The Interplay Between Cholesterol Metabolism and Intrinsic Ageing

Part of the Subcellular Biochemistry book series (SCBI, volume 90)


The last few decades have witnessed remarkable progress in our understanding of ageing. From an evolutionary standpoint it is generally accepted that ageing is a non-adaptive process which is underscored by a decrease in the force of natural selection with time. From a mechanistic perspective ageing is characterized by a wide variety of cellular mechanisms, including processes such as cellular senescence, telomere attrition, oxidative damage, molecular chaperone activity, and the regulation of biochemical pathways by sirtuins. These biological findings have been accompanied by an unrelenting rise in both life expectancy and the number of older people globally. However, despite age being recognized demographically as a risk factor for healthspan, the processes associated with ageing are routinely overlooked in disease mechanisms. Thus, a central goal of biogerontology is to understand how diseases such as cardiovascular disease (CVD) are shaped by ageing. This challenge cannot be ignored because CVD is the main cause of morbidity in older people. A worthwhile way to examine how ageing intersects with CVD is to consider the effects ageing has on cholesterol metabolism, because dysregualted cholesterol metabolism is the key factor which underpins the pathology of CVD. The aim of this chapter is to outline a hypothesis which accounts for how ageing intersects with intracellular cholesterol metabolism. Moreover, we discuss the implications of this relationship for the onset of disease in the ‘oldest old’ (individuals ≥85 years of age). We conclude the chapter by discussing the important role mathematical modelling has to play in improving our understanding of cholesterol metabolism and ageing.


Cholesterol metabolism Reactive oxygen species Cardiovascular disease ‘Oldest old’ 


  1. Aditya R, Kiran AR, Varma DS, Vemuri R, Gundamaraju R (2017) A review on SIRtuins in diabetes. Curr Pharm Des 23(16):2299–2307. PubMedCrossRefGoogle Scholar
  2. Arguello G, Balboa E, Arrese M, Zanlungo S (2015) Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta 1852(9):1765–1778. PubMedCrossRefGoogle Scholar
  3. Arnoult N, Karlseder J (2015) Complex interactions between the DNA-damage response and mammalian telomeres. Nat Struct Mol Biol 22(11):859–866PubMedPubMedCentralCrossRefGoogle Scholar
  4. August E, Parker KH, Barahona M (2007) A dynamical model of lipoprotein metabolism. Bull Math Biol 69(4):1233–1254PubMedCrossRefGoogle Scholar
  5. Blackburn EH, Gall JG (1978) A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol 120(1):33–53PubMedCrossRefGoogle Scholar
  6. Cadet J, Wagner JR (2013) DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol 5(2).
  7. Carrel A (1912) On the permanent LIFE of tissues outside of the organism. J Exp Med 15(5):516–528PubMedPubMedCentralCrossRefGoogle Scholar
  8. Chang HC, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25(3):138–145. PubMedCrossRefGoogle Scholar
  9. Choi H, Mc Auley MT, Lawrence DA (2015) Prenatal exposures and exposomics of asthma. AIMS Environ Sci 2(1):87–109CrossRefGoogle Scholar
  10. Chun PW, Espinosa AJ, Lee CW, Shireman RB, Brumbaugh EE (1985) Low density lipoprotein receptor regulation. Kinet Models Biophys Chem 21:185–196. CrossRefGoogle Scholar
  11. Cobbold C, Sherratt J, Maxwell S (2002) Lipoprotein oxidation and its significance for atherosclerosis: a mathematical approach. Bull Math Biol 64(1):65–95PubMedCrossRefGoogle Scholar
  12. Cohen DE (2008) Balancing cholesterol synthesis and absorption in the gastrointestinal tract. J Clin Lipidol 2(2):S1–S3. PubMedPubMedCentralCrossRefGoogle Scholar
  13. Comfort A (1964) Ageing. The biology of senescence. Rinehart and Winstons, New YorkGoogle Scholar
  14. Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34(10):1637–1659PubMedGoogle Scholar
