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1.6 14th August 1997



Vestn Ross Akad Med Nauk 1996;6:31-38

Hierarchical thermodynamics and gerontology.

[Article in Russian]

Gladyshev GP, Komarov FI

The phenomenon of ageing of living creatures may be studied in the context of hierarchic thermodynamics. Ageing (ontogenesis) is regarded as a process of formation of the body's submolecular structure. A concept of the degree of ageing (the completion of ontogenesis) which is evaluated from changes in the Gibbs specific function of formation of the submolecular structure of the body's biological tissues is introduced. Quantitative criteria are proposed to find differences between the chronological and thermodynamic age of biological objects. The experimentally based thermodynamic approach reveals the impact of environmental parameters on longevity. The new discipline thermodynamic gerontology which will, in terms of the physical theory, substantially affect human longevity may be hoped to be formed in the coming years.

Mech Ageing Dev 1996 Nov 13;91(3):211-218

There is substantial agreement among interspecies estimates of DNA repair activity.

Cortopassi GA, Wang E

Dept. of Molecular Biosciences, University of California, Davis 95616, USA.

Faithful maintenance of the genetic material is essential for cellular and organismal function. Thus the activity with which nuclear and mitochondrial DNA is repaired in somatic cells is likely to be an crucial determinant of maximal lifespan (MLS). However there has been controversy over both the actual rates of DNA repair in a variety of species, and the correlation of those rates with maximal lifespan. Five comparative studies of DNA repair have been re-analyzed with reference to an internal repair standard. Although some variance in measurements of DNA repair activity of the same species in different laboratories was observed, overall there is good agreement on the rank order of repair activity once those studies are internally calibrated. A six-fold range of relative DNA repair activity was observed, with mouse, rat and shrew lowest (0.9 to 1.0), and human and gorilla highest (4.5 to 5.3). The correlation between DNA repair activity and MLS was good, but not excellent (r2 = 0.845); a possible explanation is that active DNA repair is a necessary but not sufficient condition for long MLS. We investigated the kinetics of mitochondrial mutagenesis and tumorigenesis in mice and humans, and observed that each proceeds at a rate approximately 40-fold faster in mice than in humans. Thus one likely consequence of the deficiency of DNA repair in small rodents is an increased rate of mutagenesis and tumorigenesis. The large differences in metabolic investment in genomic maintenance in mice versus humans is a prediction of the disposable soma theory of aging, which is discussed.

Mutat Res 1997 Mar;386(1):69-101

Somatic mutation theory, DNA repair rates, and the molecular epidemiology of p53 mutations.

Holmquist GP, Gao S

Beckman Research Institute of the City of Hope, Department of Biology, Duarte CA 91010, USA.

The theory of somatic mutagenesis predicts that the frequency pattern of induced selectable mutations along a gene is the product of the probability patterns of the several sequential steps of mutagenesis, e.g., damage, repair, polymerase misreading, and selection. Together, the variance of these component steps is propagated to generate a mutagen's induced mutational spectrum along a gene. The step with the greatest component of variance will drive most of the variability of the mutation frequency along a gene. This most variable step, for UV-induced mutations, is the cyclobutyl pyrimidine dimer repair rate. The repair rate of cyclopyrimidine dimers is quite variable from nucleotide position to nucleotide position and we show that this variation along the p53 gene drives the C-->T transition frequency of non-melanocytic skin tumors. On showing that the kinetics of cyclopyrimidine dimer repair at any one nucleotide position are first order, we use this kinetic and the somatic mutation theory to derive Leq, the adduct frequency along a gene as presented to a DNA polymerase after a cell population reaches damage-repair equilibrium from a chronic dose of mutagen. Leq is the product of the first two sequential steps of mutagenesis, damage and repair, and the frequency of this product is experimentally mapped using ligation-mediated PCR. The concept of Leq is applied to mutagenesis theory, chronic dose genetic toxicology, genome evolution, and the practical problems of molecular epidemiology.

J Invest Dermatol 1997 Apr;108(4):430-437

Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model.

Ashcroft GS, Horan MA, Ferguson MW

School of Biological Sciences, University of Manchester, U.K.

The concept that aging impairs wound healing is largely unsubstantiated, the literature being contradictory because of poor experimental design and a failure to adequately characterize animal models. This study tested the hypothesis that aging retards the rate of wound repair using standardized cutaneous incisional wounds in a well-characterized aging mouse colony. Against the background of age-related changes in normal dermal composition, marked differences in healing were observed. Immunostaining for fibronectin was decreased in the wounds of the old mice, with a delay in the inflammatory response, re-epithelialization, and the appearance of extracellular matrix components. Heparan sulfate and blood vessel staining were both unexpectedly increased in the wounds of the old animals at late time points. Despite an overall decrease in collagen I and III deposition in the wounds of old mice, the dermal organization was surprisingly similar to that of normal dermal basket-weave collagen architecture. By contrast, young animals developed abnormal, dense scars. Intriguingly, some of these age-related changes in scar quality and inflammatory cell profile are similar to those seen in fetal wound healing. The rate of healing in young animals appears to be increased at the expense of the scar quality, perhaps resulting from an altered inflammatory response.

Med Hypotheses 1997 Feb;48(2):143-148

Deleterious network hypothesis of aging.

Ying W

School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA.

It is becoming increasingly apparent that free-radical damage, mitochondrial defects, glycation/Maillard reaction and calcium dyshomeostasis play crucial roles in cellular and organism senescence. Based on the evidence indicating close relationships among these four aging-promoting factors, a unifying hypothesis of senescence-the deleterious network hypothesis of aging-is proposed: In living organisms, both endogenous and exogenous detrimental factors produce age-dependent accumulation of triggering of a deleterious network, which is constructed on the basis of the interactions among oxidative impairments, mitochondrial defects, calcium mismetabolism and glycation/Maillard reaction. The age-related triggering of the network leads to numerous senescent alterations. It appears that this novel theory has synthesized multiple hypotheses of aging, and is capable of providing consistent explanations to a larger number of senescent changes than any previous hypotheses. Based on the new theory of senescence, it is proposed that the approaches which can inhibit the initiation of the four key age-promoting factors should be applied combinatively to slow down the aging process and to prevent and treat age-associated illnesses.

Bioessays 1997 Feb;19(2):161-166

A proposed refinement of the mitochondrial free radical theory of aging.

de Grey AD

Department of Genetics, University of Cambridge, UK.

Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non-dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging.



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