Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1999 Oct;107(10):791–797. doi: 10.1289/ehp.99107791

Biology of senescent liver peroxisomes: role in hepatocellular aging and disease.

J Youssef 1, M Badr 1
PMCID: PMC1566613  PMID: 10504144

Abstract

Despite rising interest in the health problems of the elderly, information on senescence-related alterations in essential metabolic pathways and their responses to various chemicals is scarce. Although peroxisomal pathways are involved in a multitude of cellular functions, little attention has been given to the potential relationship between senescence of these organelles and the process of aging and disease. Although the prevailing experimental evidence points to a decline in liver peroxisomal enzyme activities and a muted response to peroxisome-proliferating chemicals in aged animals, it is also evident that aged animals are more susceptible, in comparison to their young counterparts, to the hepatocarcinogenic effects of these chemicals. Furthermore, little is known about extraperoxisomal effects of peroxisome proliferators in aged animals. This review evaluates published studies on the impact of aging on basal hepatic peroxisomal metabolism, response to peroxisome proliferators, and changes in signal transduction pathways involved in these processes, with the aim of stimulating research efforts in this important area. The potential intricate relationship among senescent peroxisomes, aged hepatocytes, and health are also discussed.

Full text

PDF
791

Images in this article

792Figure 1
on p.792
795Figure 2
on p.795

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BUCHER N. L. REGENERATION OF MAMMALIAN LIVER. Int Rev Cytol. 1963;15:245–300. doi: 10.1016/s0074-7696(08)61119-5. [DOI] [PubMed] [Google Scholar]
  2. Bayly A. C., Roberts R. A., Dive C. Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin. J Cell Biol. 1994 Apr;125(1):197–203. doi: 10.1083/jcb.125.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beier K., Völkl A., Fahimi H. D. The impact of aging on enzyme proteins of rat liver peroxisomes: quantitative analysis by immunoblotting and immunoelectron microscopy. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993;63(3):139–146. doi: 10.1007/BF02899254. [DOI] [PubMed] [Google Scholar]
  4. Bentley P., Calder I., Elcombe C., Grasso P., Stringer D., Wiegand H. J. Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem Toxicol. 1993 Nov;31(11):857–907. doi: 10.1016/0278-6915(93)90225-n. [DOI] [PubMed] [Google Scholar]
  5. Berger J., Leibowitz M. D., Doebber T. W., Elbrecht A., Zhang B., Zhou G., Biswas C., Cullinan C. A., Hayes N. S., Li Y. Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718–6725. doi: 10.1074/jbc.274.10.6718. [DOI] [PubMed] [Google Scholar]
  6. Birnbaum L. S. Altered hepatic drug metabolism in senescent mice. Exp Gerontol. 1980;15(4):259–267. doi: 10.1016/0531-5565(80)90030-3. [DOI] [PubMed] [Google Scholar]
  7. Castelein H., Gulick T., Declercq P. E., Mannaerts G. P., Moore D. D., Baes M. I. The peroxisome proliferator activated receptor regulates malic enzyme gene expression. J Biol Chem. 1994 Oct 28;269(43):26754–26758. [PubMed] [Google Scholar]
  8. Cattley R. C., Marsman D. S., Popp J. A. Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver. Carcinogenesis. 1991 Mar;12(3):469–473. doi: 10.1093/carcin/12.3.469. [DOI] [PubMed] [Google Scholar]
  9. Cone C. D., Jr Unified theory on the basic mechanism of normal mitotic control and oncogenesis. J Theor Biol. 1971 Jan;30(1):151–181. doi: 10.1016/0022-5193(71)90042-7. [DOI] [PubMed] [Google Scholar]
