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An Unsolved Problem in Gerontology Yet: Molecular Mechanisms of Biological Aging—A Historical and Critical Overview

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Aging Mechanisms II

Abstract

I discuss the historical background of the original proposals and modern versions of the selected theories of the molecular mechanisms of biological aging, i.e., the mutation or genome instability theory, the free radical or oxidative stress theory, the mitochondrial theory, the error catastrophe theory, the altered protein or protein homeostasis or proteostasis theory, the dysdifferentiation or epigenetic theory, and the hyperfunction theory, adding a brief comment on a recent popular theory of “epigenetic clock” in this revised version of my previous overview (Goto, Aging mechanisms. Longevity, metabolism and brain aging, Springer, Berlin, 2015). I have involved the development of some of the theories, which are therefore described in more detail than others. A discussion on the definition of aging and general comments on the aging theory are described. A most popular theory of aging, the free radical or oxidative theory, was proposed more than half a century ago but has recently faced severe criticisms to which I shall refer. So far, no single theory has been able to successfully explain the mechanism of biological aging. We are thus awaiting emergence of a new paradigm or an integration of the existing theories for better understanding of the mechanism.

This article is a revised version of my previous contribution to the Springer book (Goto 2015).

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References

  • Arking R (1998) Biology of aging. Observations and principles, 2nd edn. Sinauer Associates, Sunderland

    Google Scholar 

  • Austad SN, Hoffman JM (2018) Is antagonistic pleiotropy ubiquitous in aging biology? Evol Med Public Health 2018(1):287–294. PMID: 30524730

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellizzi D, D’Aquila P, Montesanto A, Corsonello A, Mari V, Mazzei B et al (2012) Global DNA methylation in old subjects is correlated with frailty. Age (Dordr) 34:169–117

    Article  CAS  Google Scholar 

  • Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297:842–857

    Article  CAS  PubMed  Google Scholar 

  • Blagosklonny MV (2008) Aging: ROS or TOR. Cell Cycle 7:3344–3354

    Article  CAS  PubMed  Google Scholar 

  • Blagosklonny MV (2012) Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging (Albany NY) 4:350–358

    Article  CAS  Google Scholar 

  • Brown-Borg HM (2006) Longevity in mice: is stress resistance a common factor? Age (Dordr) 28:145–162

    Article  CAS  Google Scholar 

  • Brunet A, Berger SL (2014) Perspective. Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S17–S20

    Article  PubMed  PubMed Central  Google Scholar 

  • Bushati N, Cohen SM (2007) microRNA functions. Annu Rev Cell Dev Biol 23:175–205

    Article  CAS  PubMed  Google Scholar 

  • Cabelof DC, Raffoul JJ, Yanamadala S, Ganir C, Guo Z, Heydari AR (2002) Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. Mutat Res 500:135–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calabrese EJ, Mattson MP (2011) Hormesis provides a generalized quantitative estimate of biological plasticity. J Cell Commun Signal 5:25–38

    Article  PubMed  PubMed Central  Google Scholar 

  • Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605

    Article  CAS  PubMed  Google Scholar 

  • Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–86

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6:79–87

    Article  CAS  PubMed  Google Scholar 

  • Comfort A (1964) Ageing. The biology of senescence. Routledge & Kegan Paul Ltd, London

    Google Scholar 

  • Cuervo AM, Dice JF (2000) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275:31505–31513

    Article  CAS  PubMed  Google Scholar 

  • Cutler RG (1991) Recent progress in testing the longevity determinant and dysdifferentiation hypotheses of aging. Arch Gerontol Geriatr 12:75–98

    Article  CAS  PubMed  Google Scholar 

  • Cutler RG, Rodriguez H (2003) Critical review of oxidative stress and aging. Advances in basic science, diagnostics and intervention, vol I & II. World Scientific, Singapore

    Google Scholar 

  • Cypser JR, Johnson TE (2002) Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity. J Gerontol A Biol Sci Med Sci 57:B109–B114

