LITERATURE.1991

Dr.S.Baranidharan barani at mace.cc.purdue.edu
Thu Jan 19 19:08:01 EST 1995


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\section*{1}
  Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA 
of human diaphragm.

  Hayakawa M, Torii K, Sugiyama S, Tanaka M, Ozawa T
  Department of Biomedical Chemistry, Faculty of Medicine, University of 
Nagoya, Japan.

  Biochem Biophys Res Commun  Sep 16 1991  179 (2) p1023-9
  
  This is the first report that age-associated accumulation of 8-
hydroxydeoxyguanosine (8-OH-dG) does occur in human mitochondrial DNA (mtDNA) 
in muscle of diaphragm.  We extracted mtDNA from human diaphragm muscles from 
differing age groups, and determined the amount of 8-OH-dG by ultramicro-high 
performance liquid chromatography/mass-spectrometry system.  With the same 
specimen, multiple deletions of mtDNA were detected by electrophoresis after 
amplification by the polymerase chain reaction method.  In subjects below age 
55, the level of 8-OH-dG in mtDNA was below 0.02% of the total deoxyguanosine 
(dG), whereas, in subjects over age 65, the level of 8-OH-dG increased with age 
at a rate of ca.  0.25% per 10 years, reaching 0.51% at age 85.  Moreover, a 
concomitant increase in multiple deletions was detected with the increase in 
age.  These results suggest that, in younger diaphragms, replication of mtDNA 
dilutes out 8-OH-dG being not detectable.  In the elderly subjects aged over 
65, the replication rate might be slowed down leading to the accumulation of 8-
OH-dG in mtDNA, which would accelerate the age-associated multiple deletions of 
mtDNA observed among the subjects.


\section*{2}
  Genetic diseases of premature aging as models of senescence.

  Brown WT
  North Shore University Hospital-Cornell University Medical College.

  Annu Rev Gerontol Geriatr  1990  10 p23-42


\section*{3}
  DNA processing, aging, and cancer. The impact of new technology.

  Vijg J, Gossen JA, De Leeuw WJ, Mullaart E, Slagboom PE, Uitterlinden AG
  Medscand Ingeny, Rijswijk, The Netherlands.

  Ann N Y Acad Sci  1991  621 p53-65


\section*{4}
  Diverse gene sequences are overexpressed in werner syndrome fibroblasts 
undergoing premature replicative senescence.

  Murano S, Thweatt R, Shmookler Reis RJ, Jones RA, Moerman EJ, Goldstein S
  Departments of Medicine, University of Arkansas for Medical Sciences, Little 
Rock.

  Mol Cell Biol  Aug 1991  11 (8) p3905-14
  
  Genes that play a role in the senescent arrest of cellular replication are 
likely to be overexpressed in human diploid fibroblasts (HDF) derived from 
subjects with Werner syndrome (WS) because these cells have a severely 
curtailed replicative life span.  To identify some of these genes, a cDNA 
library was constructed from WS HDF after they had been serum depleted and 
repleted (5 days in medium containing 1% serum followed by 24 h in medium 
containing 20% serum).  Differential screening of 7,500 colonies revealed 102 
clones that hybridized preferentially with [32P]cDNA derived from RNA of WS 
cells compared with [32P]cDNA derived from normal HDF.  Cross-hybridization and 
partial DNA sequence determination identified 18 independent gene sequences, 9 
of them known and 9 unknown.  The known genes included alpha 1(I) procollagen, 
alpha 2(I) procollagen, fibronectin, ferritin heavy chain, insulinlike growth 
factor-binding protein-3 (IGFBP-3), osteonectin, human tissue plasminogen 
activator inhibitor type I, thrombospondin, and alpha B-crystallin.  The nine 
unknown clones included two novel gene sequences and seven additional sequences 
that contained both novel segments and the Alu class of repetitive short 
interspersed nuclear elements, five of these seven Alu+ clones also contained 
the long interpersed nuclear element I (KpnI) family of repetitive elements.  
Northern (RNA) analysis, using the 18 sequences as probes, showed higher levels 
of these mRNAs in WS HDF than in normal HDF.  Five selected mRNAs studied in 
greater detail [alpha 1(I) procollagen, fibronectin, insulinlike growth factor-
binding protein-3, WS3-10, and WS9-14] showed higher mRNA levels in both WS and 
late-passage normal HDF than in early-passage normal HDF at various intervals 
following serum depletion/repletion and after subculture and growth from sparse 
to high-density confluent arrest.  These results indicate that senescence of 
both WS and normal HDF is accompanied by overexpression of similar sets of 
diverse genes which may play a role in the senescent arrest of cellular 
replication and in the genesis of WS, normal biological aging, and attendant 
diseases.

\section*{5}
  Correlation between complementation group for immortality and DNA synthesis 
inhibitors.

  Spiering AL, Pereira-Smith OM, Smith JR
  Roy M. and Phyllis Gough Huffington Center on Aging, Baylor College of 
Medicine, Houston, Texas 77030.

  Exp Cell Res  Aug 1991  195 (2) p541-5
  
  Previous studies had demonstrated that a DNA synthesis inhibitor(s) was 
produced by senescent but not young human diploid fibroblasts (HDF).  Analysis 
of immortal human cell lines led to the finding that SUSM-1, carcinogen-treated 
immortal human liver fibroblast cells, expressed a potent inhibitor of DNA 
synthesis that was active in proliferation-competent young HDF but did not 
affect the SUSM-1 cell line itself.  To determine whether one mechanism of 
escape from senescence to the immortal phenotype involved the loss of response 
to such DNA synthesis inhibitors, we initiated the present study analyzing a 
larger number of immortal human cell lines representative of the four 
complementation groups for indefinite division identified to date.  We have 
found a correlation between the assignment of a cell line to Complementation 
Group D and the production of DNA synthesis inhibitors coupled with inability 
to respond to the inhibitory factors.  We have also observed a correlation 
between the ability of immortal cell lines to respond to such DNA synthesis 
inhibitory factors and assignment to Complementation Group B. These data 
suggest DNA synthesis inhibitors are involved in the limited lifespan of normal 
cells and that the immortalization process may involve alterations in the 
activity of or response to such inhibitors.

