Programmed Aging Theory Information


Aging Theories -- Historical Chronology of Theories and Discoveries

Traditional evolutionary mechanics theories and dependent non-adaptive aging theories Alternative evolutionary mechanics theories and dependent adaptive aging theories Experimental evidence applicable to aging theory
Before Darwin - Some believe organisms gradually wear out and deteriorate in the same manner as non-living thingsBefore 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

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  
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 Goldsmith 2004) 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 Goldsmith 2004)

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 (Weismann 1889; see Kirkwood & Cremer 1982) 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 Kirkwood & Cremer 1982)

1892 - Weismann disavows his 1889 idea (Weismann 1892; see Kirkwood & Cremer 1982)
- Wear and tear hypotheses and stochastic hypothesis about aging (reviews of these hypotheses in: Kowald & Kirkwood 1996; Kirkwood & Kowald 1997; Kirkwood 1998, 2002; Fossel 2004)
1913 - Carrel "demonstrates" that cells explanted and cultivated in vitro multiplied an unlimited number of times and so Weissmann?s hypothesis is unacceptable (Carrel 1913)
1945+ - Modern synthesis and neo-Darwinism codify traditional mechanics theory

1952+ - Mutation accumulation theory (Medawar 1952; Hamilton 1966; Edney & Gill 1968; Mueller 1987; Partridge & Barton 1993)

1957+ - Antagonistic pleiotropy theory (Williams 1957; Rose 1991)

1961+ - Discovery of cell limits in duplication ("Hayflick limit") (Hayflick & Moorhead 1961; Hayflick 1965; Schneider & Mitsui 1976)

1962+ - Group selection theory (Wynne-Edwards 1962, 1986)

1964+ - Kin selection theory (Hamilton 1964; Hamilton 1970; Trivers 1971; Trivers & Hare 1976; Wilson 1975)

1972 - "Apoptosis" phenomenon is described (Kerr et al. 1972)

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 (Watson 1972)

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 (Olovnikov 1973)
1977+ - Disposable soma theory (Kirkwood 1977; Kirkwood & Holliday 1979)
1977 - Discovery of complex octopus suicide mechanism (Wodinsky 1977)

1979+ - Many examples of animals that do not show age-related increasing mortality are documented (Comfort 1979; Finch 1990)

1980+ - Programmed cell death by apoptosis, selectively triggered for some cells in specific times, causes cell turnover in healthy adult organs (Wyllie et al. 1980; Lynch et al. 1986; Israels & Israels 1999; Medh & Thompson 2000) (as documented for many tissues and organs: see Libertini 2006)

1983+ - Kin selection based aging theory (Libertini 1983, 1988, 2006, 2009a) 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 (Pontèn et al. 1983; Jones et al. 1985)

1985 - Discovery of telomerase, an enzyme capable of adding new segments of telomeric repetitive sequence (Greider & Blackburn 1985)

1990 - Telomere shortening at each replication is demonstrated (Harley et al. 1990)

1990 - Various alternatives to aging in its common definition (i.e., age-related increasing mortality) are documented (Finch 1990)

1991 - Telomere is shown to be a highly conserved repetitive sequence (Blackburn 1991)
  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 (Rose 1991)
  - 1993+ - Various studies prove that "aging" in C. elegans is influenced strongly by many genes (Kenyon et al. 1993; Dorman et al. 1995; see other studies at:

1996+ - Evolvability theories (Wagner & Altenberg 1996)
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 (Campisi 1997, 2000; Wright & Shay 2005). 1997+ - Evolvability-based aging theories (Skulachev 1997; Goldsmith 2003, 2004, 2006, 2008) 1997+ - "Proapoptosis" (Hochman 1997), a form of eubacterial cell suicide, is shown to be clearly related to eukaryotic apoptosis (Koonin & Aravind 2002) and this indicates a very old evolutionary persistence and similarity

1997+ - Description of an apoptosis-like phenomenon in yeast (Madeo et al. 1997), elicited by factors present in multicellular organisms (Longo et al. 1997; Ligr et al. 1998)
1998 - A well-publicized study claims to discern a cost of reproduction in a historic database of British nobility, thus supporting Disposable Soma theory (Westendorp & Kirkwood 1998)
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 (Klapper, Heidorn et al. 1998; Klapper, Kuhne et al. 1998)

1998 - Telomerase introduction in somatic cells makes them able to innumerable duplications and reverts manifestations of cell senescence (Bodnar et al. 1998, Counter et al. 1998 , Vaziri & Benchimol 1998, de Lange & Jacks 1999)