  15. Eussen SR, Rompelberg CJ, Klungel OH, van Eijkeren JC (2011) Modelling approach to simulate reductions in LDL cholesterol levels after combined intake of statins and phytosterols/-stanols in humans. Lipids Health Dis 10:187. PubMedPubMedCentralCrossRefGoogle Scholar
  16. Felix-Redondo FJ, Grau M, Fernandez-Berges D (2013) Cholesterol and cardiovascular disease in the elderly. Facts and gaps. Ageing Dis 4(3):154–169Google Scholar
  17. Freitas AA, de Magalhaes JP (2011) A review and appraisal of the DNA damage theory of ageing. Mutat Res 728(1–2):12–22. PubMedCrossRefGoogle Scholar
  18. Gems D, Partridge L (2008) Stress-response hormesis and ageing: “that which does not kill us makes us stronger”. Cell Metab 7(3):200–203. PubMedCrossRefGoogle Scholar
  19. Goldstein JL, Brown MS (2015) A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161(1):161–172. PubMedPubMedCentralCrossRefGoogle Scholar
  20. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43(2 Pt 1):405–413PubMedCrossRefGoogle Scholar
  21. Groen A, Oude Elferink R, Verkade H, Kuipers F (2004) The ins and outs of reverse cholesterol transport. Ann Med 36(2):135–145PubMedCrossRefGoogle Scholar
  22. Guarente L (2011) Sirtuins, ageing, and metabolism. Cold Spring Harb Symp Quant Biol 76:81–90. PubMedCrossRefGoogle Scholar
  23. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345(6274):458–460. PubMedPubMedCentralCrossRefGoogle Scholar
  24. Harman D (1956) Ageing: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300PubMedCrossRefGoogle Scholar
  25. Hartl FU (2016) Cellular homeostasis and ageing. Annu Rev Biochem 85:1–4. PubMedCrossRefGoogle Scholar
  26. Harwood HJ Jr, Pellarin LD (1997) Kinetics of low-density lipoprotein receptor activity in Hep-G2 cells: derivation and validation of a Briggs-Haldane-based kinetic model for evaluating receptor-mediated endocytotic processes in which receptors recycle. Biochem J 323(Pt 3):649PubMedPubMedCentralCrossRefGoogle Scholar
  27. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  28. Hernell O, Staggers JE, Carey MC (1990) Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. Biochemistry 29(8):2041–2056PubMedCrossRefGoogle Scholar
  29. Huang L, Fan B, Ma A, Shaul PW, Zhu H (2015) Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice. J Lipid Res 56(5):986–997. PubMedPubMedCentralCrossRefGoogle Scholar
  30. Hübner K, Schwager T, Winkler K, Reich J-G, Holzhütter H-G (2008) Computational lipidology: predicting lipoprotein density profiles in human blood plasma. PLoS Comput Biol 4(5):e1000079PubMedPubMedCentralCrossRefGoogle Scholar
  31. Imai SI, Guarente L (2016) It takes two to tango: NAD(+) and sirtuins in ageing/longevity control. NPJ Ageing Mech Dis 2:16017. CrossRefGoogle Scholar
  32. Ji LL (1993) Antioxidant enzyme response to exercise and ageing. Med Sci Sports Exerc 25(2):225–231PubMedCrossRefGoogle Scholar
  33. Joyce C, Skinner K, Anderson RA, Rudel LL (1999) Acyl-coenzyme A: cholesteryl acyltransferase 2. Curr Opin Lipidol 10(2):89–95PubMedCrossRefGoogle Scholar
  34. Kilner J, Corfe BM, McAuley MT, Wilkinson SJ (2016) A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids. Mol BioSyst 12(1):93–101PubMedCrossRefGoogle Scholar
  35. Kirkwood TB (1977) Evolution of ageing. Nature 270(5635):301–304PubMedPubMedCentralCrossRefGoogle Scholar
  36. Kirkwood TB, Cremer T (1982) Cytogerontology since 1881: a reappraisal of August Weismann and a review of modern progress. Hum Genet 60(2):101–121PubMedCrossRefGoogle Scholar
  37. Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in ageing and disease. J Cell Biol 217(1):51–63. PubMedPubMedCentralCrossRefGoogle Scholar
  38. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and ageing: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215. PubMedCrossRefGoogle Scholar
  39. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD (2004) Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 117(Pt 11):2417–2426. PubMedCrossRefGoogle Scholar
  40. Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L (2007) SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 28(1):91–106. PubMedCrossRefGoogle Scholar