\section*{6}
  Ageing-associated 5 kb deletion in human liver mitochondrial DNA.

  Yen TC, Su JH, King KL, Wei YH
  Department of Biochemistry, National Yang-Ming Medical College, Taipei, 
Taiwan, Republic of China.

  Biochem Biophys Res Commun  Jul 15 1991  178 (1) p124-31
  
  Using PCR technique and restriction mapping, we analyzed liver mitochondrial 
DNA (mtDNA) of 2 stillborn babies and 55 Chinese subjects from 27 to 86 years 
old and blood cell mtDNA from 20 subjects of various ages.  An ageing-
associated 4,977-bp deletion was detected between nucleotide position 8,469 and 
13,447 (or between 8,482 and 13,460) in the liver mtDNA of older subjects.  In 
the region containing the junction fragment, we observed a 13 bp repeat 
"ACCTCCCTCACCA".  Moreover, the incidence of the deleted mtDNA of each of the 
study subjects was found to increase with age.  The deletion was found in 5 out 
of 8 patients of the 31-40 age group and 9 out of 11 patients of the 41-50 age 
group, and in all the patients over 50 years old.  The deletion was not 
observed in either the mtDNA of the liver of the stillbirth or the blood cells 
of subjects of all the age groups.  These results support our previous 
contention that liver mitochondrial respiratory functions decline with age and 
the hypothesis that continuous accumulation of mitochondrial DNA mutation is an 
important contributor to ageing process.


\section*{7}
  Werner's syndrome combined with quintuplicate malignant tumors: a case report 
and review of literature data.

  Tsuchiya H, Tomita K, Ohno M, Inaoki M, Kawashima A
  Department of Orthopaedic Surgery, School of Medicine, Kanazawa University.

  Jpn J Clin Oncol  Apr 1991  21 (2) p135-42
  
  The authors report a case of Werner's syndrome complicated by quintuplicate 
malignancy, and review the literature data.  Four malignancies occurred 
synchronously in the case: osteosarcoma of the left distal tibia, malignant 
melanoma of the left plantar region, gastric cancer, pulmonary coin lesion.  
The osteosarcoma and malignant melanoma were treated by below-knee amputation 
and the gastric cancer by palliative surgery, the pulmonary coin lesion did not 
respond to cisplatin chemotherapy.  It was difficult to treat the multiple 
primary cancer curatively, and patient died of respiratory failure due to a 
brain tumor seven months after surgery.  The postmortem examination revealed a 
papillary carcinoma of the thyroid gland and a leiomyosarcoma of the lung.  In 
some cases of Werner's syndrome, attention should be paid to the concurrent 
occurrence of multiple primary malignant neoplasms.  


\section*{8}
  A mathematical model of proliferation and aging of cells in culture.

  Zheng T
  Department of Cell Biology, Institute of Zoology, Chinese Academy of Science, 
Beijing.

  J Theor Biol  Apr 7 1991  149 (3) p287-315
  
  A mathematical model is presented which describes the proliferative 
senescence of cells in culture.  The model is based on the DNA damage 
hypothesis of cellular aging and is able to account for both the limited and 
unlimited in vitro proliferative potential of normal and transformed cells.  It 
is predicted that the destiny of a cell population is determined by two 
counteracting factors: the proliferation rate of the dividable cells and the 
gene damage accumulation rate.  The formation of an immortal cell line requires 
high rate of proliferation and/or low rate of gene damage accumulation.  The 
related computer simulations on a number of proliferative properties of cell 
culture produces results in agreement, in the general properties, with 
experimental observations.


\section*{9}
  Molecular biology of aging. Part II: A synopsis of current research.

  Mooradian AD, Wong NC
  Tucson VA Medical Center, Arizona.

  J Am Geriatr Soc  Jul 1991  39 (7) p717-23


\section*{10}
  Werner's syndrome in a Nigerian: case report.

  Jaiyesimi AE, Sada AI, Jimoh O
  Department of Medicine, Ogun State University Teaching Hospital, Sagamu, Ogun 
State, Nigeria.

  Cent Afr J Med  Feb 1991  37 (2) p63-7
  

\section*{11}
  Evidence for membrane protein oxidation during in vivo aging of human 
erythrocytes.

  Seppi C, Castellana MA, Minetti G, Piccinini G, Balduini C, Brovelli A
  Dipartimento di Biochimica, Universita degli Studi, Pavia, Italy.

  Mech Ageing Dev  Mar 1991  57 (3) p247-58
  
  Oxidative lesions to membrane proteins were studied in human erythrocytes of 
different age and were evaluated on ghost membrane preparations by assaying 
thiol and methionine sulphoxide groups, and in situ on intact cells, after 
treating erythrocytes with the fluorochrome N-(7-dimethyl-amino-4-methyl-
coumarinyl) maleimide (DACM).  DACM reacts with thiol groups and the amount of 
this reagent bound by membrane proteins was quantified after SDS-PAGE 
separation.  Results obtained show that during aging of normal cells the 
oxidative state of membrane proteins increases: this was better shown by the 
assay of methionine sulphoxide residues rather than by the thiol titration, 
when studies were carried out on ghost membranes.  After separation of 
individual membrane proteins by SDS-PAGE, decreased accessibility of DACM to 
thiol groups of band 3 and of the main proteins of the membrane skeleton was 
evident in senescent erythrocytes.  These results show that during aging, band 
3 and membrane skeleton proteins undergo conformational changes and/or 
oxidation.  Similar results were obtained when thiol distribution was studied 
in membrane proteins separated by SDS-PAGE in both reducing and non-reducing 
conditions.


\section*{12}
  Cellular senescence: a reflection of normal growth control, differentiation, 
or aging?

  Peacocke M, Campisi J
  Department of Dermatology, Boston University School of Medicine, 
Massachusetts 02118.