1998+ - Ricklefs documents an inverse relation between extrinsic and intrinsic mortality in natural conditions (Ricklefs 1998, 2008)) 1998+ - Inactivated telomerase and short telomeres increase the probability of apoptosis (Ozen et al. 1998; Seimiya et al. 1999; Holt et al. 1999; Ren et al. 2001; Fossel 2004)

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" (Skulachev 1999) 1999+ - For yeast apoptosis-like phenomenon a common phylogenetic origin with apoptosis in multicellular eukaryotes is indicated (Madeo et al. 1999; Longo et al. 2005; Kaeberlein et al. 2007)

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 (Skulachev 1999, 2002, 2003; Fabrizio et al. 2004; Longo et al. 2005; Skulachev & Longo 2005; Mitteldorf 2006b)
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 (Kirkwood & Austad 2000)
2000 - A too short telomere length does not allow further replications (Shay & Wright 2000)
2000 - Shanley and Kirkwood formulate a Disposable Soma model in mice that try to explain the effects of calorie restriction on aging (Shanley & Kirkwood 2000")
2000- Blackburn?s model explains the graduality of cell senescence in a culture (Blackburn 2000)

2000+ - When telomeres are shortened, there is a great vulnerability to cancer as a consequence of dysfunctional telomere-induced instability (DePinho 2000; Artandi 2002)

2001 -Mitteldorf shows that the Shanley & Kirkwood 2000 model is hardly tenable (Mitteldorf 2001)
2002 - Historical hypothesis (De Magalhães & Toussaint 2002)

2004 - Vaupel et al. try to explain negative senescence with non-adaptive theories (Vaupel et al. 2004)
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?) (Fossel 2004)

2004+ - The hypothesis that replicative senescence, cell senescence and telomere-telomerase system are a general defence against cancer is challenged (Fossel 2004; Libertini 2006, 2009a, 2009b) 2004+ - Cell senescence, replicative senescence and aging are related (Fossel?s "cell senescence general model" of aging) (Fossel 2004; Libertini 2006, 2009a, 2009b)

2005 - Cell senescence is defined as a "fundamental cellular program" (Ben-Porath & Weinberg 2005) 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.

2006 - Libertini underlines the contradiction between Ricklefs' data and traditional aging hypotheses (Libertini 2006)

2006 - Group selection based aging theory (Mitteldorf 2006a)

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 (Bjelakovic et al. 2007)

2008 - The empirical evidence in support of adaptive theories of aging and against non-adaptive hypotheses is highlighted (Libertini 2008)

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 (Mitteldorf 2009)

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 (Libertini 2009b)

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" (Milewski 2010)

2010 - Age-related fitness decline is defined "slow phenoptosis" (Skulachev 2010)
2010 - Most gerontologists continue to believe non-adaptive aging theories 2010 - Extensive and increasing interest in alternative mechanics but no consensus. Steadily increasing observational evidence for adaptive aging theories
2011 - For the first time, Kirkwood, an authoritative supporter of non-adaptive hypotheses about ageing, admits that “ageing might occasionally be adaptive” (Kirkwood & Melov 2011) 2011 - For the first time, it is proposed a phylogeny of the age-related fitness decline (alias mortality increase) – a phenomenon generally referred imprecisely “aging” – and of related phenomena (Libertini 2011) 2011 - The first (prudent) attempt of a mild stimulation of telomerase activity to preserve health conditions (Harley et al. 2011)

2011 - Telomerase reactivation in aged mice with artificially blocked telomerase shows a marked reversal of degenerative manifestations, even for nervous system (Jaskelioff et al. 2011)

2011 - Human senescent and centenarian cells are transformed into pluripotent stem cells with reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, which are indistinguishable from young embryonic stem cells (Lapasset et al. 2011). This is another experiment proving how cell senescent state is not an irreversible condition caused by the accumulation of “errors” or toxic substances, but a physiologic state that is entirely reversible by an opportune reprogramming.

2012 - Special issue of the journal Biochemistry (Moscow), directed by V. Skulachev, exclusively about Phenoptosis phenomenon (Vol. 77, n. 7). For the first time in an academic journal, vertebrate aging is correctly framed within phenomena of programmed death, alias phenoptosis. 2012 - In adult or old normal mice, telomerase expression, induced by adenoviruses, delays aging and increases longevity without increasing cancer risk (de Jesus et al. 2012)

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