  41. Libby P, Lichtman AH, Hansson GK (2013) Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38(6):1092–1104. PubMedPubMedCentralCrossRefGoogle Scholar
  42. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith DL, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell MM, Reeves SA, Bates GP, Neri C, Thompson LM, Marsh JL, Kazantsev AG (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107(17):7927–7932. PubMedPubMedCentralCrossRefGoogle Scholar
  43. Lv Y-B, Yin Z-X, Chei C-L, Qian H-Z, Kraus VB, Zhang J, Brasher MS, Shi X-M, Matchar DB, Zeng Y (2015) Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: data from the Chinese Longitudinal Healthy Longevity Survey. Atherosclerosis 239(1):137–142. PubMedPubMedCentralCrossRefGoogle Scholar
  44. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063. PubMedPubMedCentralCrossRefGoogle Scholar
  45. Mc Auley MT, Mooney KM (2014) Lipid metabolism and hormonal interactions: impact on cardiovascular disease and healthy ageing. Expert Rev Endocrinol Metab 9(4):357–367PubMedCrossRefGoogle Scholar
  46. Mc Auley MT, Mooney KM (2015) Computationally modeling lipid metabolism and ageing: a mini-review. Comput Struct Biotechnol J 13:38–46. PubMedCrossRefGoogle Scholar
  47. Mc Auley MT, Mooney KM (2017) LDL-C levels in older people: cholesterol homeostasis and the free radical theory of ageing converge. Med Hypotheses 104:15–19. PubMedCrossRefGoogle Scholar
  48. Mc Auley M, Mooney K (2018) Using computational models to study ageing. In: Conn’s handbook of models for human ageing, 2nd edn. Elsevier, New York, pp 79–91CrossRefGoogle Scholar
  49. Mc Auley M, Jones J, Wilkinson D, Kirkwood T (2005) Modelling lipid metabolism to improve healthy ageing. BMC Bioinform 6(3):P21CrossRefGoogle Scholar
  50. Mc Auley MT, Wilkinson DJ, Jones JJ, Kirkwood TB (2012) A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation. BMC Syst Biol 6:130. PubMedPubMedCentralCrossRefGoogle Scholar
  51. Mc Auley MT, Proctor CJ, Corfe BM, Cuskelly GJ, Mooney KM (2013) Nutrition research and the impact of computational systems biology. J Comput Sci Syst Biol 6(5):271–285CrossRefGoogle Scholar
  52. Mc Auley MT, Choi H, Mooney K, Paul E, Miller VM (2015a) Systems biology and synthetic biology: a new epoch for toxicology research. Adv Toxicol 2015:1–14CrossRefGoogle Scholar
  53. Mc Auley MT, Mooney KM, Angell PJ, Wilkinson SJ (2015b) Mathematical modelling of metabolic regulation in ageing. Meta 5(2):232–251. CrossRefGoogle Scholar
  54. Mc Auley MT, Mooney KM, Salcedo-Sora JE (2016) Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing. Brief Bioinform 19(2):bbw116CrossRefGoogle Scholar
  55. Mc Auley MT, Guimera AM, Hodgson D, McDonald N, Mooney KM, Morgan AE, Proctor CJ (2017a) Modelling the molecular mechanisms of ageing. Biosci Rep 37(1):BSR20160177. PubMedPubMedCentralCrossRefGoogle Scholar
  56. Mc Auley MT, Morgan A, Mooney KM (2017) The role of mathematical modelling in understanding ageing. In: Book chapter in ageing: a complex phenomenon. CRC Press, Taylor and Francis Group, Boca Raton, pp 637–652 .
  57. McAuley MT, Kenny RA, Kirkwood TB, Wilkinson DJ, Jones JJ, Miller VM (2009) A mathematical model of ageing-related and cortisol induced hippocampal dysfunction. BMC Neurosci 10:26. PubMedPubMedCentralCrossRefGoogle Scholar
  58. Medawar PB (1952) An unsolved problem of biology. University College, LondonGoogle Scholar
  59. Mishra S, Somvanshi PR, Venkatesh K (2014) Control of cholesterol homeostasis by entero-hepatic bile transport–the role of feedback mechanisms. RSC Adv 4(103):58964–58975CrossRefGoogle Scholar
  60. Mooney KM, Mc Auley MT (2016) Cardiovascular disease and healthy ageing. Journal of Integr Cardiol 1(4):76–78Google Scholar
  61. Mooney KM, Morgan AE, Mc Auley MT (2016) Ageing and computational systems biology. Wiley Interdiscip Rev Syst Biol Med 8(2):123–139. PubMedCrossRefGoogle Scholar