  J Cell Biochem  Feb 1991  45 (2) p147-55
  
  Normal cells, with few exceptions, cannot proliferate indefinitely.  Cell 
populations in vivo and in culture generally undergo only a limited number of 
doublings before proliferation invariably and irreversibly ceases.  This 
process has been termed the finite lifespan phenotype or cellular senescence.  
There is long-standing, albeit indirect, evidence that cellular senescence 
plays an important role in complex biological processes as diverse as normal 
growth control, differentiation, development, aging, and tumorigenesis.  In 
recent years, it has been possible to develop a molecular framework for 
understanding some of the fundamental features of cellular senescence.  This 
framework derives primarily from the physiology, genetics, and molecular 
biology of cells undergoing senescence in culture.  Our understanding of 
senescence, and the mechanisms that control it, is still in its infancy.  
Nonetheless, recent data raise some intriguing possibilities regarding 
potential molecular bases for the links between senescence in culture and 
normal and abnormal growth control, differentiation, and aging.  


\section*{13}
  Protein, lipid and DNA repair systems in oxidative stress: the free-radical 
theory of aging revisited.

  Pacifici RE, Davies KJ
  Institute for Toxicology, University of Southern California, Los Angeles.

  Gerontology  1991  37 (1-3) p166-80
  
  Aerobic organisms are constantly exposed to oxygen radicals and related 
oxidants.  The antioxidant compounds and enzymes they have evolved remove most 
of the potentially damaging radicals/oxidants, however, damage to cellular 
proteins, lipids, nucleic acids and carbohydrates can be observed even under 
normal physiological conditions.  Re-reduction of cellular components (direct 
repair) may be important for some biomolecules.  In most cases studied to date, 
however, enzymatic degradation (by proteases, lipases, nucleases) appears to 
release damaged elements for excretion and conserve undamaged components for 
reutilization (indirect repair).  In addition, the removal of damaged 
components appears to prevent or diminish the potential cytotoxicity of 
oxidized macromolecules.  Several studies have reported an accumulation of 
oxidatively damaged cellular components with age (e.g., cataract formation, 
lipofuscin).  Such reports are evidence that oxidant damage is one of several 
factors which contribute to the aging process, and provide at least partial 
support for the free-radical theory of aging.  Studies of age-related changes 
in the activities, or levels of antioxidant enzymes and antioxidant compounds, 
however, have not provided complete understanding of the putative role of free 
radicals/oxidants in the aging process.  In this review, we present the 
hypothesis that decreased activities or constitutive levels of oxidant repair 
enzymes may contribute to a progressive accumulation of oxidant damage with 
aging.  Furthermore, the ability to mount an effective response to oxidative 
stress (induction of oxidant stress genes and proteins) may decline with age, 
thus predisposing older cells and organisms to oxidant damage.


\section*{14}
  Cellular models and tissue equivalent systems for evaluating the structures 
and significance of age-modified proteins.

  Gracy RW, Yuksel KU, Jacobson TM, Chapman ML, Hevelone JC, Wise GE, 
Dimitrijevich SD
  Department of Biochemistry, University of North Texas/Texas College of 
Osteopathic Medicine, Fort Worth.

  Gerontology  1991  37 (1-3) p113-27
  
  The accumulation of modified proteins in aging is well documented in many 
aging models.  For example, the deamidated isoforms of triosephosphate 
isomerase accumulate in: (a) old erythrocytes, (b) fibroblasts from old donors, 
(c) fibroblasts aged in vitro, (d) premature-aging syndromes and (e) old cells 
in the eye lens.  However, a fundamental remaining question is: 'Do such 
modified proteins interfere with cellular function?' It has been difficult to 
assess this question at the molecular level using whole-organism models and 
equally frustrating to evaluate the physiological significance of such changes 
using classical cellular models.  Tissue equivalent systems (TES) provide an 
opportunity for examining the molecular basis and physiological consequences of 
modified proteins during aging.  TES are composed of differentiating and 
proliferating heterogeneous cell types with symbiotic cell-cell and cell-matrix 
interactions.  They closely resemble, both morphologically and functionally, 
the tissues from which they were derived.  Aging studies utilizing TES can 
provide information on modifications of protein structures, isozyme patterns, 
enzymes of the cellular environmental protection system and metabolic 
parameters which may regulate protein synthesis and degradation.


\section*{15}
  Insulin receptor gene expression is reduced in cells from a progeric patient.

  Briata P, Bellini C, Vignolo M, Gherzi R
  Laboratories of Immunobiology, National Cancer Institute, Genoa, Italy.

  Mol Cell Endocrinol  Jan 1991  75 (1) p9-14
  
  We have studied a 15-year-old girl (P1) suffering from the Hutchinson-Gilford 
syndrome (progeria) associated with a severe insulin resistance.  Insulin 
binding activity to P1 erythrocytes was 85% reduced when compared to that 
measured in ten normal controls matched for sex and age.  This finding was 
confirmed in Epstein-Barr virus (EBV)-transformed lymphoblasts and depends on a 
reduction in insulin receptor number.  Also the amount of total insulin 
receptors, [35S]methionine labeled and immunoprecipitated, was 90% reduced in 
P1 lymphoblasts when compared to controls.  Next, we measured insulin receptor 
mRNA levels and we found undetectable levels of insulin receptor transcript in 
P1 EBV-transformed lymphoblasts, in the absence of any rearrangement of insulin 
receptor gene as evaluated by Southern blot analysis.  The marked reduction in 
insulin receptor gene expression probably accounts for the severe insulin 
resistance presented by the patient.  Despite extensive studies, the molecular 
basis of progeria is still unknown.  The near complete absence of a molecule 
crucial in the transduction of cell growth and differentiation signals could be 
involved in the accelerated aging of the patient.


\section*{16}
  Abnormal gene expression in skin fibroblasts from a Hutchinson-Gilford 
patient.

  Colige A, Roujeau JC, De la Rocque F, Nusgens B, Lapiere CM
  Laboratory of Experimental Dermatology, Centre Hospitalier Universitaire Sart 
Tilman, University of Liege, Sart Tilman, Belgium.

