The relationship between apoptosis and aging

DOI: 10.4236/abb.2012.326091   PDF   HTML     7,669 Downloads   12,951 Views   Citations


Apoptosis is involved in aging and age-related disease, with respect to aging, apoptosis acting in a celltype-specific manner. The rate of apoptosis is elevated in-most types of aging cell populations and organs. In stable cells and certain continuously dividing cells, apoptosisserves to eliminate presumably dysfunctional cellsthat show homeostatic failure due to oxidative stress, glycation, and DNA damage, thereby maintaining homeostasis in the body. What’smore, apoptosis, at least in part, plays some important role inthe regulation of aging process and anti-tumorigenesis in mammals. Age-enhanced apoptosis may be aninnateprotective mechanism against age-associated tumorigenesis. There is clear evidence to indicate that senescentcells are remarkably resistant to apoptosis. The intensity of global apoptosis and autophagy clearance significantly declines in humans during aging, as aging repress the apoptotic response. In this paper, we will review the relationship between apoptosis and aging, and outline how are they interact each other.

Share and Cite:

Lu, B. , Chen, H. and Hong-Guang, H. (2012) The relationship between apoptosis and aging. Advances in Bioscience and Biotechnology, 3, 705-711. doi: 10.4236/abb.2012.326091.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kerr, Wyllie, and Currie (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 4, 239-57.
[2] Verheij and Bartelink (2000) Radiation-induced apoptosis. Cell Tissue Res, 1, 133-42.
[3] Chen, Kang, Xia, Li, Yang, Chen, Sun, Song, Xiang, Wang, Wang, Wan, and Bi (2008) p53-related apoptosis resistance and tumor suppression activity in UVB-induced premature senescent human skin fibroblasts. Int J Mol Med, 5, 645-53.
[4] Lettre and Hengartner (2006) Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol, 2, 97-108.
[5] Pecina-Slaus (2010) Wnt signal transduction pathway and apoptosis: a review. Cancer Cell Int, 22.
[6] Oberdoerffer and Sinclair (2007) The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol, 9, 692-702.
[7] Fischer, Janicke, and Schulze-Osthoff (2003) Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ, 1, 76-100.
[8] Chipuk and Green (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol, 4, 157-64.
[9] Griner and Kazanietz (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer, 4, 281-94.
[10] Ramakrishna, Suresh, and Baek (2011) The role of deubiquitinating enzymes in apoptosis. Cell Mol Life Sci, 1, 15-26.
[11] Kurz, Terman, Gustafsson, and Brunk (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem Cell Biol, 4, 389-406.
[12] Estaquier, Vallette, Vayssiere, and Mignotte (2012) The mitochondrial pathways of apoptosis. Adv Exp Med Biol, 157-83.
[13] Freund, Orjalo, Desprez, and Campisi (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med, 5, 238-46.
[14] Circu and Aw (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med, 6, 749-62.
[15] Maiuri, Zalckvar, Kimchi, and Kroemer (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 9, 741-52.
[16] Harman (2001) Aging: overview. Ann N Y Acad Sci, 1-21.
[17] Rattan (2006) Theories of biological aging: genes, proteins, and free radicals. Free Radic Res, 12, 1230-8.
[18] Muller (2009) Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations. Antioxid Redox Signal, 1, 59-98.
[19] Weinert and Timiras (2003) Invited review: Theories of aging. J Appl Physiol, 4, 1706-16.
[20] Troen (2003) The biology of aging. Mt Sinai J Med, 1, 3-22.
[21] Salminen and Kaarniranta (2010) Genetics vs. entropy: longevity factors suppress the NF-kappaB-driven entropic aging process. Ageing Res Rev, 3, 298-314.
[22] Warner (1997) Aging and regulation of apoptosis. Curr Top Cell Regul, 107-21.
[23] Warner (1999) Apoptosis: a two-edged sword in aging. Ann N Y Acad Sci, 1-11.
[24] Higami and Shimokawa (2000) Apoptosis in the aging process. Cell Tissue Res, 1, 125-32.
[25] Muradian and Schachtschabel (2001) The role of apoptosis in aging and age-related disease: update. Z Gerontol Geriatr, 6, 441-6.
[26] Alt, Senst, Murthy, Slakey, Dupin, Chaffin, Kadowitz, and Izadpanah (2012) Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res, 2, 215-25.
[27] Wilson, Shehadeh, Yu, and Webster (2010) Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells. BMC Genomics, 229.