    Article  PubMed  Google Scholar 

  • Dato S, Rose G, Crocco P, Monti D, Garagnani P, Franceschi C, Passarino G (2017) The genetics of human longevity: an intricacy of genes, environment, culture and microbiome. Mech Ageing Dev 165:147–155

    Article  CAS  PubMed  Google Scholar 

  • Davies KJ (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83:301–310

    Article  CAS  PubMed  Google Scholar 

  • Dollé ME, Snyder WK, Gossen JA, Lohman PH, Vijg J (2000) Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc Natl Acad Sci U S A 97:8403–8408

    Article  PubMed  PubMed Central  Google Scholar 

  • Drummond DA, Wilke CO (2009) The evolutionary consequences of erroneous protein synthesis. Nat Rev Genet 10:715–724

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de Duve C (1983) Lysosomes revisited. Eur J Biochem 137:391–397

    Article  PubMed  Google Scholar 

  • Fedorova M, Bollineni RC, Hoffmann R (2014) Protein carbonylation as a major hallmark of oxidative damage: update of analytical strategies. Mass Spectrom Rev 33:79–97

    Article  CAS  PubMed  Google Scholar 

  • Fersht AR (1980) Enzymic editing mechanisms in protein synthesis and DNA replication. Trends Biochem Sci. 5:262–265

    Article  CAS  Google Scholar 

  • Finch CE (1990) Longevity, senescence, and the genome. The University of Chicago Press, Chicago

    Google Scholar 

  • Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194:7–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN (1990) Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A 87:4533–4537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gems D, Partridge L (2008) Stress-response hormesis and aging: “that which does not kill us makes us stronger”. Cell Metab 7:200–203

    Article  CAS  PubMed  Google Scholar 

  • Gems D, Partridge L (2013) Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 75:621–644

    Article  CAS  PubMed  Google Scholar 

  • Gershon H, Gershon D (1970) Detection of inactive enzyme molecules in ageing organisms. Nature 227:1214–1217

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Cabrera MC, Domenech E, Viña J (2008) Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med 44:126–131

    Article  CAS  PubMed  Google Scholar 

  • Goto S (2015) The biological mechanisms of aging: a historical and critical overview. In: Mori N, Mook-Jung I (eds) Aging mechanisms. Longevity, metabolism and brain aging, vol 2015. Springer, Berlin, pp 3–27

    Google Scholar 

  • Goto S, Nakamura A (1997) Age-associated, oxidatively modified proteins: a critical evaluation. Age (Omaha) 20:81–89

    Article  CAS  Google Scholar 

  • Goto S, Radák Z (2009) Hormetic effects of reactive oxygen species by exercise: a view from animal studies for successful aging in human. Dose Response 8:68–72

    PubMed  PubMed Central  Google Scholar 

  • Goto S, Takahashi R, Kumiyama A, Radák Z, Hayashi T, Takenouchi M et al (2001) Implications of protein degradation in aging. Ann N Y Acad Sci 928:54–64

    Article  CAS  PubMed  Google Scholar 

  • Goto S, Kawakami K, Naito H, Katamoto S, Radak Z. (2015) Epigenetic modulation of gene expression by exercise. In: Yu BP (ed) Nutrition, exercise and epigenetics, vol 2015. Springer, Berlin, pp 85–100

    Google Scholar 

  • Grasso M, Piscopo P, Confaloni A, Denti MA (2014) Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules 19:6891–6910

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grune T, Catalgol B, Licht A, Ermak G, Pickering AM, Ngo JK et al (2011) HSP70 mediates dissociation and reassociation of the 26S proteasome during adaptation to oxidative stress. Free Radic Biol Med 51:1355–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harley CB, Pollard JW, Chamberlain JW, Stanners CP, Goldstein S (1980) Protein synthetic errors do not increase during aging of cultured human fibroblasts. Proc Natl Acad Sci U S A 77:1885–1889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1968) Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF mice. J Gerontol 23:476–482