  Lab Invest  Jun 1991  64 (6) p799-806
  
  We had the opportunity to investigate a new case of Hutchinson-Gilford 
progeria, a rare disease commonly regarded as a model in the study of aging.  
Two strains of fibroblasts (strains 1 and 2) were derived from two pieces of a 
skin biopsy.  These two populations multiplied as normal cells at low 
population doubling level but senesced rapidly and stopped proliferating after 
14 or 15 population doubling levels.  Interestingly, an unusual pattern of 
growth in clusters was observed for strain 1. The level of collagen and 
noncollagen protein synthesis of both strains of affected fibroblasts was 
similar to that of normal fibroblasts as determined by [3H]proline 
incorporation measurement and was similarly affected by varying serum 
concentrations.  The pattern of the main types of newly synthesized collagen 
polypeptides analyzed by sodium dodecyl sulfate-polyacrylamide gel 
electrophoresis was similar in normal and progeria cells.  The steady-state 
level of mRNAs coding for macromolecules of the extracellular matrix did not 
provide any differences between affected and control fibroblasts except for a 
strong increase of elastin and of alpha 1 and alpha 2 type IV procollagen mRNA 
mainly in strain 1 and less marked in strain 2. Interestingly, senescent 
progeria fibroblasts exhibited a reduced level of all the tested mRNAs, whereas 
collagen type IV and elastin mRNAs remained elevated.  As suggested by 
immunofluorescence and immunoblotting studies, the increased amount of type IV 
mRNAs was paralleled by an enhanced production of type IV collagen by 
fibroblasts in vitro.  Histologic examination of the skin revealed a 
superabundant network of abnormal elastic fibers in the reticular dermis and a 
thickening of basement membranes.  The relationship between these alterations 
and aging in progeria is discussed.


\section*{17}
  DNA sequence changes in aging: how frequent, how important?

  Vijg J
  Department of Molecular Biology, TNO Institute for Experimental Gerontology, 
Rijswijk, The Netherlands.

  Aging (Milano)  Jun 1990  2 (2) p105-23


\section*{18}
  Genomic instability: a challenge for aging research [editorial]

  Franceschi C

  Aging (Milano)  Jun 1990  2 (2) p101-4

\section*{19}
  Molecular biology of aging, Part I: An introduction to laboratory techniques 
of molecular biology.

  Mooradian AD, Wong NC
  Tucson VA Medical Center, Arizona.

  J Am Geriatr Soc  Jun 1991  39 (6) p611-9


\section*{20}
  Searching for the molecular basis of aging: the need for life extension 
models [editorial]

  Vijg J

  Aging (Milano)  Sep 1990  2 (3) p227-9
  

\section*{21}
  Age-dependent increase in deleted mitochondrial DNA in the human heart: 
possible contributory factor to presbycardia.

  Hattori K, Tanaka M, Sugiyama S, Obayashi T, Ito T, Satake T, Hanaki Y, Asai 
J, Nagano M, Ozawa T
  Department of Internal Medicine, Faculty of Medicine, University of Nagoya, 
Japan.

  Am Heart J  Jun 1991  121 (6 Pt 1) p1735-42
  
  Cardiac function deteriorates with age, and endogenous damage to 
mitochondrial DNA (mt DNA) is believed to be a major contributory factor to 
aging.  Mitochondria occupy a pivotal position in energy metabolism, and 
mitochondria have their own DNA, which encodes 13 subunits of the mitochondrial 
energy transducing system.  Other subunits are encoded by nuclear DNA.  DNA has 
been shown to have a high mutation rate, and genetic mutation might primarily 
be ascribed to mtDNA mutation in the energy transducing system.  Recent 
advances in gene technology, especially in polymerase chain reactions (PCR), 
permit us to analyze mtDNA mutations in a small quantity of tissue.  We devised 
rapid and accurate methods to detect mitochondrial mutations the primer shift 
PCR method, PCR-Southern method, the modified primer shift PCR method, and the 
asymmetric PCR method.  With these methods, we analyzed myocardia mtDNA in 
human cadavers of various ages (from 3 years old to 97 years old, mean 57 years 
old).  The 7.4 kb deletion of mtDNA was commonly detected in elderly subjects, 
and the proportion of deleted mtDNA to normal mtDNA increased with age.  
Deleted mtDNA was observed in all subjects that were over 70 years old.  The 
mutation was based on the directly repeated sequence: 5'-CATCAA-CAACCG-3', 
which exists in both the adenosine triphosphatase 6 gene and the displacement 
loop (D-loop) region.  Replication impairment occurred at that directly 
repeated sequence, which caused the elimination of genomes between the 
adenosine triphosphatase 6 gene and the D-loop region and resulted in a 7.4 kb 
deletion.(ABSTRACT TRUNCATED AT 250 WORDS)


\section*{22}
  Sister chromatid exchanges and inhibition of DNA synthesis in irradiated 
human cells.

  Pleskach NM, Andriadze MI, Mikhelson VM, Zhestyanikov VD
  Institute of Cytology, Academy of Sciences USSR, Leningrad.

  Acta Biol Hung  1990  41 (1-3) p209-13
  
  X-ray irradiation inhibits DNA synthesis and enhances the frequency of sister 
chromatid exchanges (SCE) in normal human lymphocytes.  On the contrary, cells 
from patients with Down's syndrome, Xeroderma pigmentosum (form II) and 
progeria, characterized by radioresistant DNA synthesis, do not show such an 
increase in SCE frequency.  We suggest that radiation-induced SCE frequency is 
a result of inhibition of DNA replication, rather than a direct damage of 
chromosomes by ionizing radiation.  It is in agreement with Painter's /13/ 
hypothesis according to which SCE are formed due to asynchronous completion of 
replication in contiguous replicon clusters.  So, probability of SCE formation 
is the more the lower is rate of replication.  Thus, the extent of radiation 
damage cannot be measured directly by the SCE frequency.


\section*{23}
  Mitochondrial gene mutation: the ageing process and degenerative diseases.

  Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang CF, Marzuki S
  Centre for Molecular Biology and Medicine, Monash University, Clayton, 
Victoria, Australia.