[28] Todd Allen, Robertson, Harwood, Sasho, Williams, Pomerleau, and Amiel (2004) Characterization of mature vs aged rabbit articular cartilage: analysis of cell density, apoptosis-related gene expression and mechanisms controlling chondrocyte apoptosis. Osteoarthritis Cartilage, 11, 917-23.
[29] Cao, Gollapudi, Sharman, Jia, and Gupta (2010) Age-related alterations of gene expression patterns in human CD8+ T cells. Aging Cell, 1, 19-31.
[30] Tyner, Venkatachalam, Choi, Jones, Ghebranious, Igelmann, Lu, Soron, Cooper, Brayton, Park, Thompson, Karsenty, Bradley, and Donehower (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature, 6867, 45-53.
[31] Maier, Gluba, Bernier, Turner, Mohammad, Guise, Sutherland, Thorner, and Scrable (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev, 3, 306-19.
[32] Tsujimoto (2003) Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol, 2, 158-67.
[33] Kujoth, Hiona, Pugh, Someya, Panzer, Wohlge-muth, Hofer, Seo, Sullivan, Jobling, Morrow, Van Remmen, Sedivy, Yamasoba, Tanokura, Weindruch, Leeuwenburgh, and Prolla (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science, 5733, 481-4.
[34] Gupta (2005) Molecular mechanisms of apoptosis in the cells of the immune system in human aging. Immunol Rev, 114-29.
[35] Johnstone, Ruefli, and Lowe (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell, 2, 153-64.
[36] Su, Kesslak, Head, and Cotman (2002) Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain. Acta Neuropathol, 1, 1-6.
[37] Bredesen, Rao, and Mehlen (2006) Cell death in the nervous system. Nature, 7113, 796-802.
[38] Mattson (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol, 2, 120-9.
[39] Soo, Atkin, Farg, Walker, Horne, and Nagley (2012) Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis. PLoS One, 4, e35413.
[40] Milnerwood, Kaufman, Sepers, Gladding, Zhang, Wang, Fan, Coquinco, Qiao, Lee, Wang, Cynader, and Raymond (2012) Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington's disease mice. Neurobiol Dis, 1, 40-51.
[41] Pollack, Phaneuf, Dirks, and Leeuwenburgh (2002) The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y Acad Sci, 93-107.
[42] Jejurikar, Henkelman, Cederna, Marcelo, Urbanchek, and Kuzon (2006) Aging increases the susceptibility of skeletal muscle derived satellite cells to apoptosis. Exp Gerontol, 9, 828-36.
[43] Zhang and Herman (2002) Ageing and apoptosis. Mech Ageing Dev, 4, 245-60.
[44] Proskuryakov, Gabai, Konoplyannikov, Zamulaeva, and Kolesnikova (2005) Immunology of apoptosis and necrosis. Biochemistry (Mosc), 12, 1310-20.
[45] Suh (2002) Cell signaling in aging and apoptosis. Mech Ageing Dev, 8, 881-90.
[46] Zhang, Hanks, Boucher, Florell, Allen, Alexander, Brash, and Grossman (2005) UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis, 1, 249-57.
[47] Rochette and Brash (2008) Progressive apoptosis resistance prior to senescence and control by the anti-apoptotic protein BCL-xL. Mech Ageing Dev, 4, 207-14.
[48] Rai, Tripathi, Sharma, and Shukla (2005) Apoptosis: a basic physiologic process in wound healing. Int J Low Extrem Wounds, 3, 138-44.
[49] Gosain and DiPietro (2004) Aging and wound healing. World J Surg, 3, 321-6.
[50] Ballas and Davidson (2001) Delayed wound healing in aged rats is associated with increased collagen gel remodeling and contraction by skin fibroblasts, not with differences in apoptotic or myofibroblast cell populations. Wound Repair Regen, 3, 223-37.
[51] DePinho (2000) The age of cancer. Nature, 6809, 248-54.
[52] Camplejohn, Gilchrist, Easton, McKenzie-Edwards, Barnes, Eccles, Ardern-Jones, Hodgson, Duddy, and Eeles (2003) Apoptosis, ageing and cancer susceptibility. Br J Cancer, 4, 487-90.
[53] Suh, Lee, Kim, Han, Vijg, and Park (2002) Aging alters the apoptotic response to genotoxic stress. Nat Med, 1, 3-4.
[54] Polyak, Wu, Hamilton, Kinzler, and Vogelstein (1997) Less death in the dying. Cell Death Differ, 3, 242-6.
