Programmed Aging Theory Information Genetically Determined and Regulated Mechanisms
Limiting Cell Turnover and, Therefore, Lifespan


"Somatic cell reproduction capacities have well-known limits in vitro (Hayflick limit [Hayflick & Moorhead 1961]; [Hayflick 1965]) and in vivo [Schneider & Mitsui 1976], of which the underlying mechanisms have been defined [Shay & Wright 2000].

Eukaryotic chromosomal DNA is linear and in the replication a small portion of one of the two ends (telomeric DNA) is lost [Olovnikov 1973]. Telomeric DNA, a highly conserved repetitive sequence (TTAGGG in vertebrates, slime molds, trypanosomes, and many other organisms [Blackburn 1991]), in general several kilobase pairs long, at each replication shortens [Harley et al. 1990] up to a length not allowing further replications [Shay & Wright 2000].

Enzyme telomerase adds new segments of the repetitive sequence [Greider & Blackburn 1985] and telomerase introduction in somatic cells “immortalizes” them, namely makes them able to innumerable duplications [Bodnar et al. 1998].

There is not a tight relation between the length of telomeric DNA and the number of possible duplication (e.g.: mouse telomeric DNA is much longer than man telomeric DNA but the number of possible duplication is smaller). The length of telomeric DNA is a sort of counter but its effects are in function of the relative variation of the length and of a species-specific regulation [Fossel 2004].

Telomeric DNA shortening is in inverse function of the activity of telomerase, which for some cells is always active (cells of the germinal line), for others is always inactive (most of human somatic cells), for others is sporadically more or less active in certain conditions [Fossel 2004].

In short, cell duplication capacity is not a simple mechanical outcome of an unsolvable defect in DNA replication and of a telomeric DNA finite length but a potentiality varying without an upper limit from cell to cell in function of telomere-telomerase regulation, viz. not a phenomenon caused by insurmountable ties but a genetically determined and regulated function.

Moreover, with the progressive shortening of telomeric DNA, the expression of many genes, among those usually expressed by the cell, results impaired, altering cell overall functionality and, consequently, the functions of extracellular matrix and of other near or physiologically interdependent cells. It has been documented extensively and soundly that this decay of cell functions (cell senescence), as well the progressive reduction of cell duplication capacities (replicative senescence), depends somehow from the relative shortening of telomeric DNA (Fossel’s “cell senescence limited model”) [Fossel 2004].

Besides, the concept of a sharp drop of cell duplication capacities when the shortening of telomeric DNA length exceeds a certain limit, has been revised and formulated in a more sophisticated way. The telomere, constituted by the telomeric DNA and a proteinic component, is a dynamic complex with the telomeric DNA oscillating between a capped phase (DNA tied to the proteinic component) and an uncapped phase (DNA not tied). The fraction of time in which telomeric DNA is capped is directly proportional to its relative length. Uncapped telomeric DNA is more vulnerable to the blockage of duplication capacity. Therefore, replicative senescence is gradual and progressive and not abrupt [Blackburn 2000].

Since organism functional efficiency for many species (e.g.: vertebrates) depends on a continuous cell turnover, the progressive replicative senescence and the progressive alterations caused by cell senescence bring about a progressive decay of living functions (Fossel’s "cell senescence general model" of aging) [Libertini 2006]; [Fossel 2004].

This overall decay of functions is certainly defined by anybody as aging in its evident and extreme manifestations, which we may observe only in artificial conditions of low extrinsic mortality. But, the initial phases of this decay, surely observable in the wild, mean a limited fitness reduction, i.e. the fitness decline of a species showing "increasing mortality with increasing chronological age in the wild" (IMICAW) and, therefore Fossel’s general model can be reformulated as cell senescence general model of IMICAW too.

Non-adaptive hypotheses does not predict the existence of mechanisms genetically determined and regulated causing fitness decline. Mechanisms above reported could be compatible with the non-adaptive hypothesis only if an adaptive function is a plausible and exhaustive evolutionary justification for their existence.

A possible purpose for replicative senescence and cell senescence is that of a general defense against the threat of malignant tumors [Campisi 1997]; [Wright & Shay 2005], in a sort of evolutionary trade-off between aging and cancer restriction [Campisi 2000]. But, this hypothesis does not justify the great differences of duplication limits and of cell overall functionality decay from species to species, unless the risk of malignant tumors is postulated as varying from species to species in direct correlation with the limits imposed to cell duplication capacities and to cell overall functionality by the genetic modulation of telomere-telomerase system.

As extreme examples: old rainbow trout and lobster individuals, “animals with negligible senescence”, have in the wild the same levels of telomerase activity of young individuals [Klapper, Heidorn et al. 1998]; [Klapper, Kuhne et al. 1998]. and increasing problems of carcinogenesis at older ages are not plausible for them since, as their definition says, their mortality rates does not increase with age.

Moreover: 1) The decline of duplication capacities and of cell overall functionality weakens immune system efficiency [Fossel 2004], which is known from a long time to be inversely related to cancer incidence [Rosen 1985]; 2) When telomeres are shortened there is a great vulnerability to cancer as a consequence of dysfunctional telomere-induced instability [DePinho 2000]; [Artandi 2002]; 3) “The role of the telomere in chromosomal stability ... argues that telomerase protects against carcinogenesis ..., especially early in carcinogenesis when genetic stability is critical ..., as well as protecting against aneuploidy and secondary speciation ... . The role of telomerase depends on the stage of malignancy ...; expression is late and permissive, not causal ...” [Fossel 2004] (p. 78, references have been left out from the quotation)." [Libertini 2008]

- Artandi, S.E. (2002) Telomere shortening and cell fates in mouse models of neoplasia. Trends Mol. Med. 8(1):44-47. [PubMed] [Google Scholar]
- Blackburn, E.H. (1991) Structure and function of telomeres. Nature 350, 569-573. [PubMed] [Google Scholar]
- Blackburn, E.H. (2000) Telomere states and cell fates. Nature 408, 53-56. [PubMed] [Google Scholar]
- Bodnar, A.G., Ouellette, M., Frolkis, M., Holt, S.E., Chiu, C., Morin, G.B., Harley, C.B., Shay, J.W., Lichsteiner, S. and Wright, W.E. (1998) Extension of Life-Span by Introduction of Telomerase into Normal Human Cells. Science 279, 349-352. [PubMed] [Google Scholar]
- Campisi, J. (1997) The biology of replicative senescence. Eur. J. Cancer 33(5):703-709. [PubMed] [Google Scholar]
- Campisi, J. (2000) Cancer, aging and cellular senescence. In Vivo 14(1):183-8. [PubMed] [Google Scholar]
- DePinho, R.A. (2000) The age of cancer. Nature 408, 248-254. [PubMed] [Google Scholar]
- Fossel, M.B. (2004) Cells, Aging and Human Disease. Oxford University Press, Oxford, USA. [Google Scholar]
- Greider, C.W. & Blackburn, E.H. (1985) Identification of a specific telomere terminal transferase enzyme with two kinds of primer specificity. Cell 51, 405-413. [PubMed] [Google Scholar]
- Harley, C.B., Futcher, A.B. & Greider, C.W. (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345, 458-460. [PubMed] [Google Scholar]
- Hayflick, L. & Moorhead, P.S. (1961) The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621. [PubMed] [Google Scholar]
- Hayflick, L. (1965) The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614-636. [PubMed] [Google Scholar]
- Klapper, W., Heidorn, K., Kuhne, K., Parwaresch, R., & Krupp, G. (1998) Telomerase in 'immortal fish'. FEBS Letters (Federation of European Biochemical Societies) 434, 409-412. [PubMed] [Google Scholar]
- Klapper, W., Kuhne, K., Singh, K.K., Heidorn, K., Parwaresch, R. & Krupp G. (1998). Longevity of lobsters is linked to ubiquitous telomerase expression. FEBS Letters 439, 143-146. [PubMed] [Google Scholar]
- Libertini, G. (2006) Evolutionary explanations of the “actuarial senescence in the wild” and of the “state of senility”. TheScientificWorldJOURNAL 6, 1086-1108 DOI 10.1100/tsw.2006.209. [PubMed] [Google Scholar] [Free]
- Libertini G. (2008) Empirical evidence for various evolutionary hypotheses on species demonstrating increasing mortality with increasing chronological age in the wild. TheScientificWorldJOURNAL 8, 182-93 DOI 10.1100/tsw.2008.36. [PubMed] [Google Scholar] [Free]
- Olovnikov, A.M. (1973) A theory of marginotomy: The incomplete copying of template margin in enzyme synthesis of polynucleotides and biological significance of the problem. J. Theor. Biol. 41, 181-190. [PubMed] [Google Scholar]
- Rosen, P. (1985) Aging of the immune system. Med Hypotheses 18(2):157-161. [PubMed] [Google Scholar]
- Schneider, E.L. & Mitsui, Y. (1976) The relationship between in vitro cellular aging and in vivo human age. Proc. Natl. Acad. Sci. USA 73:3584-3588. [PubMed] [Google Scholar]
- Shay, J.W. & Wright, W.E. (2000) Hayflick, his limit, and cellular ageing. Nat. Rev. Mol. Cell. Biol. 1(1):72-78. [PubMed] [Google Scholar]
- Wright, W.E. & Shay, J.W. (2005) Telomere biology in aging and cancer. J. Am. Geriatr. Soc. 53(9 Suppl):S292-294. [PubMed] [Google Scholar]

Sponsored by Azinet LLC © 2009