  Biochem Int  Dec 1990  22 (6) p1067-76
  
  Polymerase chain reaction (PCR) amplification was carried out on total DNA 
from a range of autopsy tissues from deceased human subjects with no known 
mitochondrial disease, aged from birth (80 minutes) to 87 years.  We report the 
finding of an age-related 5 kb deletion in the mitochondrial genomes of these 
subjects.  The deletion occurs between nucleotide positions 8470 and 13459 of 
the mitochondrial genome, and is flanked by a 13 bp direct repeat.  All tissues 
from adult subjects showed the presence of mitochondrial DNA molecules with the 
deletion after a 30 cycle PCR amplification, by contrast the deletion was not 
similarly detected in any of the infant tissues analysed.  However, the 
occurrence of the deletion was detected in the infant tissues after 60 PCR 
cycles of MtDNA amplification.  It is concluded that such deletions are not 
necessarily associated with particular mitochondrial diseases but occur 
naturally, and with increasing frequency with age.  A consequence of the 
accumulation of this deletion could be a progressive decrease with age of 
bioenergetic capacity which in turn could influence the rate of ageing and 
predispose to age-associated degenerative diseases.


\section*{24}
  Progeria: report of a case and review of the literature.

  Yu QX, Zeng LH
  Faculty of Stomatology, Sun Yat-Sen University of Medical Sciences, 
Guangzhou, China.

  J Oral Pathol Med  Feb 1991  20 (2) p86-8
  
  A case of progeria is reported.  The literatures in this topic is reviewed.  
The oral manifestation of the patients with progeria is summarized.


\section*{25}
  Progeria syndrome with characteristic deformation of proximal radius observed 
on CT.

  Sood S, Rao RC, Ragav B, Berry M
  Department of Radio-Diagnosis, All India Institute of Medical Sciences, New 
Delhi.

  Acta Radiol  Jan 1991  32 (1) p67-8
  
  The progeria syndrome (Hutchinson-Gilford) is an uncommon disease.  A 
peculiar shape of the proximal radial metaphyseal region caused by an infolding 
of the cortex was observed on CT in 2 brothers suffering from this disorder, a 
feature not previously reported.  A brief review of the radiologic literature 
was undertaken.  This new observation needs to be further evaluated as it may 
provide a clinching diagnostic feature of this disease.

\section*{26}
  Hutchinson-Gilford syndrome.

  Hogan PA, Krafchik BR
  Hospital for Sick Children, Toronto, Ontario, Canada.

  Pediatr Dermatol  Dec 1990  7 (4) p317-9
  

\section*{27}
  Homologous recombination is elevated in some Werner-like syndromes but not 
during normal in vitro or in vivo senescence of mammalian cells.

  Cheng RZ, Murano S, Kurz B, Shmookler Reis RJ
  Department of Medicine, University of Arkansas for Medical Sciences, Little 
Rock.

  Mutat Res  Sep-Nov 1990  237 (5-6) p259-69
  
  Werner syndrome (WS) is a recessive genetic condition associated with 
markedly reduced replicative lifespans of cells in culture, high chromosomal 
instability in vivo and in vitro, and premature appearance of many 
characteristics of normal aging, including an increased incidence of cancer.  
We have monitored plasmid homologous recombination frequencies in diploid 
fibroblasts from 6 Werner or Werner-like syndrome patients, following 
transfection with a plasmid substrate containing 2 overlapping fragments of the 
TN5 Neor gene.  Plasmid DNA recovered from these cells was then assayed for 
homologous recombination by (a) transformation of recA- bacteria to Ampr 
(indicating total viable plasmid) or Neor (indicating viable recombinant 
plasmid), and (b) by limited-cycle polymerase chain reaction (PCR) to co-
amplify a recombinant fragment containing the overlap region, and a control 
region of the same plasmid, without bacterial transformation.  Bacterial assay 
data indicated that recombination rates in 3 of the 6 WS strains were 
significantly elevated above normal controls, 4 of 6 appeared elevated by PCR 
assay.  The highest-recombination WS strain showed evidence of reduced 
degradation of transfected plasmid DNA.  For this small sample of WS strains, 
clinical severity of WS was not well correlated with recombination rate as 
determined by either assay (Pearson r = 0.78, not significant, for PCR assay), 
elevated recombination may, however, define a subset of WS at greatest risk for 
cancer and/or atherosclerosis.  PCR assay of a hyperoxia-resistant HeLa cell 
line, displaying substantially increased chromosome breakage, indicated 
increased recombination between direct-repeat fragments.  Nevertheless, 
elevated recombination in WS strains is unlikely to be secondary to impaired 
replicative capacity characteristic of WS cells, or to defective repair of 
chromosome damage which is increased in WS, since recombination in non-WS 
strains was unaffected by passage level or repeated UV irradiation.


\section*{28}
  Reduced DNA-repair capacity in cells originating from a progeria patient.

  Wang SM, Nishigori CK, Zhang JM, Takebe H
  Department of Experimental Radiology, Kyoto University, Japan.

  Mutat Res  Sep-Nov 1990  237 (5-6) p253-7
  
  A Chinese boy was identified to be suffering from progeria (Hutchinson-
Gilford syndrome), the first case of the disease ever reported in China.  Cells 
originating from the patient had a reduced amount of unscheduled DNA synthesis 
after irradiation with ultraviolet light (UV).  The fractions of the progeria 
cells surviving against UV irradiation measured by colony-forming ability, and 
the host-cell reactivation capacity of the progeria cells, measured by the 
plaque formation of UV-irradiated herpes simplex virus were lower than those 
measured in normal cells.  The progeria cells appear to have a reduced capacity 
to repair UV excision damage.


\section*{29}
  Proliferation-dependent regulation of DNA glycosylases in progeroid cells.

  Cool BL, Sirover MA
  Fels Institute for Cancer Research and Molecular Biology, Temple University 
School of Medicine, Philadelphia, PA 19140.

  Mutat Res  Sep-Nov 1990  237 (5-6) p211-20
  
  The regulation of the base excision repair enzymes uracil DNA glycosylase and 
hypoxanthine DNA glycosylase was examined in 2 different progeroid cell strains.  
The immunoreactivity of the uracil DNA glycosylase in progeroid cells was 
examined by enzyme linked immunosorbent assay (ELISA) and by immunoblot 
analysis.  The enzyme was recognized in a quantitative manner by 2 different 
anti-human uracil DNA glycosylase monoclonal antibodies in the ELISA.  Western 
blot analysis identified a glycosylase protein of Mr = 37,000.  In randomly 
proliferating progeroid cells, the uracil DNA glycosylase was enhanced 3-fold 
during cell growth.  In synchronous cells, uracil DNA glycosylase and 
hypoxanthine DNA glycosylase were induced with an extent of induction (5-6-
fold) comparable to that observed for normal human cells.  Further, the 
activity of each base excision repair enzyme was enhanced with a comparable 
temporal sequence prior to the induction of DNA synthesis and DNA polymerase 
activity.  These results indicate a normal cell cycle regulation of base 
excision repair in progeroid cells.


