Theories of Aging

Although the specific biologic basis of aging remains obscure, there is general agreement that its elucidation will be at the molecular level. Furthermore, it should be consistent, not only with the life span differences between species, but also with the fact that noncycling cells (e.g., neurons and myocytes) undergo a relatively uniform functional decline with age. 

The somatic mutation theory is based, in part, on the idea that background radiation and/or various endogenous mutagens produce random chromosome damage in all cells. Over time, the genetic loci become sufficiently altered such that various critical functions fail and the cell dies. The fact that irradiation of laboratory animals results in accelerated aging and premature death lends some support to this hypothesis. However, since irradiation produces free radicals, it could be considered part of that theory. 

Deoxyribonucleic acid (DNA) has limited chemical stability. As a result, oxidative damage, hydrolysis, and nonenzymatic DNA methylation occur in vivo at significant rates (L6). Thus, another aspect of this theory is that of intrinsic somatic mutations and the ability of cells to repair the damage to both mitochondrial and nuclear DNA. Indeed, mammalian cells have an elaborate system of DNA repair enzymes which become less efficient with time. Thus, failure to repair damaged DNA or to misrepair it could lead to gene inactivation or possible excision of 

The error catastrophe hypothesis suggests that through random errors in translation or transcription, erroneous copies of proteins associated with chromosomes lead to genetic abnormalities (02). This, in turn, may result in persistently abnormal protein synthesis, and an eventual error catastrophe destroys the cell. As a result, the ability of a cell to produce its normal complement of functional proteins depends not only on the correct genetic specification of the various amino acid sequences, but also on the competence and fidelity of the protein-synthesizing apparatus (i.e., the information must be translated correctly). 

Although it is true that abnormal proteins increase with age, most of them are a result of posttranslational changes. An example is the various isoforms of creatine kinase (CK). Here, the major isoenzyme, CK-MM (isoform CK-33), is normally synthesized in the heart and skeletal muscle. However, after its release into the circulation, carboxypeptidase hydrolyzes the terminal lysine from one of the M-peptides to form CK-32. Subsequent hydrolysis of the terminal lysine from the second M-peptide produces the third isoform, CK-3i (W8). Numerous similar posttranslational proteins are produced. Hence, the presence of abnormal proteins per se does not support this aging theory. 

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ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

Since Harman s famous work [440] on free radical theory of aging in 1956, numerous studies have been dedicated to the development of his theory, which were reviewed by many authors (see, for example, early reviews, Refs. [441-444]). There is of course no necessity and possibility to discuss these reviews, which have been perfectly considered by their authors. 

Recent development of mitochondrial theory of aging is so-called reductive hotspot hypothesis. De Grey [465] proposed that the cells with suppressed oxidative phosphorylation survive by reducing dioxygen at the plasma membrane rather than at the mitochondrial inner membrane. Plasma membrane redox system is apparently an origin of the conversion of superoxide into hydroxyl and peroxyl radicals and LDL oxidation. Morre et al. [466] suggested that plasma membrane oxidoreductase links the accumulation of lesions in mitochondrial DNA to the formation of reactive oxygen species on the cell surface. 

Harman, D., The free radical theory of aging the effect of age on serum mercaptan levels, J. Gerontol. 15, 38 10, 1960. 

Goldstein S, Gallo JJ, Reichel W. Biologic theories of aging. Am Fam Physicia 1989 40 195-200. 

Lee, R.D., Rethinking the evolutionary theory of aging Transfers, not births, shape senescence in social species, Proc. Natl. Acad. Sci. USA, 100, 9637, 2003. 

The Mitochondrial Theory of Aging Involvement of Mitochondrial DNA Damage and Repair... 

As discussed previously, the mitochondrial theory of ageing rests on the observation that mitochondrial DNA is exposed to high levels of reactive oxygen species when the mitochondrion is performing its redox chemistry. These reactive oxygen species cause mutation. These mutations accumulate, gradually damaging the mitochondrion s ability to function. This happens in... 

Allen JF (1996) Separate sexes and the mitochondrial theory of ageing. J Theor Biol 180 135-140 Allen JF (2003) The function of genomes in bioenergetic organelles. Philos Trans Roy Soc Lond B Biol Sci 358 19-38... 

As discussed previously, the immune theory of aging is based, to a considerable degree, on the fact that the immune system becomes less efficient with aging. Importantly, Zn also plays a role in the immune system. For example, Zn supplementation in the elderly (a) increases the number of circulating T-lymphocytes (b) improves delayed cutaneous hypersensitivity to various antigens and (c) increases the immunoglobulin G antibody response to tetanus vaccine (D13). This early study is supported by additional recent reports which also demonstrate that Zn supplementation improves the immune system in the elderly (F9, R6). 

Wl. Walford, L., The Immunologic Theory of Aging. Williams Wilkins, Baltimore, 1969. 

W2. Walford, L., Immunologic theory of aging Current status. Fed. Proc. 33, 2020-2027 (1974). 

H7. Harman, D., Free radical theory of aging Role of free radicals in the origination and evolution of life aging and disease process. In Aging and Degenerative Disease Processes. Alan R. Liss, New York, 1996. 

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