  62. Morgan A, Mooney K, Mc Auley M (2016a) Obesity and the dysregulation of fatty acid metabolism: implications for healthy ageing. Expert Rev Endocrinol Metab 11(6):501–510PubMedCrossRefGoogle Scholar
  63. Morgan AE, Mooney KM, Wilkinson SJ, Pickles NA, Mc Auley MT (2016b) Cholesterol metabolism: a review of how ageing disrupts the biological mechanisms responsible for its regulation. Ageing Res Rev 27:108–124. PubMedCrossRefGoogle Scholar
  64. Morgan AE, Mooney KM, Wilkinson SJ, Pickles NA, Mc Auley MT (2016c) Mathematically modelling the dynamics of cholesterol metabolism and ageing. Bio Systems 145:19–32. PubMedCrossRefGoogle Scholar
  65. Morgan A, Mooney KM, Wilkinson SJ, Pickles N, Mc Auley MT (2017) Investigating cholesterol metabolism and ageing using a systems biology approach. Proc Nutr Soc 76(3):378–391PubMedCrossRefGoogle Scholar
  66. Murphy AJ, Westerterp M, Yvan-Charvet L, Tall AR (2012) Anti-atherogenic mechanisms of high density lipoprotein: effects on myeloid cells. Biochim Biophys Acta 1821(3):513–521. PubMedCrossRefGoogle Scholar
  67. Nelson RH (2013) Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care 40(1):195–211. PubMedCrossRefGoogle Scholar
  68. Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41(1):181–190PubMedCrossRefGoogle Scholar
  69. Paalvast Y, Kuivenhoven JA, Groen AK (2015) Evaluating computational models of cholesterol metabolism. Biochim Biophys Acta 1851(10):1360–1376. PubMedCrossRefGoogle Scholar
  70. Pallottini V, Martini C, Pascolini A, Cavallini G, Gori Z, Bergamini E, Incerpi S, Trentalance A (2005) 3-Hydroxy-3-methylglutaryl coenzyme A reductase deregulation and age-related hypercholesterolemia: a new role for ROS. Mech Ageing Dev 126(8):845–851. PubMedCrossRefGoogle Scholar
  71. Pallottini V, Martini C, Bassi AM, Romano P, Nanni G, Trentalance A (2006) Rat HMGCoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. J Hepatol 44(2):368–374. PubMedCrossRefGoogle Scholar
  72. Pallottini V, Martini C, Cavallini G, Bergamini E, Mustard KJ, Hardie DG, Trentalance A (2007) Age-related HMG-CoA reductase deregulation depends on ROS-induced p38 activation. Mech Ageing Dev 128(11–12):688–695. PubMedCrossRefGoogle Scholar
  73. Park SW (2013) Intestinal and hepatic niemann-pick c1-like 1. Diabetes Metab J 37(4):240–248. PubMedPubMedCentralCrossRefGoogle Scholar
  74. Patil R, Sood GK (2017) Non-alcoholic fatty liver disease and cardiovascular risk. World J Gastrointest Pathophysiol 8(2):51–58. PubMedPubMedCentralCrossRefGoogle Scholar
  75. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12(6):662–667. PubMedCrossRefGoogle Scholar
  76. Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH (2009) The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res 50(Suppl):S189–S194. PubMedPubMedCentralCrossRefGoogle Scholar
  77. Ramasamy I (2014) Recent advances in physiological lipoprotein metabolism. Clin Chem Lab Med 52(12):1695–1727. PubMedCrossRefGoogle Scholar
  78. Ravnskov U, Diamond DM, Hama R, Hamazaki T, Hammarskjold B, Hynes N, Kendrick M, Langsjoen PH, Malhotra A, Mascitelli L, McCully KS, Ogushi Y, Okuyama H, Rosch PJ, Schersten T, Sultan S, Sundberg R (2016) Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 6(6):e010401. PubMedPubMedCentralCrossRefGoogle Scholar
  79. Rensen P, Herijgers N, Netscher M, Meskers S, Van Eck M, van Berkel TJ (1997) Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo. J Lipid Res 38(6):1070–1084PubMedGoogle Scholar
  80. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ (2002) Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J Biol Chem 277(21):18793–18800PubMedCrossRefGoogle Scholar
  81. Rose MR (1991) Evolutionary biology of ageing. Oxford University Press on Demand, New YorkGoogle Scholar
  82. Roy S (2014) Atherosclerotic cardiovascular disease risk and evidence-based management of cholesterol. N Am J Med Sci 6(5):191–198. PubMedPubMedCentralCrossRefGoogle Scholar
  83. Saeedi R, Li M, Frohlich J (2015) A review on lecithin: cholesterol acyltransferase deficiency. Clin Biochem 48(7–8):472–475. PubMedCrossRefGoogle Scholar