  10. De La Iglesia F. A., Lewis J. E., Buchanan R. A., Marcus E. L., McMahon G. Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis. 1982 May;43(1):19–37. doi: 10.1016/0021-9150(82)90096-x. [DOI] [PubMed] [Google Scholar]
  11. Devchand P. R., Keller H., Peters J. M., Vazquez M., Gonzalez F. J., Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996 Nov 7;384(6604):39–43. doi: 10.1038/384039a0. [DOI] [PubMed] [Google Scholar]
  12. Dice J. F. Cellular and molecular mechanisms of aging. Physiol Rev. 1993 Jan;73(1):149–159. doi: 10.1152/physrev.1993.73.1.149. [DOI] [PubMed] [Google Scholar]
  13. Dice J. F. Cellular theories of aging as related to the liver. Hepatology. 1985 May-Jun;5(3):508–513. doi: 10.1002/hep.1840050328. [DOI] [PubMed] [Google Scholar]
  14. Diehl A. M., Rai R. M. Liver regeneration 3: Regulation of signal transduction during liver regeneration. FASEB J. 1996 Feb;10(2):215–227. doi: 10.1096/fasebj.10.2.8641555. [DOI] [PubMed] [Google Scholar]
  15. Eacho P. I., Foxworthy P. S., Johnson W. D., Hoover D. M., White S. L. Hepatic peroxisomal changes induced by a tetrazole-substituted alkoxyacetophenone in rats and comparison with other species. Toxicol Appl Pharmacol. 1986 May;83(3):430–437. doi: 10.1016/0041-008x(86)90225-5. [DOI] [PubMed] [Google Scholar]
  16. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  17. Fausto N., Laird A. D., Webber E. M. Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 1995 Dec;9(15):1527–1536. doi: 10.1096/fasebj.9.15.8529831. [DOI] [PubMed] [Google Scholar]
  18. Forman B. M., Chen J., Evans R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312–4317. doi: 10.1073/pnas.94.9.4312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fringes B., Reith A. Time course of peroxisome biogenesis during adaptation to mild hyperthyroidism in rat liver: a morphometric/stereologic study by electron microscopy. Lab Invest. 1982 Jul;47(1):19–26. [PubMed] [Google Scholar]
  20. Goldfischer S., Moore C. L., Johnson A. B., Spiro A. J., Valsamis M. P., Wisniewski H. K., Ritch R. H., Norton W. T., Rapin I., Gartner L. M. Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. Science. 1973 Oct 5;182(4107):62–64. doi: 10.1126/science.182.4107.62. [DOI] [PubMed] [Google Scholar]
  21. Greene M. E., Blumberg B., McBride O. W., Yi H. F., Kronquist K., Kwan K., Hsieh L., Greene G., Nimer S. D. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995;4(4-5):281–299. [PMC free article] [PubMed] [Google Scholar]
  22. Gustafsson J. A. Fatty acids in control of gene expression. Nutr Rev. 1998 Feb;56(2 Pt 2):s20–s75. doi: 10.1111/j.1753-4887.1998.tb01682.x. [DOI] [PubMed] [Google Scholar]
  23. Göttlicher M., Widmark E., Li Q., Gustafsson J. A. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653–4657. doi: 10.1073/pnas.89.10.4653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Haining J. L., Legan J. S. Catalase turnover in rat liver and kidney as a function of age. Exp Gerontol. 1973 Apr;8(2):85–91. doi: 10.1016/0531-5565(73)90018-1. [DOI] [PubMed] [Google Scholar]
  25. Herbener G. H. A morphometric study of age-dependent changes in mitochondrial population of mouse liver and heart. J Gerontol. 1976 Jan;31(1):8–12. doi: 10.1093/geronj/31.1.8. [DOI] [PubMed] [Google Scholar]
  26. Hey M. J., Clough J. M., Taylor D. J. Ion effects on macromolecules in aqueous solution. Nature. 1976 Aug 26;262(5571):807–809. doi: 10.1038/262807a0. [DOI] [PubMed] [Google Scholar]
  27. Horie S., Ishii H., Suga T. Changes in peroxisomal fatty acid oxidation in the diabetic rat liver. J Biochem. 1981 Dec;90(6):1691–1696. doi: 10.1093/oxfordjournals.jbchem.a133645. [DOI] [PubMed] [Google Scholar]