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147

    Article  CAS  PubMed  Google Scholar 

  • Harman D, Harman H (2003) “I thought, thought, thought for four months in vain and suddenly the idea came” – an interview with Denham and Helen Harman. Interview by K. Kitani and G.O. Ivy. Biogerontology 4:401–412

    Article  PubMed  Google Scholar 

  • Harris H, Watts JW (1958) Turnover of protein in a non-multiplying animal cell. Nature 181:1582–1584

    Article  CAS  PubMed  Google Scholar 

  • Hart RW, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci U S A 71:2169–2173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi T, Goto S (1998) Age-related changes in the 20S and 26S proteasome activities in the liver of male F344 rats. Mech Ageing Dev 102:55–66

    Article  CAS  PubMed  Google Scholar 

  • Hayflick L (2007) Biological aging is no longer an unsolved problem. Ann N Y Acad Sci 1100:1–13

    Article  CAS  PubMed  Google Scholar 

  • Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20:421–435

    Article  CAS  PubMed  Google Scholar 

  • Hogness DS, Cohn M, Monod J (1955) Studies on the induced synthesis of beta-galactosidase in Escherichia coli: the kinetics and mechanism of sulfur incorporation. Biochim Biophys Acta 16:99–116

    Article  CAS  PubMed  Google Scholar 

  • Holliday R (2006) Aging is no longer an unsolved problem in biology. Ann N Y Acad Sci 1067:1–9

    Article  PubMed  Google Scholar 

  • Hopfield JJ (1974) Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc Natl Acad Sci USA 71:4135–4139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115

    Article  PubMed  PubMed Central  Google Scholar 

  • Houben A, Raes M, Houbion A, Remacle J (1984) Alteration of enzymes in ageing human fibroblasts in culture. I. Conditions for the appearance of an alteration in glucose 6-phosphate dehydrogenase. Mech Ageing Dev 25:23–34

    Article  CAS  PubMed  Google Scholar 

  • Imashimizu M, Oshima T, Lubkowska L, Kashlev M (2013) Direct assessment of transcription fidelity by high-resolution RNA sequencing. Nucleic Acids Res 41:9090–9104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishigami A, Goto S (1990) Age-related change in the degradation rate of ovalbumin microinjected into mouse liver parenchymal cells. Arch Biochem Biophys 277:189–195

    Article  CAS  PubMed  Google Scholar 

  • Ishii T, Sakurai T, Usami H, Uchida K (2005) Oxidative modification of proteasome: identification of an oxidation-sensitive subunit in 26 S proteasome. Biochemistry 44:13893–13901

    Article  CAS  PubMed  Google Scholar 

  • Jylhava J, Pedersen NL, Hagg S (2017) Biological age predictors. EBioMedicine 21:29–36

    Article  PubMed  PubMed Central  Google Scholar 

  • Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL et al (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11:453–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawakami K, Nakamura A, Ishigami A, Goto S, Takahashi R (2009) Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10:415–421

    Article  CAS  PubMed  Google Scholar 

  • Kennedy EP (2001) Hitler’s gift and the era of biosynthesis. J Biol Chem 276:42619–42631

    Article  CAS  PubMed  Google Scholar 

  • Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512

    Article  CAS  PubMed  Google Scholar 

  • Khrapko K, Kraytsberg Y, de Grey AD, Vijg J, Schon EA (2006) Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging? Aging Cell 5:279–282

    Article  CAS  PubMed  Google Scholar 

  • Kinser HE, Pincus Z (2020) MicroRNAs as modulators of longevity and the aging process. Hum Genet 139:291–308

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood TB, Finch CE (2002) Ageing: the old worm turns more slowly. Nature 419:794–795

    Article  CAS  PubMed  Google Scholar 

  • Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10:205–215

    Article  CAS  PubMed  Google Scholar 

  • Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56

    Article  PubMed  Google Scholar 

  • Kurz T, Terman A, Gustafsson B, Brunk UT (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem Cell Biol 129:389–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Labbadia J, Morimoto RI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lapointe J, Hekiimi S (2010) When a theory of aging ages badly. Cell Mol Life Sci 67:1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavie L, Reznick AZ, Gershon D (1982) Decreased protein and puromycinyl-peptide degradation in livers of senescent mice. Biochem J 202:47–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG et al (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478

