Abstract
Imperfect autophagic degradation of oxidatively damaged macromolecules and organelles (so-called biological “garbage”) is considered an important contributor to ageing and consequent death of postmitotic (non-dividing) cells, such as neurons and cardiac myocytes. In contrast, proliferating cells apparently escape senescence by a continuous dilution and repair of damaged structures during division. Postmitotic ageing can be mimicked and studied in cultures of potentially dividing cells if their mitotic activity is inhibited. To test the “garbage accumulation” theory of ageing, we compared survival of density-dependent growth-arrested (confluent) and proliferating human fibroblasts and astrocytes following inhibition of autophagic sequestration with 3-methyladenine (3MA). Exposure of confluent fibroblast cultures to 3MA for two weeks resulted in a significantly increased proportion of dying cells compared to both untreated confluent cultures and dividing cells with 3MA-inhibited autophagy. Similar results were obtained when autophagic degradation was suppressed by the protease inhibitor leupeptin. In 3MA- or leupeptin-exposed cultures, dying cells were overloaded with undegraded autofluorescent material. The results support a key role of biological lysosomal “garbage” accumulation in the triggering of ageing and death of postmitotic cells, as well as the anti-ageing role of cell division.
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References
BN Ames LS Gold (1990) ArticleTitleToo many rodent carcinogens: mitogenesis increases mutagenesis Science 249 970–971
KB Beckman BN Ames (1998) ArticleTitleThe free radical theory of aging matures Physiol Rev 78 547–581
E Bergamini G Cavallini A Donati Z Gori (2003) ArticleTitleThe anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically Biomed Pharmacother 57 203–208
EF Blommaart U Krause JP Schellens H Vreeling-Sindelarova AJ Meijer (1997) ArticleTitleThe phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes Eur J Biochem 243 240–246
UT Brunk A Terman (2002) ArticleTitleLipofuscin: mechanisms of age-related accumulation and influence on cell functions Free Radic Biol Med 33 611–619
UT Brunk A Terman (2002) ArticleTitleThe mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis Eur J Biochem 269 1996–2002
FM Burnet (1973) ArticleTitleA genetic interpretation of ageing Lancet 2 480–483
E Cadenas KJ Davies (2000) ArticleTitleMitochondrial free radical generation, oxidative stress, and aging Free Radic Biol Med 29 222–230
J Campisi (1996) ArticleTitleReplicative senescence: an old lives’ tale? Cell 84 497–500
J Campisi (2000) ArticleTitleCancer, aging and cellular senescence In Vivo 14 183–188
AD Grey Particlede (2002) ArticleTitleBioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome Trends Biotechnol 20 452–455
J Fonager R Beedholm BF Clark SI Rattan (2002) ArticleTitleMild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro Exp Gerontol 37 1223–1228
LM Gerland L Genestier S Peyrol MC Michallet S Hayette I Urbanowicz P Ffrench JP Magaud M Ffrench (2004) ArticleTitleAutolysosomes accumulate during in vitro CD8(+) T-lymphocyte aging and may participate in induced death sensitization of senescent cells Exp Gerontol 39 789–800
AL Goldberg (2003) ArticleTitleProtein degradation and protection against misfolded or damaged proteins Nature 426 895–899
T Grune K Merker G Sandig KJ Davies (2003) ArticleTitleSelective degradation of oxidatively modified protein substrates by the proteasome Biochem Biophys Res Commun 305 709–718
D Harman (1956) ArticleTitleAging: a theory based on free radical and radiation chemistry J Gerontol 211 298–300
HR Hirsch (1978) ArticleTitleThe waste-product theory of aging: waste dilution by cell division Mech Ageing Dev 8 51–62
GO Ivy F Schottler J Wenzel M Baudry G Lynch (1984) ArticleTitleInhibitors of lysosomal enzymes: accumulation of lipofuscin-like dense bodies in the brain Science 226 985–987
TB Kirkwood (1989) ArticleTitleDNA, mutations and aging Mutat Res 219 1–7
M Leist M Jaattela (2001) ArticleTitleFour deaths and a funeral: from caspases to alternative mechanisms Nat Rev Mol Cell Biol 2 589–598
RA Lockshin Z Zakeri (2004) ArticleTitleCaspase-independent cell death? Oncogene 23 2766–2773
DE Martinez (1998) ArticleTitleMortality patterns suggest lack of senescence in hydra Exp Gerontol 33 217–225
A Melendez Z Talloczy M Seaman EL Eskelinen DH Hall B Levine (2003) ArticleTitleAutophagy genes are essential for dauer development and life-span extension in C. elegans Science 301 1387–1391
LE Orgel (1973) ArticleTitleAgeing of clones of mammalian cells Nature 243 441–445
A Petiot E Ogier-Denis EF Blommaart AJ Meijer P Codogno (2000) ArticleTitleDistinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells J Biol Chem 275 992–998
AR Sheldrake (1974) ArticleTitleThe ageing, growth and death of cells Nature 250 381–385
RS Sohal BH Sohal (1991) ArticleTitleHydrogen peroxide release by mitochondria increases during aging Mech Ageing Dev 57 187–202
A Terman (2001) ArticleTitleGarbage catastrophe theory of aging: imperfect removal of oxidative damage? Redox Rep 6 15–26
A Terman N Abrahamsson UT Brunk (1999) ArticleTitleCeroid/lipofuscin-loaded human fibroblasts show increased susceptibility to oxidative stress Exp Gerontol 34 755–770
A Terman UT Brunk (1998) ArticleTitleCeroid/lipofuscin formation in cultured human fibroblasts: the role of oxidative stress and lysosomal proteolysis Mech Ageing Dev 104 277–291
Terman A and Brunk UT (2004) Aging as a catabolic malfunction. Int J Biochem Cell Biol 36 (in press)
A Terman H Dalen UT Brunk (1999) ArticleTitleCeroid/lipofuscin-loaded human fibroblasts show decreased survival time and diminished autophagocytosis during amino acid starvation Exp Gerontol 34 943–957
A Terman H Dalen JW Eaton J Neuzil UT Brunk (2003) ArticleTitleMitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis Exp Gerontol 38 863–876
P Verbeke J Fonager BF Clark SI Rattan (2001) ArticleTitleHeat shock response and ageing: mechanisms and applications Cell Biol Int 25 845–857
GF Weber J Daley SK Kraeft LB Chen H Cantor (1997) ArticleTitleMeasurement of apoptosis in heterogenous cell populations Cytometry 27 136–144
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Stroikin, Y., Dalen, H., Brunk, U.T. et al. Testing the “garbage” accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy. Biogerontology 6, 39–47 (2005). https://doi.org/10.1007/s10522-004-7382-y
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DOI: https://doi.org/10.1007/s10522-004-7382-y