  28. Huber W., Kraupp-Grasl B., Esterbauer H., Schulte-Hermann R. Role of oxidative stress in age dependent hepatocarcinogenesis by the peroxisome proliferator nafenopin in the rat. Cancer Res. 1991 Apr 1;51(7):1789–1792. [PubMed] [Google Scholar]
  29. Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990 Oct 18;347(6294):645–650. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar]
  30. Jakobs B. S., Wanders R. J. Conclusive evidence that very-long-chain fatty acids are oxidized exclusively in peroxisomes in human skin fibroblasts. Biochem Biophys Res Commun. 1991 Aug 15;178(3):842–847. doi: 10.1016/0006-291x(91)90967-c. [DOI] [PubMed] [Google Scholar]
  31. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Devchand P., Wahli W., Willson T. M., Lenhard J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4318–4323. doi: 10.1073/pnas.94.9.4318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kraupp-Grasl B., Huber W., Taper H., Schulte-Hermann R. Increased susceptibility of aged rats to hepatocarcinogenesis by the peroxisome proliferator nafenopin and the possible involvement of altered liver foci occurring spontaneously. Cancer Res. 1991 Jan 15;51(2):666–671. [PubMed] [Google Scholar]
  33. Lake B. G., Evans J. G., Gray T. J., Körösi S. A., North C. J. Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig, and marmoset. Toxicol Appl Pharmacol. 1989 Jun 1;99(1):148–160. doi: 10.1016/0041-008x(89)90120-8. [DOI] [PubMed] [Google Scholar]
  34. Lazarow P. B., Fujiki Y. Biogenesis of peroxisomes. Annu Rev Cell Biol. 1985;1:489–530. doi: 10.1146/annurev.cb.01.110185.002421. [DOI] [PubMed] [Google Scholar]
  35. Levy E., Slusser R. J., Ruebner B. H. Hepatic changes produced by a single dose of endotoxin in the mouse. Electron microscopy. Am J Pathol. 1968 Feb;52(2):477–502. [PMC free article] [PubMed] [Google Scholar]
  36. Makrides S. C. Protein synthesis and degradation during aging and senescence. Biol Rev Camb Philos Soc. 1983 Aug;58(3):343–422. doi: 10.1111/j.1469-185x.1983.tb00394.x. [DOI] [PubMed] [Google Scholar]
  37. Masters C. J., Crane D. I. On the role of the peroxisome in ontogeny, ageing and degenerative disease. Mech Ageing Dev. 1995 May 12;80(2):69–83. doi: 10.1016/0047-6374(94)01563-2. [DOI] [PubMed] [Google Scholar]
  38. Miller R. T., Glover S. E., Stewart W. S., Corton J. C., Popp J. A., Cattley R. C. Effect on the expression of c-met, c-myc and PPAR-alpha in liver and liver tumors from rats chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14,643. Carcinogenesis. 1996 Jun;17(6):1337–1341. doi: 10.1093/carcin/17.6.1337. [DOI] [PubMed] [Google Scholar]
  39. Moser A. B., Rasmussen M., Naidu S., Watkins P. A., McGuinness M., Hajra A. K., Chen G., Raymond G., Liu A., Gordon D. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr. 1995 Jul;127(1):13–22. doi: 10.1016/s0022-3476(95)70250-4. [DOI] [PubMed] [Google Scholar]
  40. Mukherjee R., Jow L., Noonan D., McDonnell D. P. Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol. 1994 Nov;51(3-4):157–166. doi: 10.1016/0960-0760(94)90089-2. [DOI] [PubMed] [Google Scholar]
  41. Mukherjee R., Strasser J., Jow L., Hoener P., Paterniti J. R., Jr, Heyman R. A. RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo. Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):272–276. doi: 10.1161/01.atv.18.2.272. [DOI] [PubMed] [Google Scholar]