    Article  CAS  PubMed  Google Scholar 

  • Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S (2018) An epigenetic biomaker of aging for lifespan and healthspan. Aging (Albany NY) 10:573–591

    Article  Google Scholar 

  • Lindop PJ, Rotblat J (1961) Shortening of life and causes of death in mice exposed to a single whole-body dose of radiation. Nature 189:645–648

    Article  CAS  PubMed  Google Scholar 

  • Ljungquist B, Berg S, Lanke J, McClearn GE, Pedersen NL (1998) The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry. J Gerontol A Biol Sci Med Sci 53:M441–M446

    Article  CAS  PubMed  Google Scholar 

  • Logan A, Shabalina IG, Prime TA, Rogatti S, Kalinovich AV, Hartley RC et al (2014) In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice. Aging Cell 13:765–768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luft R, Landau BR (1995) Mitochondrial medicine. J Intern Med 238:405–421

    Article  CAS  PubMed  Google Scholar 

  • Martin GM (2012) Stochastic modulations of the pace and patterns of ageing: impacts on quasi-stochastic distributions of multiple geriatric pathologies. Mech Ageing Dev 133:107–111

    Article  PubMed  Google Scholar 

  • Martin I, Grotewiel MS (2006) Oxidative damage and age-related functional declines. Mech Ageing Dev 127:411–423

    Article  CAS  PubMed  Google Scholar 

  • Martin GM, Austad SN, Johnson TE (1996a) Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 13:25–34

    Article  CAS  PubMed  Google Scholar 

  • Martin GM, Ogburn CE, Colgin LM, Gown AM, Edland SD, Monnat RJ (1996b) Somatic mutations are frequent and increase with age in human kidney epithelial cells. Hum Mol Genet 5:215–221

    Article  CAS  PubMed  Google Scholar 

  • McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055

    Article  CAS  PubMed  Google Scholar 

  • Medawar PB (1952) An unsolved problem of biology. Lewis, London

    Google Scholar 

  • Medvedev ZA (1990) An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc 65:375–398

    Article  CAS  PubMed  Google Scholar 

  • Medvediev ZA (1962) Ageing at the molecular level and some speculation concerning maintaining the functioning of systems for replication of specific macromolecules. Colombia University Press, New York

    Google Scholar 

  • Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286:774–779

    Article  CAS  PubMed  Google Scholar 

  • Miquel J, Economos AC, Fleming J, Johnson JE (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591

    Article  CAS  PubMed  Google Scholar 

  • Mori N, Mizuno D, Goto S (1979) Conservation of ribosomal fidelity during ageing. Mech Ageing Dev 10:379–398

    Article  CAS  PubMed  Google Scholar 

  • Mori N, Hiruta K, Funatsu Y, Goto S (1983) Codon recognition fidelity of ribosomes at the first and second positions does not decrease during aging. Mech Ageing Dev 22:1–10

    Article  CAS  PubMed  Google Scholar 

  • Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE (2012) The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 12(2):661–684

    Article  PubMed  CAS  Google Scholar 

  • Nakamura A, Goto S (1996) Analysis of protein carbonyls with 2,4-dinitrophenyl hydrazine and its antibodies by immunoblot in two-dimensional gel electrophoresis. J Biochem 119:768–774

    Article  CAS  PubMed  Google Scholar 

  • Nagy I (1986) Memorial lecture: Verzár’s ideas on the age-dependent protein cross-linking in the light of the present knowledge. Arch Gerontol Geriatr 5:267–280

    Article  CAS  PubMed  Google Scholar 

  • Nakamoto H, Kaneko T, Tahara S, Hayashi E, Naito H, Radak Z, Goto S (2007) Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats. Exp Gerontol 42:287–295

