatr 155:627–632
Vijg J, Suh Y (2005) Genetics of longevity and aging. Annu Rev Med 56:193–212
Waldenstrom U, Engstrom AB, Hellberg D, Nilsson S (2009) Low-oxygen compared with high-oxygen atmosphere in blastocyst culture, a prospective randomized study. Fertil Steril 91:2461–2465
Warner MJ, Ozanne SE (2010) Mechanisms involved in the developmental programming of adulthood disease. Biochem J 427:333–347
Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411
Willing BP, Van Kessel AG (2009) Intestinal microbiota differentially affect brush border enzyme activity and gene expression in the neonatal gnotobiotic pig. J Anim Physiol Anim Nutr 93:586–595
Yan SF, Ramasamy R, Naka Y, Schmidt AM (2003) Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res 93:1159–1169
Yang X, Li C, Xu X, Deng C (1998) The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci USA 95:3667–3672
Yin D, Chen K (2005) The essential mechanisms of aging: irreparable damage accumulation of biochemical side-reactions. Exp Gerontol 40:455–465
Yu H, Kim PM, Sprecher E, Trifonov V, Gerstein M (2007) The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol 3:e59
Zafon C (2007) Jekyll and Hyde, the p53 protein, pleiotropics antagonisms and the thrifty aged hypothesis of senescence. Med Hypotheses 68:1371–1377
Zhu D, Deng X, Xu J, Hinton DR (2009) What determines the switch between atrophic and neovascular forms of age related macular degeneration?—the role of BMP4 induced senescence. Aging 1:740–745
Acknowledgments
This work was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Grant number 471769/2007-0 and 300301/2009-0) and the Programa Institutos Nacionais de Ciência e Tecnologia (INCT de Processos Redox em Biomedicina-Redoxoma; Grant number 573530/2008-4). Contract/grant sponsor: CNPq.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Feltes, B.C., de Faria Poloni, J. & Bonatto, D. The developmental aging and origins of health and disease hypotheses explained by different protein networks. Biogerontology 12, 293–308 (2011). https://doi.org/10.1007/s10522-011-9325-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-011-9325-8