  42. Neat C. E., Thomassen M. S., Osmundsen H. Induction of peroxisomal beta-oxidation in rat liver by high-fat diets. Biochem J. 1980 Jan 15;186(1):369–371. doi: 10.1042/bj1860369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. O'Brien M. L., Rangwala S. M., Henry K. W., Weinberger C., Crick D. C., Waechter C. J., Feller D. R., Noonan D. J. Convergence of three steroid receptor pathways in the mediation of nongenotoxic hepatocarcinogenesis. Carcinogenesis. 1996 Feb;17(2):185–190. doi: 10.1093/carcin/17.2.185. [DOI] [PubMed] [Google Scholar]
  44. PAGET G. E. EXPERIMENTAL STUDIES OF THE TOXICITY OF ATROMID WITH PARTICULAR REFERENCE TO FINE STRUCTURAL CHANGES IN THE LIVERS OF RODENTS. J Atheroscler Res. 1963 Sep-Dec;3:729–736. doi: 10.1016/s0368-1319(63)80059-9. [DOI] [PubMed] [Google Scholar]
  45. Pallet V., Azaïs-Braesco V., Enderlin V., Grolier P., Noël-Suberville C., Garcin H., Higueret P. Aging decreases retinoic acid and triiodothyronine nuclear expression in rat liver: exogenous retinol and retinoic acid differentially modulate this decreased expression. Mech Ageing Dev. 1997 Dec 15;99(2):123–136. doi: 10.1016/s0047-6374(97)00098-5. [DOI] [PubMed] [Google Scholar]
  46. Popper H. Aging and the liver. Prog Liver Dis. 1986;8:659–683. [PubMed] [Google Scholar]
  47. Périchon R., Bourre J. M. Aging-related decrease in liver peroxisomal fatty acid oxidation in control and clofibrate-treated mice. A biochemical study and mechanistic approach. Mech Ageing Dev. 1996 Jun 7;87(2):115–126. doi: 10.1016/0047-6374(96)01705-8. [DOI] [PubMed] [Google Scholar]
  48. Périchon R., Bourre J. M. Peroxisomal beta-oxidation activity and catalase activity during development and aging in mouse liver. Biochimie. 1995;77(4):288–293. doi: 10.1016/0300-9084(96)88138-7. [DOI] [PubMed] [Google Scholar]
  49. Rigatuso J. L., Legg P. G., Wood R. L. Microbody formation in regenerating rat liver. J Histochem Cytochem. 1970 Dec;18(12):893–900. doi: 10.1177/18.12.893. [DOI] [PubMed] [Google Scholar]
  50. Rikans L. E., Moore D. R. Effect of age and sex on allyl alcohol hepatotoxicity in rats: role of liver alcohol and aldehyde dehydrogenase activities. J Pharmacol Exp Ther. 1987 Oct;243(1):20–26. [PubMed] [Google Scholar]
  51. Roberts R. A., James N. H., Woodyatt N. J., Macdonald N., Tugwood J. D. Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR alpha). Carcinogenesis. 1998 Jan;19(1):43–48. doi: 10.1093/carcin/19.1.43. [DOI] [PubMed] [Google Scholar]
  52. Roberts R. A., Soames A. R., Gill J. H., James N. H., Wheeldon E. B. Non-genotoxic hepatocarcinogens stimulate DNA synthesis and their withdrawal induces apoptosis, but in different hepatocyte populations. Carcinogenesis. 1995 Aug;16(8):1693–1698. doi: 10.1093/carcin/16.8.1693. [DOI] [PubMed] [Google Scholar]
  53. Roth G. S. Age changes in signal transduction and gene expression. Mech Ageing Dev. 1997 Dec;98(3):231–238. doi: 10.1016/s0047-6374(97)00110-3. [DOI] [PubMed] [Google Scholar]
  54. Roth G. S., Joseph J. A., Mason R. P. Membrane alterations as causes of impaired signal transduction in Alzheimer's disease and aging. Trends Neurosci. 1995 May;18(5):203–206. doi: 10.1016/0166-2236(95)93902-a. [DOI] [PubMed] [Google Scholar]
  55. Rubin H. Cell aging in vivo and in vitro. Mech Ageing Dev. 1997 Oct;98(1):1–35. doi: 10.1016/s0047-6374(97)00067-5. [DOI] [PubMed] [Google Scholar]
  56. Sakuma M., Yamada J., Suga T. Comparison of the inducing effect of dehydroepiandrosterone on hepatic peroxisome proliferation-associated enzymes in several rodent species. A short-term administration study. Biochem Pharmacol. 1992 Mar 17;43(6):1269–1273. doi: 10.1016/0006-2952(92)90502-a. [DOI] [PubMed] [Google Scholar]