    Article  CAS  PubMed  Google Scholar 

  • Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T et al (2013) Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123:3272–3291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ngo JK, Pomatto LC, Davies KJ (2013) Upregulation of the mitochondrial Lon protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging. Redox Biol 1:258–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oblak L, van der Zaag J, Higgins-Chen AT, Levine ME, Boks MP (2021) A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Res Rev 69:101348. https://doi.org/10.1016/j.arr.2021.101348

    Article  CAS  PubMed  Google Scholar 

  • Ogrodnik JP, Wulf JH, Cutler RG (1975) Altered protein hypothesis of mammalian ageing processes-II. Discrimination ratio of methionine vs ethionine in the synthesis of ribosomal protein and RNA of C57BL/6J mouse liver. Exp Gerontol 10:119–136

    Article  CAS  PubMed  Google Scholar 

  • Ono T, Cutler RG (1978) Age-dependent relaxation of gene repression: increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice. Proc Natl Acad Sci U S A 75:4431–4435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orgel LE (1963) The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proc Natl Acad Sci USA 49:517–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Partridge L, Gems D (2002) Mechanisms of ageing: public or private? Nat Rev Genet 3:165–175

    Article  CAS  PubMed  Google Scholar 

  • Pearl R (1928) The rate of living. Knopf, New York

    Google Scholar 

  • Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756

    Article  CAS  PubMed  Google Scholar 

  • Pérez VI, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y et al (2009) Is the oxidative stress theory of aging dead? Biochim Biophys Acta 1790:1005–1014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pickering AM, Lehr M, Gendron CM, Pletcher SD, Miller RA (2017) Mitochondrial thioredoxin reductase 2 is elevated in long-lived primate as well as rodent species and extends fly mean lifespan. Aging Cell 16:683–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radák Z, Kaneko T, Tahara S, Nakamoto H, Pucsok J, Sasvári M et al (2001) Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem Int 38:17–23

    Article  PubMed  Google Scholar 

  • Radák Z, Chung HY, Goto S (2005) Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology 6:71–75

    Article  PubMed  CAS  Google Scholar 

  • Raj K, Horvath S (2020) Current perspectives on the cellular and molecular features of epigenetic ageing. Exp Biol Med (Maywood) 245:1532–1542

    Article  CAS  Google Scholar 

  • Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20:709–711

    Article  CAS  PubMed  Google Scholar 

  • Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106:8665–8670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robert L (2006) Fritz Verzár was born 120 years ago: his contribution to experimental gerontology through the collagen research as assessed after half a century. Arch Gerontol Geriatr 43:13–43

    Article  PubMed  Google Scholar 

  • Rothstein M (1981) Posttranslational alteration o proteins. CRC Press, Boca Raton

    Google Scholar 

  • Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695

    Article  CAS  PubMed  Google Scholar 

  • Ryan CP (2021) “Epigenetic clocks”: theory and applications in human biology. Am J Hum Biol 33:e23488. https://doi.org/10.1002/ajhb.23488

    Article  PubMed  Google Scholar 

  • Sadowska-Bartosz I, Bartosz G (2014) Effect of antioxidants supplementation on aging and longevity. Biomed Res Int 2014:404680. https://doi.org/10.1155/2014/404680. Epub 2014 Mar 25. PMID: 24783202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saez I, Vilchez D (2014) The mechanistic links between proteasome activity, aging and age-related diseases. Curr Genom 15:38–51

    Article  CAS  Google Scholar 

  • Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M et al (2011) Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A 108:4135–4140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911

    Article  CAS  PubMed  Google Scholar 

  • Schubert U, Antón LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    Article  CAS  PubMed  Google Scholar 

  • Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6:280–293

    Article  CAS  PubMed  Google Scholar 

  • Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326:140–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibatani T, Nazir M, Ward WF (1996) Alteration of rat liver 20S proteasome activities by age and food restriction. J Gerontol A Biol Sci Med Sci 51:B316–B322

