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Yousin Suh

Publications and source records attributed to Yousin Suh.

13 recordsLinked to original sources
PubMed2006

Extended longevity mechanisms in short-lived progeroid mice: identification of a preservative stress response associated with successful aging.

Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typical of long-lived endocrine-mutant and dietary-restricted animals in short-lived progeroid mice. These data suggest that a subset of symptoms observed in premature aging, and possibly normal aging as well, may be indirect manifestations of a beneficial adaptive stress response to endogenous oxidative damage, rather than a detrimental result of the damage itself.

Aging↗
PubMed2006

Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

Aging↗
PubMed2005

Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice.

Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling- and caspase 3-stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of approximately 2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals.

Animals↗
PubMed2005

SNP discovery in associating genetic variation with human disease phenotypes.

With the completion of the human genome project, attention is now rapidly shifting towards the study of individual genetic variation. The most abundant source of genetic variation in the human genome is represented by single nucleotide polymorphisms (SNPs), which can account for heritable inter-individual differences in complex phenotypes. Identification of SNPs that contribute to susceptibility to common diseases will provide highly accurate diagnostic information that will facilitate early diagnosis, prevention, and treatment of human diseases. Over the past several years, the advancement of increasingly high-throughput and cost-effective methods to discover and measure SNPs has begun to open the door towards this endeavor. Genetic association studies are considered to be an effective approach towards the detection of SNPs with moderate effects, as in most common diseases with complex phenotypes. This requires careful study design, analysis and interpretation. In this review, we discuss genetic association studies and address the prospect for candidate gene association studies, comparing the strengths and weaknesses of indirect and direct study designs. Our focus is on the continuous need for SNP discovery methods and the use of currently available prescreening methods for large-scale genetic epidemiological research until more advanced sequencing methods currently under development will become available.

Base Sequence↗
PubMed2005

Genetics of longevity and aging.

Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.

Aging↗
PubMed2003

A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.

Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl(-) currents and HCO3(-) -transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.

Alleles↗
PubMed2003

Up-regulation of cytoskeletal-associated protein 2 in primary human gastric adenocarcinomas.

BACKGROUND AND METHOD: We performed differential-display polymerase chain reaction to find up-regulated sequences in primary human gastric cancers, and cloned one up-regulated sequence, which was expressed in all the gastric cancer cells that we examined. The cloned sequence was identified as cytoskeletal-associated protein 2 (CKAP2). We also cloned a shorter splice variant, CKAP2-s. The CKAP2 or CKAP2-s protein in HeLa cells was localized to microtubule organizing centers (MTOC) and microtubules. This co-localization pattern was disrupted by nocodazole, a microtubule-destabilizing agent. RESULTS: These observations suggested that CKAP2 might be associated with microtubule networks. CKAP2 protein was detected in neither normal GI tract nor normal gastric mucosa. However, both CKAP2 and CKAP2-s mRNAs were up-regulated in 55% (23 out of 42 samples) of primary human gastric cancers by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, CKAP2 proteins were detected in immunohistochemical staining in all the gastric cancer samples that we examined. CKAP2 protein-expressing cells were also found in gastric adenomas. The average number of CKAP2 protein-positive cells in adenocarcinomas was 48.8%, which was significantly higher than the number in tubular adenomas, 9.1%. CONCLUSION: When these points were taken together, we concluded that CKAP2 is up-regulated in primary human gastric adenocarcinomas at high frequency and might be useful for diagnosing and discriminating adenocarcinomas from tubular adenomas of the stomach.

Adenocarcinoma↗
PubMed2003

Functional genomics of ageing.

Ageing is the most complex phenotype currently known, since it becomes manifest in all organs and tissues, affects an organism's entire physiology, impacts function at all levels and increases susceptibility to all major chronic diseases. Insight into the molecular and cellular targets of the ageing process would offer the unprecedented opportunity to postpone and prevent some, if not all, of its deteriorative aspects by preventive and therapeutic means. Thus far, our understanding of the causes of ageing is limited. To an important extent this is due to our inability, in the past, to study ageing systems. Instead, ample information has been gathered about individual cellular components at various ages, but this has not allowed a clear understanding of the integrated genomic circuits that control mechanisms of ageing, survival and stress responses. With the emergence of functional genomics, we finally have the opportunity to study ageing in a comprehensive manner, as a function of the dynamic network of genes that determines the physiology of an individual organism over time.

Aging↗
PubMed2002

Cell signaling in aging and apoptosis.

Alterations in apoptotic potential, due to perturbations in cell signaling cascades, could underlie age-related organ-specific cellular degeneration and death. While increased apoptosis could lead to cell loss, as in neuronal degeneration, loss of apoptosis competence might well result in the loss of phenotypic fidelity of somatic cells, which could explain to some extent, the age-related increase in cancer incidence. Results from our laboratory indicate that after subjecting young and old rats to genotoxic stress in the form of methyl methanesulfonate (MMS), an apoptotic response is quickly mounted in the liver of the young animals but virtually absent in the same organ of old animals (Nature Med. 8 (2002) 3). To address the possible molecular signaling defect(s) responsible for the age-related dysfunction of apoptosis in response to MMS, mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinases (JNKs) and p38 MAPKs, were evaluated in the liver of young and old rats after MMS treatment. The results demonstrated distinct age-specific patterns of MMS-induced MAPKs activation, suggesting that the balance between cell survival and apoptosis after genotoxic stress may be impaired during aging. These results are discussed in terms of the relative importance in aging of biological redundancy, a concept put forward by the late Bernard Strehler, and cellular fidelity.

Animals↗
PubMedDate not supplied

Maintaining genetic integrity in aging: a zero sum game.

Aging of somatic cells can be defined as the gradual loss of the information embedded in the global and local properties of complex macromolecular networks. This loss of information may reflect the dynamic interplay between stochastic factors, such as the accumulation of unrepaired somatic damage, and gene-encoded programmatic responses. This would ultimately result in loss of function, impaired response to environmental challenge, and a progressively increased incidence of disease. Here the authors present the case for aging as a continuous battle between maintaining genomic integrity and ensuring sufficient cell functional mass. Focusing on aging of the liver in rodents, evidence is presented that normal aging is associated with a gradual accumulation of random alterations in the DNA of the genome as a consequence of imperfect DNA repair and a decrease in the rate of DNA damage-induced apoptosis. Apoptosis is the cell's genome maintenance mechanism of last resort and an imbalance towards apoptosis can contribute to manifestations of aging-related phenotypes, as exemplified by mouse models of premature aging due to genetic defects in genome maintenance. Prospects to reset the clock in this zero sum game between survival and the maintenance of phenotypic integrity will be discussed.

Aging↗