  57. Schapiro H., Hotta S. S., Outten W. E., Klein A. W. The effect of aging on rat liver regeneration. Experientia. 1982 Sep 15;38(9):1075–1076. doi: 10.1007/BF01955375. [DOI] [PubMed] [Google Scholar]
  58. Schmucker D. L., Wang R. K. Age-related changes in liver drug metabolism: structure vs function. Proc Soc Exp Biol Med. 1980 Nov;165(2):178–187. doi: 10.3181/00379727-165-40955. [DOI] [PubMed] [Google Scholar]
  59. Schutgens R. B., Heymans H. S., Wanders R. J., van den Bosch H., Tager J. M. Peroxisomal disorders: a newly recognised group of genetic diseases. Eur J Pediatr. 1986 Feb;144(5):430–440. doi: 10.1007/BF00441734. [DOI] [PubMed] [Google Scholar]
  60. Semsei I., Rao G., Richardson A. Changes in the expression of superoxide dismutase and catalase as a function of age and dietary restriction. Biochem Biophys Res Commun. 1989 Oct 31;164(2):620–625. doi: 10.1016/0006-291x(89)91505-2. [DOI] [PubMed] [Google Scholar]
  61. Sher T., Yi H. F., McBride O. W., Gonzalez F. J. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993 Jun 1;32(21):5598–5604. doi: 10.1021/bi00072a015. [DOI] [PubMed] [Google Scholar]
  62. Shimozawa N., Suzuki Y., Zhang Z., Imamura A., Tsukamoto T., Osumi T., Tateishi K., Okumoto K., Fujiki Y., Orii T. Peroxisome biogenesis disorders: identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX 13. Biochem Biophys Res Commun. 1998 Feb 13;243(2):368–371. doi: 10.1006/bbrc.1997.8067. [DOI] [PubMed] [Google Scholar]
  63. Singh I. Biochemistry of peroxisomes in health and disease. Mol Cell Biochem. 1997 Feb;167(1-2):1–29. doi: 10.1023/a:1006883229684. [DOI] [PubMed] [Google Scholar]
  64. Singh I., Lazo O., Contreras M., Stanley W., Hashimoto T. Rhizomelic chondrodysplasia punctata: biochemical studies of peroxisomes isolated from cultured skin fibroblasts. Arch Biochem Biophys. 1991 Apr;286(1):277–283. doi: 10.1016/0003-9861(91)90041-g. [DOI] [PubMed] [Google Scholar]
  65. Singh I., Moser A. E., Goldfischer S., Moser H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4203–4207. doi: 10.1073/pnas.81.13.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Soliman M. S., Cunningham M. L., Morrow J. D., Roberts L. J., 2nd, Badr M. Z. Evidence against peroxisome proliferation-induced hepatic oxidative damage. Biochem Pharmacol. 1997 May 9;53(9):1369–1374. doi: 10.1016/s0006-2952(97)87956-7. [DOI] [PubMed] [Google Scholar]
  67. Stubbs C. D., Smith A. D. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta. 1984 Jan 27;779(1):89–137. doi: 10.1016/0304-4157(84)90005-4. [DOI] [PubMed] [Google Scholar]
  68. Stäubli W., Hess R., Weibel E. R. Correlated morphometric and biochemical studies on the liver cell. II. Effects of phenobarbital on rat hepatocytes. J Cell Biol. 1969 Jul;42(1):92–112. doi: 10.1083/jcb.42.1.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Su J. L., Simmons C. J., Wisely B., Ellis B., Winegar D. A. Monitoring of PPAR alpha protein expression in human tissue by the use of PPAR alpha-specific MAbs. Hybridoma. 1998 Feb;17(1):47–53. doi: 10.1089/hyb.1998.17.47. [DOI] [PubMed] [Google Scholar]
  70. Takai Y., Kikkawa U., Kaibuchi K., Nishizuka Y. Membrane phospholipid metabolism and signal transduction for protein phosphorylation. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984;18:119–158. [PubMed] [Google Scholar]
  71. Thomas H., Schladt L., Knehr M., Oesch F. Effect of diabetes and starvation on the activity of rat liver epoxide hydrolases, glutathione S-transferases and peroxisomal beta-oxidation. Biochem Pharmacol. 1989 Dec 1;38(23):4291–4297. doi: 10.1016/0006-2952(89)90528-5. [DOI] [PubMed] [Google Scholar]