    Article  CAS  PubMed  Google Scholar 

  • Silber JR, Fry M, Martin GM, Loeb LA (1985) Fidelity of DNA polymerases isolated from regenerating liver chromatin of aging Mus musculus. J Biol Chem 260:1304–1310

    Article  CAS  PubMed  Google Scholar 

  • Somel M, Khaitovich P, Bahn S, Pääbo S, Lachmann M (2006) Gene expression becomes heterogeneous with age. Curr Biol 16:R359–R360

    Article  CAS  PubMed  Google Scholar 

  • Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P et al (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3:87–95

    Article  CAS  PubMed  Google Scholar 

  • Stadtman ER (1988) Protein modification in aging. J Gerontol 43:B112–B120

    Article  CAS  PubMed  Google Scholar 

  • Stadtman ER (1993) Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Annu Rev Biochem 62:797–821

    Article  CAS  PubMed  Google Scholar 

  • Stefani M (2004) Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world. Biochim Biophys Acta 1739:5–25

    Article  CAS  PubMed  Google Scholar 

  • St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790

    Article  CAS  PubMed  Google Scholar 

  • Strehler BL (1977) Time, cells and aging. Academic, New York

    Google Scholar 

  • Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E et al (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68:6–16

    Article  CAS  PubMed  Google Scholar 

  • Subba Rao K, Martin GM, Loeb LA (1985) Fidelity of DNA polymerase-beta in neurons from young and very aged mice. J Neurochem 45:1273–1278

    Article  CAS  PubMed  Google Scholar 

  • Szilard L (1959) On the nature of the aging process. Proc Natl Acad Sci U S A 45:30–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi R, Goto S (1988) Fidelity of aminoacylation by rat-liver tyrosyl-tRNA synthetase. Effect of age. Eur J Biochem 178:381–386

    Article  CAS  PubMed  Google Scholar 

  • Takahashi R, Goto S (1990) Alteration of aminoacyl-tRNA synthetase with age: heat-labilization of the enzyme by oxidative damage. Arch Biochem Biophys 277:228–233

    Article  CAS  PubMed  Google Scholar 

  • Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A (2013) Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis 2:1–14

    PubMed  PubMed Central  Google Scholar 

  • Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–423

    Article  CAS  PubMed  Google Scholar 

  • Van Remmen H, Ward WF, Sabia RV, Richardson A (1995) Gene expression and protein degradation. Oxford University Press, New York

    Book  Google Scholar 

  • Vaupel JW, Carey JR, Christensen K, Johnson TE, Yashin AI, Holm NV et al (1998) Bio-demographic trajectories of longevity. Science 280:855–860

    Article  CAS  PubMed  Google Scholar 

  • Vijg J, Campisi J (2008) Puzzles, promises and a cure for ageing. Nature 454:1065–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vijg J, Suh Y (2013) Genome instability and aging. Annu Rev. Physiol 75:645–668

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Scheffler K, Esbensen Y, Strand JM, Stewart JB, Bjørås M et al (2014) Addressing RNA integrity to determine the impact of mitochondrial DNA mutations on brain mitochondrial function with age. PLoS One 9:e96940

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2:a006734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zahn JM, Poosala S, Owen AB, Ingram DK, Lustig A, Carter A et al (2007) AGEMAP: a gene expression database for aging in mice. PLoS Genet 3:e201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Health and Sports Science & Medicine, Juntendo University Graduate School, Chiba, Japan

    Sataro Goto

  2. Department of Aging Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Sataro Goto

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  1. Sataro Goto
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Correspondence to Sataro Goto .

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  1. Fukuoka International University of Health and Welfare, Fukuoka, Japan

    Nozomu Mori

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Goto, S. (2022). An Unsolved Problem in Gerontology Yet: Molecular Mechanisms of Biological Aging—A Historical and Critical Overview. In: Mori, N. (eds) Aging Mechanisms II . Springer, Singapore. https://doi.org/10.1007/978-981-16-7977-3_1

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