\section*{30}
  DNA damage metabolism and aging.

  Mullaart E, Lohman PH, Berends F, Vijg J
  Department of Molecular Biology, TNO Institute for Experimental Gerontology, 
Rijswijk, The Netherlands.

  Mutat Res  Sep-Nov 1990  237 (5-6) p189-210
  
  As a result of permanent exposure to low levels of various endogenous and 
exogenous genotoxic agents, large numbers of lesions are continuously induced 
in the DNA of cells of living organisms.  Such lesions could lead to 
dysfunction of cells and tissues, and they might well be the underlying cause 
of the age-related reduction of homeostatic capacity and the increased 
incidence of cancer and other diseases of old age.  The rate of damage 
induction as well as the persistence of the lesions depends on the activity, 
efficiency and reliability of a wide variety of molecular defense systems.  
However, a certain degree of imperfection seems to be a general characteristic 
of most of these defense systems and this could lead to a gradual accumulation 
of DNA alterations during aging.  Even when the original lesions are quickly 
removed, they can still lead to secondary changes in the DNA, such as DNA-
sequence changes and changes in gene expression.  This process would be 
accelerated in case of the occurrence of an age-related decline in the 
efficiency of these molecular defense systems.  This review deals with the 
present knowledge on the occurrence of 'spontaneous' DNA damage in aging 
organisms, its potential sources, the influence of preventive and processive 
cellular defense mechanisms and its consequences in terms of DNA-sequence 
changes, DNA conformational and configurational changes and changes in gene 
expression.  In general, it can be concluded from the data discussed here that, 
in spite of a number of discrepancies and conflicting results, an age-related 
accumulation of DNA alterations occurs at all levels, e.g., chemical structure, 
DNA-sequence organization and gene expression.  

\section*{31}
  Cholinergic receptors in human brain: effects of aging and Alzheimer disease.

  Giacobini E
  Department of Pharmacology, Southern Illinois University School of Medicine, 
Springfield 62794.

  J Neurosci Res  Dec 1990  27 (4) p548-60
  
  A general review of cholinergic receptors in human brain is presented.  The 
paper focuses upon changes in normal aging brain and in Alzheimer disease.  
Studies from five different approaches are reported: 1) molecular biology, 2) 
receptor binding studies, 3) studies with specific neurotoxins, 4) 
immunocytochemistry, and 5) PET scan.  These studies document profound and 
characteristic differences between the normal aging and the pathological 
Alzheimer brain with regard to cholinergic receptor localization, distribution, 
and function.  


\section*{32}
  Immunological aspects of progeria (Hutchinson-Gilford syndrome) in a 15-month-
old child.

  Harjacek M, Batinic D, Sarnavka V, Uzarevic B, Mardesic D, Marusic M
  Department of Paediatrics, University Hospital Rebro, Croatia, Yugoslavia.

  Eur J Pediatr  Nov 1990  150 (1) p40-2
  
  A thorough analysis of the immunological status was conducted in a 15-month-
old child with progeria (Hutchinson-Gilford syndrome).  Total leukocyte and 
neutrophil counts were slightly increased, and monocytes were decreased.  
Percentage and numbers of CD4+ cells in the blood were mildly decreased as well 
as the CD4/CD8 cell ratio.  CD20 (B-cell marker) bearing cells and cells 
bearing Ia-antigens were increased, as well as CD16 and CD56 marker-bearing 
cells (natural-killer cells, NK).  Lymphocyte proliferation upon stimulation 
with phytohaemagglutinin and purified protein derivative were decreased, and 
with pokeweed mitogen increased.  NK cell activity appeared increased, 
particularly at lower effector: target cell ratios.


\section*{33}
  Senescent human diploid fibroblasts are able to support DNA synthesis and to 
express markers associated with proliferation.

  Kill IR, Shall S
  Laboratory of Cell and Molecular Biology, School of Biological Sciences, 
University of Sussex, Brighton, England.

  J Cell Sci  Nov 1990  97 ( Pt 3) p473-8
  
  The characteristic limited reproductive life-span of normal human fibroblasts 
in culture is due to a steadily decreasing fraction of cells able to 
proliferate in the standard rich growth media.  We have observed that 
restricting the growth factor supply to old cells for variable lengths of time 
in culture increases the fraction of cells that can enter S-phase, although 
these cells do not go on to divide.  Thus, it seems that there is a transient 
phase between the proliferating state and the irreversibly post-mitotic, 
senescent state.  Perhaps a 'quiescent-G0' state, which can be maintained in 
the presence of growth factors, is a stage on the pathway to mortalization and 
senescence.


\section*{34}
  Progeria [letter] [see comments]

  Sahni A, Thapa BR, Mehta S

  Indian Pediatr  Sep 1990  27 (9) p995-7
  

\section*{35}
  Metal ion-catalyzed oxidation of proteins: biochemical mechanism and 
biological consequences 

  Stadtman ER

  Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, 
National Institutes of Health, Bethesda, MD 20892.