  84. Salcedo-Sora JE, Mc Auley MT (2016) A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development. Mol BioSyst 12(3):923–933PubMedCrossRefGoogle Scholar
  85. Santamarina-Fojo S, Dugi KA (1994) Structure, function and role of lipoprotein lipase in lipoprotein metabolism. Curr Opin Lipidol 5(2):117–125PubMedCrossRefGoogle Scholar
  86. Segatto M, Trapani L, Marino M, Pallottini V (2011) Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor. J Cell Physiol 226(10):2610–2616. PubMedCrossRefGoogle Scholar
  87. Semsei I, Rao G, Richardson A (1989) Changes in the expression of superoxide dismutase and catalase as a function of age and dietary restriction. Biochem Biophys Res Commun 164(2):620–625PubMedCrossRefGoogle Scholar
  88. Shankaran H, Resat H, Wiley HS (2007) Cell surface receptors for signal transduction and ligand transport: a design principles study. PLoS Comput Biol 3(6):e101. PubMedPubMedCentralCrossRefGoogle Scholar
  89. Shen WJ, Hu J, Hu Z, Kraemer FB, Azhar S (2014) Scavenger receptor class B type I (SR-BI): a versatile receptor with multiple functions and actions. Metab Clin Exp 63(7):875–886. PubMedCrossRefGoogle Scholar
  90. Shiomi M, Ito T, Fujioka T, Tsujita Y (2000) Age-associated decrease in plasma cholesterol and changes in cholesterol metabolism in homozygous Watanabe heritable hyperlipidemic rabbits. Metab Clin Exp 49(4):552–556PubMedCrossRefGoogle Scholar
  91. Tao R, Xiong X, DePinho RA, Deng CX, Dong XC (2013) Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6. J Lipid Res 54(10):2745–2753. PubMedPubMedCentralCrossRefGoogle Scholar
  92. Tindall MJ, Wattis JA, O’Malley BJ, Pickersgill L, Jackson KG (2009) A continuum receptor model of hepatic lipoprotein metabolism. J Theor Biol 257(3):371–384. PubMedCrossRefGoogle Scholar
  93. Tiwari S, Siddiqi SA (2012) Intracellular trafficking and secretion of VLDL. Arterioscler Thromb Vasc Biol 32(5):1079–1086. PubMedPubMedCentralCrossRefGoogle Scholar
  94. Tuteja S, Rader DJ (2014) High-density lipoproteins in the prevention of cardiovascular disease: changing the paradigm. Clin Pharmacol Ther 96(1):48–56. PubMedCrossRefGoogle Scholar
  95. van de Pas NC, Woutersen RA, van Ommen B, Rietjens IM, de Graaf AA (2012) A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans. J Lipid Res 53(12):2734–2746. PubMedPubMedCentralCrossRefGoogle Scholar
  96. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA (2010) The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis? J Lipid Res 51(8):2058–2073. PubMedPubMedCentralCrossRefGoogle Scholar
  97. Wang X, Li W, Hao L, Xie H, Hao C, Liu C, Li W, Xiong X, Zhao D (2018) The therapeutic potential of CETP inhibitors: a patent review. Expert Opin Ther Pat 28(4):331–340. PubMedCrossRefGoogle Scholar
  98. Watterson S, Guerriero ML, Blanc M, Mazein A, Loewe L, Robertson KA, Gibbs H, Shui G, Wenk MR, Hillston J, Ghazal P (2013) A model of flux regulation in the cholesterol biosynthesis pathway: immune mediated graduated flux reduction versus statin-like led stepped flux reduction. Biochimie 95(3):613–621. PubMedPubMedCentralCrossRefGoogle Scholar
  99. Wattis JA, O’Malley B, Blackburn H, Pickersgill L, Panovska J, Byrne HM, Jackson KG (2008) Mathematical model for low density lipoprotein (LDL) endocytosis by hepatocytes. Bull Math Biol 70(8):2303–2333. PubMedPubMedCentralCrossRefGoogle Scholar
  100. Weverling-Rijnsburger AW, Jonkers IJ, van Exel E, Gussekloo J, Westendorp RG (2003) High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med 163(13):1549–1554. PubMedCrossRefGoogle Scholar
  101. Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11(4):398–411CrossRefGoogle Scholar
  102. Williams AB, Schumacher B (2016) p53 in the DNA-damage-repair process. Cold Spring Harb Perspect Med 6(5).
  103. Wilson PW, Abbott RD, Castelli WP (1988) High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis (Dallas, Tex) 8(6):737–741Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Faculty of Science and EngineeringUniversity of ChesterChesterUK

Personalised recommendations