ÿþ<html xmlns:v="urn:schemas-microsoft-com:vml" xmlns:o="urn:schemas-microsoft-com:office:office" xmlns="http://www.w3.org/TR/REC-html40"> <head> <meta name="keywords" content="ageing, biological theories, gerontology, longevity, senescence, evolution"> <meta name="GENERATOR" content="Microsoft FrontPage 5.0"> <meta name="ProgId" content="FrontPage.Editor.Document"> <meta http-equiv="Content-Type" content="text/html; charset=windows-1252"> <title>Aging Theory History and Chronology</title> <style> <!-- p.MsoNormal {mso-style-parent:""; margin-bottom:.0001pt; font-size:12.0pt; font-family:"Times New Roman"; margin-left:0in; margin-right:0in; margin-top:0in} li.MsoNormal {mso-style-parent:""; margin-bottom:.0001pt; font-size:12.0pt; font-family:"Times New Roman"; margin-left:0in; margin-right:0in; margin-top:0in} --> </style> </head> <body> <p class="MsoNormal" style="margin-left: .5in"><span style="font-size: 28.0pt"> &nbsp; </span></p> <div align="center"> <center> <table border="0" cellpadding="0" cellspacing="0" style="border-collapse: collapse" bordercolor="#111111" width="88%"> <tr> <td width="18%"><span style="font-size: 28.0pt"> <a href="http://www.programmed-aging.org/"> <img border="0" src="http://www.programmed-aging.org/photo11.jpg" width="135" height="134" alt="Programmed Aging Theory Information"></a></span><p>&nbsp;</td> <td width="82%"><span style="font-size:26.0pt">Aging Theories -- Historical Chronology of Theories and Discoveries</span></td> </tr> </table> </center> </div> <P ALIGN="justify"> <TABLE BORDER="1" BGCOLOR="white" CELLPADDING="5" WIDTH="100%" bordercolordark="#000000" style="border-collapse: collapse" bordercolor="#111111" cellspacing="0"> <COLGROUP SPAN="3" ALIGN="center"> </COLGROUP> <TR> <TD WIDTH="25%"><B><FONT COLOR="red">Traditional evolutionary mechanics theories and dependent non-adaptive aging theories</FONT> <TD WIDTH="25%"><B><FONT COLOR="red">Alternative evolutionary mechanics theories and dependent adaptive aging theories</FONT> <TD WIDTH="25%"><b>Experimental evidence applicable to aging theory</b><TR> <TD>Before Darwin - Some believe organisms gradually wear out and deteriorate in the same manner as non-living things<TD>Before Darwin - No evidence that origin of life span different from any other organism characteristic that differs between species, i.e. organisms appear to be designed to have a species-specific life span<BR> <TD><BR> <TR> <TD>1859 Darwin's evolutionary mechanics theory proposes that the force of evolutionary selection is toward the longest possible life span and maximal reproductive capacity, i.e. immortality<TD>&nbsp;<TD>&nbsp;<TR> <TD>1859+ - Darwin’s critics note the contradiction between the Darwinian concept of natural selection favoring individuals with maximal survival and reproductive capacity and the observed progressive decline of vital and reproductive capacities, i.e. a limited life span that differed greatly between similar species (see <A HREF="#Goldsmith 2004">Goldsmith 2004</A>) <TD>1859+ - Darwin suggests that a limited life span must convey some unknown benefit that offset its otherwise adverse effect. He did not specify the nature of the benefit. (see <A HREF="#Goldsmith 2004">Goldsmith 2004</A>) <TD><BR> <TR> <TD><BR> <TD>1889 - Weismann hints that the death of old individuals was beneficial because this gave more space to new generations and that this was useful for the evolution of species (<A HREF="#Weismann 1889">Weismann 1889</A>; see <A HREF="#Kirkwood & Cremer 1982">Kirkwood & Cremer 1982</A>) <TD>1889 - Weismann observes that the cells of the various organs and tissues are renewed continuously and that when this turnover slackens or stops, the organs or the tissues reduce or lose their functionality with negative effects on fitness (see <A HREF="#Kirkwood & Cremer 1982">Kirkwood & Cremer 1982</A>) <TR> <TD><BR> <TD>1892 - Weismann disavows his 1889 idea (<A HREF="#Weismann 1892">Weismann 1892</A>; see <A HREF="#Kirkwood & Cremer 1982">Kirkwood & Cremer 1982</A>) <TD><BR> <TR> <TD>- Wear and tear hypotheses and stochastic hypothesis about aging (reviews of these hypotheses in: <A HREF="#Kowald & Kirkwood 1996">Kowald & Kirkwood 1996</A>; <A HREF="#Kirkwood & Kowald 1997">Kirkwood & Kowald 1997</A>; <A HREF="#Kirkwood 1998">Kirkwood 1998</A>, <A HREF="#Kirkwood 2002">2002</A>; <A HREF="#Fossel 2004">Fossel 2004</A>) <TD><BR> <TD>1913 - Carrel "demonstrates" that cells explanted and cultivated <i>in vitro</i> multiplied an unlimited number of times and so Weissmann’s hypothesis is unacceptable (<A HREF="#Carrel 1913">Carrel 1913</A>) <TR> <TD>1945+ - Modern synthesis and neo-Darwinism codify traditional mechanics theory <TD><BR> <TD><BR> <TR> <TD>1952+ - Mutation accumulation theory (<A HREF="#Medawar 1952">Medawar 1952</A>; <A HREF="#Hamilton 1966">Hamilton 1966</A>; <A HREF="#Edney & Gill 1968">Edney & Gill 1968</A>; <A HREF="#Mueller 1987">Mueller 1987</A>; <A HREF="#Partridge & Barton 1993">Partridge & Barton 1993</A>) <TD><BR> <TD><BR> <TR> <TD>1957+ - Antagonistic pleiotropy theory (<A HREF="#Williams 1957">Williams 1957</A>; <A HREF="#Rose 1991">Rose 1991</A>) <TD><BR> <TD><BR> <TR> <TD><BR> <TD><BR> <TD>1961+ - Discovery of cell limits in duplication ("Hayflick limit") (<A HREF="#Hayflick & Moorhead 1961">Hayflick & Moorhead 1961</A>; <A HREF="#Hayflick 1965">Hayflick 1965</A>; <A HREF="#Schneider & Mitsui 1976"> Schneider & Mitsui 1976</A>) <TR> <TD><BR> <TD>1962+ - Group selection theory (<A HREF="#Wynne-Edwards 1962">Wynne-Edwards 1962,</A><A HREF="#Wynne-Edwards 1986"> 1986</A>) <TD><BR> <TR> <TD><BR> <TD>1964+ - Kin selection theory (<A HREF="#Hamilton 1964">Hamilton 1964</A>; <A HREF="#Hamilton 1970">Hamilton 1970</A>; <A HREF="#Trivers 1971">Trivers 1971</A>; <A HREF="#Trivers & Hare 1976">Trivers & Hare 1976</A>; <A HREF="#Wilson 1975">Wilson 1975</A>) <TD><BR> <TR> <TD><BR> <TD><BR> <TD>1972 - "Apoptosis" phenomenon is described (<A HREF="#Kerr et al. 1972">Kerr et al. 1972</A>) <TR> <TD><BR> <TD><BR> <TD>1972 - DNA polymerase cannot replicate a whole molecule of DNA and a little part of an end of the molecule is unreplicated at each duplication (<A HREF="#Watson 1972">Watson 1972</A>) <TR> <TD><BR> <TD><BR> <TD>1973 - Olovnikov hypothesizes that the shortening of DNA molecule at each duplication after a certain number of times blocks cell replication capacity, i.e. determines Hayflick limit (<A HREF="#Olovnikov 1973">Olovnikov 1973</A>) <TR> <TD>1977+ - Disposable soma theory (<A HREF="#Kirkwood 1977">Kirkwood 1977</A>; <A HREF="#Kirkwood & Holliday 1979">Kirkwood & Holliday 1979</A>) <TD><BR> <TD>1977 - Discovery of complex octopus suicide mechanism (<A HREF="#Wodinsky 1977">Wodinsky 1977</A>) <TR> <TD><BR> <TD>1979+ - Many examples of animals that do not show age-related increasing mortality are documented (<A HREF="#Comfort 1979">Comfort 1979</A>; <A HREF="#Finch 1990">Finch 1990</A>) <TD><BR> <TR> <TD><BR> <TD><BR> <TD>1980+ - Programmed cell death by apoptosis, selectively triggered for some cells in specific times, causes cell turnover in healthy adult organs (<A HREF="#Wyllie et al. 1980">Wyllie et al. 1980</A>; <A HREF="#Lynch et al. 1986">Lynch et al. 1986</A>; <A HREF="#Israels & Israels 1999">Israels & Israels 1999</A>; <A HREF="#Medh & Thompson 2000">Medh & Thompson 2000</A>) (as documented for many tissues and organs: see <A HREF="#Libertini 2006">Libertini 2006</A>)<TR> <TD><BR> <TD>1983+ - Kin selection based aging theory (<A HREF="#Libertini 1983">Libertini 1983</A>, <A HREF="#Libertini 1988"> 1988</A>, <A HREF="#Libertini 