  Free Radic Biol Med  1990  9 (4) p315-25

  In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, 
a number of enzymic and nonenzymic oxygen free radical-generating systems are 
able to catalyze the oxidative modification of proteins.  Whereas random, 
global modification of many different amino acid residues and extensive 
fragmentation occurs when proteins are exposed to oxygen radicals produced by 
high energy radiation, only one or a few amino acid residues are modified and 
relatively little peptide bond cleavage occurs when proteins are exposed to 
metal-catalyzed oxidation (MCO) systems.  The available evidence indicates that 
the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 
and that these products react at metal-binding sites on the protein to produce 
active oxygen (free radical?) species (viz, OH, ferryl ion) which attack the 
side chains of amino acid residues at the metal-binding site.  Among other 
modifications, carbonyl derivatives of some amino acid residues are formed, 
prolyl and arginyl residues are converted to glutamylsemialdehyde residues, 
lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues, 
histidyl residues are converted to asparagine and/or aspartyl residues, prolyl 
residues are converted to glutamyl or pyroglutamyl residues, methionyl residues 
are converted to methionylsulfoxide residues, and cysteinyl residues to mixed-
disulfide derivatives.  The biological significance of these metal ion-
catalyzed reactions is highlighted by the demonstration: (i) that oxidative 
modification of proteins "marks" them for degradation by most common proteases 
and especially by the cytosolic multicatalytic proteinase from mammalian cells, 
(ii) protein oxidation contributes substantially to the intracellular pool of 
catalytically inactive and less active, thermolabile forms of enzymes which 
accumulate in cells during aging, oxidative stress, and in various pathological 
states, including premature aging diseases (progeria, Werner's syndrome), 
muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol 
toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-
reperfusion.  Furthermore, the metal ion-catalyzed protein oxidation is the 
basis of biological mechanisms for regulating changes in enzyme levels in 
response to shifts from anaerobic to aerobic metabolism, and probably from one 
nutritional state to another.  It is also involved in the killing of bacteria 
by neutrophils and in the loss of neutrophil function following repeated cycles 
of respiratory burst activity.  


\section*{36}
  Cytogenetic investigations of DNA damage in aging: a twin study.

  Hirsch B
  Department of Laboratory Medicine \& Pathology, University of Minnesota, 
Minneapolis.

  Basic Life Sci  1990  53 p303-13
  
\section*{37}
  Hutchinson-Gilford progeria syndrome in siblings. Report of three new cases.

  Monu JU, Benka-Coker LB, Fatunde Y
  Department of Radiology, University of Wisconsin Hospital and Clinics, 
Madison.

  Skeletal Radiol  1990  19 (8) p585-90
  
  The Hutchinson-Gilford progeria syndrome is a rare, inherited, pediatric 
condition with features of premature and accelerated aging.  The pattern of 
inheritance is uncertain though both autosomal dominant and autosomal recessive 
modes have been proposed.  The patients usually present after the 1st year of 
life with progressive skin and skeletal changes that give rise to a 
characteristic physical appearance.  Three siblings seen at the University of 
Benin Teaching Hospital are described in this report, the third documenting the 
occurrence of progeria in African black patients.  The two older siblings show 
the classic physical and radiologic changes described in progeria whereas the 
third, a 2-year-old boy, manifests only the early physical and radiologic 
changes of the disease.  We compare the radiologic features of progeria with 
those of other progeroid conditions: acrogeria, Werner's and Cockayne's 
syndromes.  

\section*{38}
  Immortalization of Werner syndrome and progeria fibroblasts.

  Saito H, Moses RE
  Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.

  Exp Cell Res  Feb 1991  192 (2) p373-9
  
  Human fibroblast cells from two different progeroid syndromes, Werner 
syndrome (WS) and progeria, were established as immortalized cell lines by 
transfection with plasmid DNA containing the SV40 early region.  The lineage of 
each immortalized cell line was confirmed by VNTR analysis.  Each of the 
immortalized cell lines maintained its original phenotype of slow growth.  DNA 
repair ability of these cells was also studied by measuring sensitivity to 
killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and 
cis-dichlorodiamine platinum.  The results showed that both WS and progeria 
cells have normal sensitivity to these agents.


\section*{39}
  A mechanism for relief of replication blocks by activation of unused origins 
and age-dependent change in the caffeine susceptibility in xeroderma 
pigmentosum variant.

  Fujiwara Y, Ichihashi M, Matsumoto A, Kataoka H
  Department of Radiation Biophysics, Kobe University School of Medicine, 
Japan.

  Mutat Res  Jan 1991  254 (1) p79-87
  
  The first XP16KO-I (age 42 without cancer) and the second XP16KO-II (age 52 
after carcinogenesis) skin fibroblasts of a xeroderma pigmentosum variant (XPV) 
were studied.  First, caffeine had no effect on XP16KO-I cells, but it 
potentiated UV killing and inhibited the recovery of DNA synthesis and the 
elongation of nascent DNA after UV irradiation in XP16KO-II cells, indicating 
an age-dependent change from caffeine resistance to sensitivity.  These results 
confirmed a previous similar change in an unrelated XPV subject and the 
existence of 2 XPV subgroups, caffeine-sensitive and -resistant.  Further, 
processing of post-excision breaks was also slightly more defective in XP16KO-
II than in XP16KO-I cells.  Second, nascent DNA pulse-labeled at 1.5 h after 5 
J/m2 indicated an initial complete blockage of elongation by each dimer in 
XP16KO-II cells and less complete blocks in XP16KO-I and normal cells.  The 
nascent DNA in 5 J/m2-irradiated XP16KO-II cells was 4 microns (8 x 10(6) Da) 
long for the peak fraction, with a possible range up to 20 microns of average 
replicon size, indicating activation of at least 4 microns-spaced new origins 
around 1.5 h post irradiation.  Post-labeling chase without caffeine allowed 
nearly normal elongation to the present maximum molecular weight of 2.60-2.80 x 
10(8) in 3-4 h in irradiated XP16KO-I and -II cells.  Thus, the activation of 
unused origins at shorter spaces is a main mechanism for relief and the 
reduction of almost all unreplicated regions or blocks initially formed by 2 
dimers in trans on both leading strands between converging forks.  Post-
labeling addition of 1 mM caffeine increased perpetuated blocks to a frequency 
of about 10% of the initial number of dimers in 4 h in XP16KO-II cells, but not 
in XP16KO-I and normal cells.


\section*{40}
  Detection of a specific mitochondrial DNA deletion in tissues of older 
humans.

  Cortopassi GA, Arnheim N
  Molecular Biology Section, University of Southern California, Los Angeles 
90089-1340.

  Nucleic Acids Res  Dec 11 1990  18 (23) p6927-33
  
  Using PCR, we found that normal heart muscle and brain from adult human 
individuals contain low levels of a specific mitochondrial DNA deletion, 
previously found only in patients affected with certain types of neuromuscular 
disease.  This deletion was not observed in fetal heart or brain.  Experimental 
tests support the idea that the deletion exists in vivo in adult mitochondria 
and is not an in vitro artifact of PCR.  Our data provide direct experimental 
support for the idea that accumulation of mitochondrial DNA deletions may be 
important in aging.