  72. Tolbert N. E. Metabolic pathways in peroxisomes and glyoxysomes. Annu Rev Biochem. 1981;50:133–157. doi: 10.1146/annurev.bi.50.070181.001025. [DOI] [PubMed] [Google Scholar]
  73. Tontonoz P., Singer S., Forman B. M., Sarraf P., Fletcher J. A., Fletcher C. D., Brun R. P., Mueller E., Altiok S., Oppenheim H. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):237–241. doi: 10.1073/pnas.94.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Tsai M. J., O'Malley B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–486. doi: 10.1146/annurev.bi.63.070194.002315. [DOI] [PubMed] [Google Scholar]
  75. Warner H. R. Aging and regulation of apoptosis. Curr Top Cell Regul. 1997;35:107–121. doi: 10.1016/s0070-2137(97)80004-0. [DOI] [PubMed] [Google Scholar]
  76. Watanabe T., Horie S., Yamada J., Isaji M., Nishigaki T., Naito J., Suga T. Species differences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes. Biochem Pharmacol. 1989 Jan 15;38(2):367–371. doi: 10.1016/0006-2952(89)90051-8. [DOI] [PubMed] [Google Scholar]
  77. Weibel E. R., Stäubli W., Gnägi H. R., Hess F. A. Correlated morphometric and biochemical studies on the liver cell. I. Morphometric model, stereologic methods, and normal morphometric data for rat liver. J Cell Biol. 1969 Jul;42(1):68–91. doi: 10.1083/jcb.42.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Weindruch R. H., Cheung M. K., Verity M. A., Walford R. L. Modification of mitochondrial respiration by aging and dietary restriction. Mech Ageing Dev. 1980 Apr;12(4):375–392. doi: 10.1016/0047-6374(80)90070-6. [DOI] [PubMed] [Google Scholar]
  79. Wilson P. D., Franks L. M. The effect of age on mitochondrial ultrastructure. Gerontologia. 1975;21(2):81–94. doi: 10.1159/000212035. [DOI] [PubMed] [Google Scholar]
  80. Wolf G. Fatty acids bind directly to and activate peroxisome proliferator-activated receptors alpha and gamma. Nutr Rev. 1998 Feb;56(2 Pt 1):61–63. doi: 10.1111/j.1753-4887.1998.tb01693.x. [DOI] [PubMed] [Google Scholar]
  81. Xia E., Rao G., Van Remmen H., Heydari A. R., Richardson A. Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction. J Nutr. 1995 Feb;125(2):195–201. doi: 10.1093/jn/125.2.195. [DOI] [PubMed] [Google Scholar]
  82. Xu L., Ash M., Abdel-aleem S., Lowe J. E., Badr M. Hyperinsulinemia inhibits hepatic peroxisomal beta-oxidation in rats. Horm Metab Res. 1995 Feb;27(2):76–78. doi: 10.1055/s-2007-979912. [DOI] [PubMed] [Google Scholar]
  83. Yamoto T., Ohashi Y., Teranishi M., Takaoka M., Manabe S., Matsunuma N., Makita T. Age-related changes in the susceptibility to clofibric acid, a hypolipidemic agent, of male rat liver. Toxicol Lett. 1995 Jul;78(2):141–145. doi: 10.1016/0378-4274(94)03247-5. [DOI] [PubMed] [Google Scholar]
  84. Youssef J., Badr M. Extraperoxisomal targets of peroxisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease. Crit Rev Toxicol. 1998 Jan;28(1):1–33. doi: 10.1080/10408449891344182. [DOI] [PubMed] [Google Scholar]
  85. Zs-Nagy I. The role of membrane structure and function in cellular aging: a review. Mech Ageing Dev. 1979 Feb;9(3-4):237–246. doi: 10.1016/0047-6374(79)90102-7. [DOI] [PubMed] [Google Scholar]
  86. del Río L. A., Sandalio L. M., Palma J. M. A new cellular function for peroxisomes related to oxygen free radicals? Experientia. 1990 Oct 15;46(10):989–992. doi: 10.1007/BF01940651. [DOI] [PubMed] [Google Scholar]
  87. van den Bosch H., Schutgens R. B., Wanders R. J., Tager J. M. Biochemistry of peroxisomes. Annu Rev Biochem. 1992;61:157–197. doi: 10.1146/annurev.bi.61.070192.001105. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES