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National Library of Medicine's PubMed directory of MEDLINE citations.
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Miquel J
Instituto de Neurociencias, Facultad de Medicina, Alicante, Spain.
Exp Gerontol 1998 Jan;33(1-2):113-126
The acceleration of fixed-postmitotic cell aging by a high metabolic rate and the age related loss of mitochondria found in that cell type led us to propose an oxygen stress-mitochondrial mutation theory of aging, according to which senescence may be linked to mutations of the mitochondrial genome (mtDNA) of the irreversibly differentiated cells. This extranuclear somatic gene mutation concept of aging is supported by the fact that mtDNA synthesis takes place at the inner mitochondrial membrane near the sites of formation of highly reactive oxygen species. Mitochondrial DNA may be unable to prevent the intrinsic mutagenesis caused by those byproducts of respiration because, in contrast to the nuclear genome, it lacks excision and recombination repair. The resulting mitochondrial impairment and concomitant cell bioenergetic decline may cause the senescent loss of physiological performance and may play a key role in the pathogenesis of many age-related degenerative diseases. These concepts are integrated with classic and contemporary hypotheses in a unitary theory that reconciles programmed and stochastic concepts of aging. Thus, it is suggested that cells are programmed to differentiate, and then they accumulate mitochondrial-genetic damage because of their high levels of oxyradical stress and the loss of the organelle rejuvenating power of mitosis.
Frasca D, Barattini P, Goso C, Pucci S, Rizzo G, Bartoloni C, Costanzo M, Errani A, Guidi L, Antico L, Tricerri A, Doria G
Laboratory of Immunology, ENEA CR Casaccia, Rome, Italy. frasca@casaccia.enea.it
Mech Ageing Dev 1998 Jan 30;100(2):197-208
Previous studies on DNA repair in ageing have demonstrated increased frequencies of single and double strand breaks in lymphocytes from elderly subjects and, as a consequence, decreased efficiency in DNA replication. We have investigated the relationship between cell proliferation and the nuclear expression of ku protein in a human population of 43 subjects of different ages. Ku is an heterodimeric protein composed of two subunits of 70 and 80 kDa, which is involved in the early steps of DNA damage recognition. In the present study, PBL from subjects of different ages were PHA-activated to evaluate the stimulation index and the production of Th1- and Th2-type cytokines. Moreover, nuclear extracts were obtained from activated lymphocytes to evaluate by a gel retardation assay the presence and the functional activity of the heterodimer ku 70/80. Our results indicate that ageing affects the mitotic responsiveness and cytokine production to a significant extent, but only marginally the expression of ku 70/80. These findings suggest that the age-related impairment in DNA repair mechanisms are only in part related to the reduced expression of ku protein able to recognize DNA damage.
Raji NS, Rao KS
Department of Biochemistry, School of Life Sciences, University of Hyderabad, India.
Mech Ageing Dev 1998 Jan 12;100(1):85-101
Down's syndrome (DS) cases from 1-40 years of age and showing no other anomalies or deficiencies were categorized into three age groups: group 1, < or = 12 years; group 2, 13-25 years; and group 3, > or = 26 years. The DNA-repair markers like unscheduled DNA synthesis (UDS), activities of DNA polymerases, (Total, beta and epsilon) and two endodeoxyribonucleases, (UV- and AP-DNases) were assessed in the peripheral lymphocytes of these subjects (under different conditions) along with age and sex matched normal healthy human subjects. The DS group showed lower DNA-repair efficiency and also an accelerated decline in DNA-repair capacity with age. These results indicate that deteriorated DNA-repair potential could be one of the probable reasons for premature aging seen in this chromosomal disorder.
Perez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G
Departamento de Fisiologia Animal, Facultad de Biologia, Universidad Complutense, Madrid, Spain.
J Comp Physiol [B] 1998 Apr;168(3):149-158
The relationship of oxidative stress with maximum life span (MLSP) in different vertebrate species is reviewed. In all animal groups the endogenous levels of enzymatic and non-enzymatic antioxidants in tissues negatively correlate with MLSP and the most longevous animals studied in each group, pigeon or man, show the minimum levels of antioxidants. A possible evolutionary reason for this is that longevous animals produce oxygen radicals at a low rate. This has been analysed at the place where more than 90% of oxygen is consumed in the cell, the mitochondria. All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds. Birds have low rates of mitochondrial oxygen radical production, frequently due to a low free radical leak in their respiratory chain. Possibly the low rate of mitochondrial oxygen radical production of longevous species can decrease oxidative damage at targets important for aging (like mitochondrial DNA) that are situated near the places of free radical generation. A low rate of free radical production can contribute to a low aging rate both in animals that conform to the rate of living (metabolic) theory of aging and in animals with exceptional longevities, like birds and primates. Available research indicates there are at least two main characteristics of longevous species: a high rate of DNA repair together with a low rate of free radical production near DNA. Simultaneous consideration of these two characteristics can explain part of the quantitative differences in longevity between animal species.
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