\section*{41}
  Marfan syndrome associated with bicuspid aortic valve, premature aging, and 
primary hypogonadism.

  Gershoni-Baruch R, Moor EV, Enat R
  Department of Pediatrics A, Rambam Medical Center, Haifa, Israel.

  Am J Med Genet  Oct 1990  37 (2) p169-72
  
  We report and discuss a patient with characteristics of Marfan syndrome 
associated with a bicuspid aortic valve, premature aging, and primary 
hypogonadism.

\section*{42}
  Damage to lymphocytes by X-ray and bleomycin measured with the cytokinesis-
block micronucleus technique.

  Odagiri Y, Dempsey JL, Morley AA
  Department of Haematology, Flinders Medical Centre, Bedford Park, SA, 
Australia.

  Mutat Res  May-Jul 1990  237 (3-4) p147-52
  
  Chromosome damage induced by X-irradiation or bleomycin was measured using 
the cytokinesis-block micronucleus assay in the peripheral blood lymphocytes of 
6 newborn, 8 young and 10 elderly individuals.  An increase in the frequency of 
spontaneous micronuclei with age was observed.  There was no difference in the 
X-irradiation-induced micronucleus frequency between the 3 groups.  There was a 
significant increase with age in the number of micronuclei induced by bleomycin.  
Kinetochore-labelling studies revealed that the percentage of kinetochore-
positive induced micronuclei was higher for bleomycin (36.2-43.3%) than for X-
irradiation (17.1-19.7%).  The age-related increase in frequency of spontaneous 
or bleomycin-induced micronuclei was due to increases in both kinetochore-
positive and kinetochore-negative micronuclei.  The frequency of kinetochore-
positive or -negative micronuclei induced by X-irradiation was not different 
between the 3 age groups.  These results suggest that bleomycin is more potent 
in inducing whole-chromosome loss than X-rays, and that lymphocytes from aged 
individuals are more sensitive to bleomycin in terms of both chromosome 
breakage and whole chromosome loss.


\section*{43}
  DNA damage and repair with age in individual human lymphocytes.

  Singh NP, Danner DB, Tice RR, Brant L, Schneider EL
  Laboratory of Molecular Genetics, National Institute on Aging, Baltimore, MD 
21224.

  Mutat Res  May-Jul 1990  237 (3-4) p123-30
  
  Previous biochemical studies on DNA repair competence and aging have been 
limited to techniques, such as alkaline elution or nucleoid sedimentation, 
involving mass cell populations.  These techniques provide no information about 
the distribution of DNA damage and repair among individual cells and are 
unlikely to detect age-dependent changes affecting a minor fraction of the cell 
population.  We have recently described a microgel electrophoretic assay (Singh 
et al., 1988) that measures, at the level of the individual cell, single-strand 
DNA breaks and alkali-sensitive sites.  Here, we employ this method to analyze 
DNA damage and repair in lymphocytes isolated from the peripheral blood of 31 
subjects (23 males and 8 females aged 25-91 years) and exposed in vitro to 200 
rads of X-irradiation.  While basal (pre-irradiation) levels of damage were 
independent of the age of the donor, an age-dependent increase in DNA damage 
was observed immediately following irradiation.  For all subjects, the mean 
level of DNA damage was restored to pre-irradiation control levels within 2 h 
of incubation at 37 degrees C. However, a distribution analysis of DNA damage 
among cells within each sample indicated the presence of a few highly damaged 
cells (4-16%) in the 2-h sample, the occurrence of which was significantly more 
common among aged individuals.  These data indicate an age-related decline in 
DNA repair competence among a small subpopulation of lymphocytes.


\section*{44}
  Immortalization of primary cells by DNA tumor viruses.

  Linder S, Marshall H
  Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital, 
Stockholm, Sweden.

  Exp Cell Res  Nov 1990  191 (1) p1-7
  
  Cellular senescence is characterized by a decline in sensitivity to growth 
factors resulting in cessation of cellular growth.  The expression of cellular 
or viral oncogenes may result in the establishment of cell lines with unlimited 
proliferative potential ("immortalization").  A variety of viral and cellular 
oncogenes have been reported to immortalize cells, suggesting that multiple 
mechanisms may lead to an escape from senescence.  Immortalization has been 
reported to occur as a result of an interaction of viral proteins with cellular 
suppressor gene products or may result from the elevated expression of 
"transforming" oncoproteins (such as the polyomavirus middle-t antigen).  Here 
we speculate that a selection for cells with a further decreased probability of 
cell cycle withdrawal can occur during the growth of cells expressing viral 
early genes, resulting in a process of tumor progression.  Explaining 
immortalization in terms of mitogenic stimulation due to the expression of 
viral oncogenes followed by genetic/epigenetic changes may help to explain why 
lytic DNA viruses have a biological activity which may not be necessary for 
their life cycle.  


\section*{45}
  Quantitative changes in T cell DNA methylation occur during differentiation 
and ageing.

  Golbus J, Palella TD, Richardson BC
  Northwestern University, Evanston Hospital.

  Eur J Immunol  Aug 1990  20 (8) p1869-72
  
  DNA methylation is one of the mechanisms involved in the regulation of 
developmentally relevant genes.  Previous experiments demonstrated that T cells 
treated with DNA methylation inhibitors reacquire some of the phenotypic and 
functional characteristics of thymocytes, suggesting that DNA methylation may 
be involved in regulating some of the changes in gene expression during thymic 
maturation.  To further examine whether changes in DNA methylation occur during 
T cell differentiation, total DNA deoxymethylcytosine content was compared in 
human thymocyte subsets and mature T cells.  A significant increase in 
deoxymethylcytosine was found at the end of T cell differentiation which then 
decreased with age.  These results suggest that increased DNA methylation may 
serve to silence genes following T cell differentiation.  The results also 
raise the possibility that age-related decreases in T cell DNA methylation may 
contribute to changes in T cell function occurring in the elderly.

\end{document}




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