2006"> 2006</A>, <A HREF="#Libertini 2009a"> 2009a</A>) <TD>1983+ - The final incapability of a cell to duplicate (replicative senescence) is shown to be not an abrupt event but a progressive reduction of cell duplication potential which depends on the reduction of telomere length (<A HREF="#Pontèn et al. 1983">Pontèn et al. 1983</A>; <A HREF="#Jones et al. 1985">Jones et al. 1985</A>) <TR> <TD><BR> <TD><BR> <TD>1985 - Discovery of telomerase, an enzyme capable of adding new segments of telomeric repetitive sequence (<A HREF="#Greider & Blackburn 1985">Greider & Blackburn 1985</A>) <TR> <TD><BR> <TD><BR> <TD>1990 - Telomere shortening at each replication is demonstrated (<A HREF="#Harley et al. 1990">Harley et al. 1990</A>) <TR> <TD><BR> <TD><BR> <TD>1990 - Various alternatives to aging in its common definition (i.e., age-related increasing mortality) are documented (<A HREF="#Finch 1990">Finch 1990</A>) <TR> <TD><BR> <TD><BR> <TD>1991 - Telomere is shown to be a highly conserved repetitive sequence (<A HREF="#Blackburn 1991">Blackburn 1991</A>) <TR> <TD>&nbsp;<TD>&nbsp;<TD>1991 - A review of studies on decreasing survival in laboratory conditions at ages not existing in the wild and for species that in the wild do not show age-related fitness decline (<A HREF="#Rose 1991">Rose 1991</A>) <TR> <TD>&nbsp;<TD>&nbsp;<TD>- 1993+ - Various studies prove that "aging" in <i>C. elegans</i> is influenced strongly by many genes (<A HREF="#Kenyon et al. 1993">Kenyon et al. 1993</A>; <A HREF="#Dorman et al. 1995">Dorman et al. 1995</A>; see other studies at: <a href="http://www.programmed-aging.org/theory-3/kenyon.html">http://www.programmed-aging.org/theory-3/kenyon.html</a>) <TR> <TD><BR> <TD>1996+ - Evolvability theories (<A HREF="#Wagner & Altenberg 1996">Wagner & Altenberg 1996</A>) <TD><BR> <TR> <TD>1997+ - To justify evolutionarily their existence, replicative senescence, cell senescence and, in general, the limits imposed by telomere-telomerase system are hypothesized as a general defense against cancer (<A HREF="#Campisi 1997">Campisi 1997</A>, <A HREF="#Campisi 2000">2000</A>; <A HREF="#Wright & Shay 2005">Wright & Shay 2005</A>). <TD>1997+ - Evolvability-based aging theories (<A HREF="#Skulachev 1997">Skulachev 1997</A>; <A HREF="#Goldsmith 2003">Goldsmith 2003</A>, <A HREF="#Goldsmith 2004">2004</A>, <A HREF="#Goldsmith 2006">2006</A>, <A HREF="#Goldsmith 2008">2008</A>) <TD>1997+ - "Proapoptosis" (<A HREF="#Hochman 1997">Hochman 1997</A>), a form of eubacterial cell suicide, is shown to be clearly related to eukaryotic apoptosis (<A HREF="#Koonin & Aravind 2002">Koonin & Aravind 2002</A>) and this indicates a very old evolutionary persistence and similarity <TR> <TD><BR> <TD><BR> <TD>1997+ - Description of an apoptosis-like phenomenon in yeast (<A HREF="#Madeo et al. 1997">Madeo et al. 1997</A>), elicited by factors present in multicellular organisms (<A HREF="#Longo et al. 1997">Longo et al. 1997</A>; <A HREF="#Ligr et al. 1998">Ligr et al. 1998</A>) <TR> <TD>1998 - A well-publicized study claims to discern a cost of reproduction in a historic database of British nobility, thus supporting Disposable Soma theory (<A HREF="#Westendorp & Kirkwood 1998">Westendorp & Kirkwood 1998</A>) <TD><BR> <TD>1998 - Old Lobsters and rainbow trouts, “animals with negligible senescence”, are shown to have, in the wild, the same levels of telomerase activity as young individuals (<A HREF="#Klapper, Heidorn et al. 1998">Klapper, Heidorn et al. 1998</A>; <A HREF="#Klapper, Kuhne et al. 1998">Klapper, Kuhne et al. 1998</A>) <TR> <TD><BR> <TD><BR> <TD>1998 - Telomerase introduction in somatic cells makes them able to innumerable duplications and reverts manifestations of cell senescence (<A HREF="#Bodnar et al. 1998">Bodnar et al. 