[55] Bassi and Sacco (2009) Cancer and aging: the molecular pathways. Urol Oncol, 6, 620-7.
[56] Feng, Hu, Rajagopal, and Levine (2008) The tumor suppressor p53: cancer and aging. Cell Cycle, 7, 842-7.
[57] Vallon, Seidl, Blechert, Li, Gilbertz, Baumgart, Aichler, Feuchtinger, Gaertner, Bruchertseifer, Morgenstern, Walch, Senekowitsch-Schmidtke, and Essler (2012) Enhanced efficacy of combined (213)Bi-DTPA-F3 and paclitaxel therapy of peritoneal carcinomatosis is mediated by enhanced induction of apoptosis and G2/M phase arrest. Eur J Nucl Med Mol Imaging,
[58] Salom, Penalver, Homesley, Burrell, Garrett, Presant, Rutledge, Chernick, Hallquist, and Perree (2012) Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response. J Transl Med, 1, 162.
[59] Bosserman, Prendergast, Herbst, Fleisher, Salom, Strickland, Raptis, Hallquist, Perree, Rajurkar, Karimi, Rogers, Davidson, Willis, Penalver, Homesley, Burrell, Garrett, Rutledge, Chernick, and Presant (2012) The Microculture-Kinetic (MiCK) Assay: The Role of a Drug-Induced Apoptosis Assay in Drug Development and Clinical Care. Cancer Res,
[60] Herr and Debatin (2001) Cellular stress response and apoptosis in cancer therapy. Blood, 9, 2603-14.
[61] Kaufmann and Earnshaw (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res, 1, 42-9.
[62] Hornsby (2010) Senescence and life span. Pflugers Arch, 2, 291-9.
[63] Chondrogianni, Stratford, Trougakos, Friguet, Rivett, and Gonos (2003) Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J Biol Chem, 30, 28026-37.
[64] Spillare, Robles, Wang, Shen, Yu, Schellenberg, and Harris (1999) p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev, 11, 1355-60.
[65] Campisi and d'Adda di Fagagna (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol, 9, 729-40.
[66] Marcotte, Lacelle, and Wang (2004) Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech Ageing Dev, 10-11, 777-83.
[67] Jackson and Pereira-Smith (2006) p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res, 17, 8356-60.
[68] Chaturvedi, Qin, Stennett, Choubey, and Nickoloff (2004) Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53. J Cell Physiol, 1, 100-9.
[69] Hampel, Malisan, Niederegger, Testi, and Jansen-Durr (2004) Differential regulation of apoptotic cell death in senescent human cells. Exp Gerontol, 11-12, 1713-21.
[70] Labinskyy, Csiszar, Orosz, Smith, Rivera, Buffenstein, and Ungvari (2006) Comparison of endothelial function, O2-* and H2O2 production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole rat, and mice. Am J Physiol Heart Circ Physiol, 6, H2698-704.
[71] Chiarugi and Giannoni (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol, 11, 1352-64.
[72] Kavathia, Jain, Walston, Beamer, and Fedarko (2009) Serum markers of apoptosis decrease with age and cancer stage. Aging (Albany NY), 7, 652-63.
[73] Hinkal, Gatza, Parikh, and Donehower (2009) Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging. Mech Ageing Dev, 4, 262-71.
[74] Devitt and Marshall (2011) The innate immune system and the clearance of apoptotic cells. J Leukoc Biol, 3, 447-57.
[75] De Martinis, Franceschi, Monti, and Ginaldi (2007) Apoptosis remodeling in immunosenescence: implica-tions for strategies to delay ageing. Curr Med Chem, 13, 1389-97.
[76] Rajawat, Hilioti, and Bossis (2009) Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev, 3, 199-213.
[77] Salminen and Kaarniranta (2009) Regulation of the aging process by autophagy. Trends Mol Med, 5, 217-24.
[78] Young and Narita (2010) Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol, 2, 234-40.
[79] Young, Narita, Ferreira, Kirschner, Sadaie, Darot, Tavare, Arakawa, Shimizu, and Watt (2009) Autophagy mediates the mitotic senescence transition. Genes Dev, 7, 798-803.
[80] Marino, Ugalde, Salvador-Montoliu, Varela, Quiros, Cadinanos, van der Pluijm, Freije, and Lopez-Otin (2008) Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum Mol Genet, 14, 2196-211.
[81] Yang, Wang, He, Lu, Chen, Liu, and Shen (2010) Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells. Cardiovasc Diabetol, 66.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.