1998</A>, <A HREF="#Counter et al. 1998">Counter et al. 1998 </A>, <A HREF="#Vaziri & Benchimol 1998">Vaziri & Benchimol 1998</A>, <A HREF="#de Lange & Jacks 1999">de Lange & Jacks 1999</A>) <TR> <TD><BR> <TD>1998+ - Ricklefs documents an inverse relation between extrinsic and intrinsic mortality in natural conditions (<A HREF="#Ricklefs 1998">Ricklefs 1998</A>, <A HREF="#Ricklefs 2008">2008)</A>) <TD>1998+ - Inactivated telomerase and short telomeres increase the probability of apoptosis (<A HREF="#Ozen et al. 1998">Ozen et al. 1998</A>; <A HREF="#Seimiya et al. 1999">Seimiya et al. 1999</A>; <A HREF="#Holt et al. 1999">Holt et al. 1999</A>; <A HREF="#Ren et al. 2001">Ren et al. 2001</A>; <A HREF="#Fossel 2004">Fossel 2004</A>) <TR> <TD><BR> <TD>1999 - The death of an individual, when not determined by accidents or diseases and as event provoked by particular mechanisms genetically regulated, namely programmed, and therefore somehow favoured by natural selection, is defined for the first time by a specific neologism, "phenoptosis" (<A HREF="#Skulachev 1999">Skulachev 1999</A>) <TD>1999+ - For yeast apoptosis-like phenomenon a common phylogenetic origin with apoptosis in multicellular eukaryotes is indicated (<A HREF="#Madeo et al. 1999">Madeo et al. 1999</A>; <A HREF="#Longo et al. 2005">Longo et al. 2005</A>; <A HREF="#Kaeberlein et al. 2007">Kaeberlein et al. 2007</A>) <TR> <TD><BR> <TD><BR> <TD>1999+ - Apoptotic patterns in yeast are interpreted as adaptive because they are useful to the survival of the clone, which is likely made up of kin individuals (<A HREF="#Skulachev 1999">Skulachev 1999</A>, <A HREF="#Skulachev 2002">2002</A>, <A HREF="#Skulachev 2003">2003</A>; <A HREF="#Fabrizio et al. 2004">Fabrizio et al. 2004</A>; <A HREF="#Longo et al. 2005">Longo et al. 2005</A>; <A HREF="#Skulachev & Longo 2005">Skulachev & Longo 2005</A>; <A HREF="#Mitteldorf 2006b">Mitteldorf 2006b</A>) <TR> <TD>2000 - Kirkwood & Austad quote Ricklefs' 1998 data as supporting non-adaptive aging theories without realizing that the contrary is true, as stated by the same Ricklefs (<A HREF="#Kirkwood & Austad 2000">Kirkwood & Austad 2000</A>) <TD><BR> <TD>2000 - A too short telomere length does not allow further replications (<A HREF="#Shay & Wright 2000">Shay & Wright 2000</A>) <TR> <TD>2000 - Shanley and Kirkwood formulate a Disposable Soma model in mice that try to explain the effects of calorie restriction on aging (<A HREF="#Shanley & Kirkwood 2000">Shanley & Kirkwood 2000"</A>) <TD><BR> <TD>2000- Blackburn’s model explains the graduality of cell senescence in a culture (<A HREF="#Blackburn 2000">Blackburn 2000</A>) <TR> <TD><BR> <TD><BR> <TD>2000+ - When telomeres are shortened, there is a great vulnerability to cancer as a consequence of dysfunctional telomere-induced instability (<A HREF="#DePinho 2000">DePinho 2000</A>; <A HREF="#Artandi 2002">Artandi 2002</A>) <TR> <TD><BR> <TD>2001 -Mitteldorf shows that the Shanley & Kirkwood 2000 model is hardly tenable (<A HREF="#Mitteldorf 2001">Mitteldorf 2001</A>) <TD><BR> <TR> <TD>2002 - Historical hypothesis (<A HREF="#De Magalhães & Toussaint 2002">De Magalhães & Toussaint 2002</A>) <TD><BR> <TD><BR> <TR> <TD>2004 - Vaupel et al. try to explain negative senescence with non-adaptive theories (<A HREF="#Vaupel et al. 2004">Vaupel et al. 2004</A>) <TD><BR> <TD>2004 - Telomere shortening is related to the progressive decay of cell functions (cell senescence) and to the progressive reduction of cell duplication capacities (replicative senescence) (Fossel’s “cell senescence limited model”) (<A HREF="#Fossel 2004">Fossel 2004</A>) <TR> <TD><BR> <TD>2004+ - The hypothesis that replicative senescence, cell senescence and telomere-telomerase system are a general defence against cancer is challenged (<A HREF="#Fossel 2004">Fossel 2004</A>; <A HREF="#Libertini 2006">Libertini 2006</A>, <A HREF="#Libertini 2009a">2009a</A>, <A HREF="#Libertini 2009b">2009b</A>) <TD>2004+ - Cell senescence, replicative senescence and aging are related (Fossel’s "cell senescence general model" of aging) (<A HREF="#Fossel 2004">Fossel 2004</A>; <A HREF="#Libertini 2006">Libertini 2006</A>, <A HREF="#Libertini 2009a">2009a</A>, <A HREF="#Libertini 2009b"> 2009b</A>) <TR> <TD><BR> <TD><BR> <TD>2005 - Cell senescence is defined as a "fundamental cellular program" (<A HREF="#Ben-Porath & Weinberg 2005">Ben-Porath & Weinberg 2005</A>) as the changes that define it are stereotyped and predictable. Replicative senescence is part of cell senescence phenomenon. The degree of senescence of a culture is determined by the fraction of cells in cell senescence state. <TR> <TD><BR> <TD>2006 - Libertini underlines the contradiction between Ricklefs' data and traditional aging hypotheses (<A HREF="#Libertini 2006">Libertini 2006</A>) <TD><BR> <TR> <TD><BR> <TD>2006 - Group selection based aging theory (<A HREF="#Mitteldorf 2006a">Mitteldorf 2006a</A>) <TD><BR> <TR> <TD><BR> <TD>2007 - In a meta-analysis of 115 studies, the antioxidant supplements were significantly associated with increased mortality, in strong contradiction with ROS theories of aging (<A HREF="#Bjelakovic et al. 2007">Bjelakovic et al. 2007</A>) <TD><BR> <TR> <TD><BR> <TD>2008 - The empirical evidence in support of adaptive theories of aging and against non-adaptive hypotheses is highlighted (<A HREF="#Libertini 2008">Libertini 2008</A>) <TD><BR> <TR> <TD><BR> <TD>2009 - Westendorp & Kirkwood 1998 study is shown to have used an inappropriate statistical test while standard linear correlation on the same database reveals a positive correlation, thus falsifying Disposable Soma theory (<A HREF="#Mitteldorf 2009">Mitteldorf 2009</A>) <TD><BR> <TR> <TD><BR> <TD>2009 - Evolutionary classification of diseases and of disease-like phenomena (as aging). Definition of a research program to master aging with the modification of its physiological mechanisms (<A HREF="#Libertini 2009b">Libertini 2009b</A>) <TD><BR> <TR> <TD><BR> <TD>2010 - Strong empirical and theoretical arguments in support of ageing adaptive theories: "Several lines of evidence suggest that [telomere-cell senescence system] was selected first and foremost to cause ageing" (<A HREF="#Milewski 2010">Milewski 2010</A>) <TD><BR> <TR> <TD><BR> <TD>2010 - Age-related fitness decline is defined "slow phenoptosis" (<A HREF="#Skulachev 2010">Skulachev 2010</A>) <TD><BR> <TR> <TD>2010 - Most gerontologists continue to believe non-adaptive aging theories <TD>2010 - Extensive and increasing interest in alternative mechanics but no consensus. Steadily increasing observational evidence for adaptive aging theories <TD>2010 - Telomerase reactivation in aged mice with artificially blocked telomerase shows a marked reversal of degenerative manifestations, even for nervous system (<A HREF="#Jaskelioff et al. 2010">Jaskelioff et al. 2010</A>) <TR> <TD><BR> <TD><BR> <TD>2011 - The first (prudent) attempt of a mild stimulation of telomerase activity to preserve health conditions (<A HREF="#Harley et al. 2011">Harley et al. 2011</A>) </TABLE> <p><BR> <B>References</B><BR> <A NAME="Artandi 2002">-</A> Artandi, S.E. (2002) Telomere shortening and cell fates in mouse models of neoplasia. <i>Trends Mol. Med.</i> 8(1):44-47. <A HREF="http://www.ncbi.nlm.nih.gov/pubmed/11796266">[PubMed]</A> <A HREF="http://scholar.google.com/scholar?hl=en&q=artandi+telomere+shortening+neoplasia&btnG=Cerca&as_ylo=&as_vis=0">[Google Scholar]</A><BR> <A NAME="#Ben-Porath & Weinberg 2005">-</A> Ben-Porath, I. & Weinberg, R. 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