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Jan Vijg

Publications and source records attributed to Jan Vijg.

At least 19 recordsLinked to original sources
PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗
PubMed2025

A blood-based DNA damage signature in patients with Parkinson's disease is associated with disease progression.

Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression.

Humans↗
PubMed2006

A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Aging↗
PubMed2006

Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate.

This study uses a base excision repair (BER)-deficient model, the DNA polymerase beta heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged beta-pol(+/-) mice express 50% less beta-pol transcripts and protein (P < 0.05) than aged beta-pol(+/+) mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in beta-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged beta-pol(+/-) mice exhibited a 6.7-fold increase in developing lymphoma (P < 0.01). Accordingly, 38% of beta-pol(+/-) mice exhibited lymphoid hyperplasia, whereas none of the beta-pol(+/+) exhibited this phenotype. beta-pol(+/-) mice were also more likely to develop adenocarcinoma (2.7-fold increase; P < 0.05) and more likely to develop multiple tumors, as 20% of the beta-pol(+/-) animals died bearing multiple tumors compared with only 5% of the beta-pol(+/+) animals (P < 0.05). In spite of accelerated tumor development, no gross effect of beta-pol heterozygosity was seen with respect to life span. However, the survival curves for the beta-pol(+/+) and beta-pol(+/-) mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P < 0.05) acceleration of the age-dependent mortality rate in beta-pol(+/-) mice. Thus, the beta-pol(+/-) mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis.

Age Factors↗
PubMed2006

Increased cell-to-cell variation in gene expression in ageing mouse heart.

The accumulation of somatic DNA damage has been implicated as a cause of ageing in metazoa. One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice. To confirm that increased stochasticity of gene expression could be a result of increased genome damage, we treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at a lacZ reporter locus. These results underscore the stochastic nature of the ageing process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.

Aging↗
PubMed2006

Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice.

Genetic defects in nucleotide excision repair (NER) are associated with premature aging, including cancer, in both humans and mice. To investigate the possible role of increased somatic mutation accumulation in the accelerated appearance of symptoms of aging as a consequence of NER deficiency, we crossed four different mouse mutants, Xpa-/-, Ercc6(Csb)-/-, Ercc2(Xpd)m/m and Ercc1-/m, with mice harboring lacZ-reporter genes to assess mutant frequencies and spectra in different organs during aging. The results indicate an accelerated accumulation of mutations in both liver and kidney of Xpa defective mice, which correlated with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum had undergone a shift, in both organs, to G:C-->T:A transversions, a signature mutation of oxidative DNA damage. Ercc1-/m mice, with their short lifespan of 6 months and severe symptoms of premature aging, especially in liver and kidney, displayed an even faster lacZ-mutant accumulation in liver. In this case, the excess mutations were mostly genome rearrangements. Csb-/- mice, with mild premature aging features and no reduction in lifespan, and Xpdm/m mice, exhibiting prominent premature aging features and about 20% reduction in lifespan, did not have elevated lacZ-mutant frequencies. It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation.

Aging, Premature↗
PubMed2006

Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging?

Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of mutations in the mutator mice typically are more than an order of magnitude higher than typical levels in aged humans. Furthermore, most of the aging-like features are not specific to the mtDNA mutator mice, but are shared with several other premature aging mouse models, where no mtDNA mutations are involved. We conclude that, although mtDNA mutator mouse is a very useful model for studies of phenotypes associated with mtDNA mutations, the aging-like phenotypes of the mouse do not imply that mtDNA mutations are necessarily involved in natural mammalian aging. On the other hand, the fact that point mutations in aged human tissues are much less abundant than those causing premature aging in mutator mice does not mean that mtDNA mutations are not involved in human aging. Thus, mtDNA mutations may indeed be relevant to human aging, but they probably differ by origin, type, distribution, and spectra of affected tissues from those observed in mutator mice.

Adult↗
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

Mutant frequencies and spectra depend on growth state and passage number in cells cultured from transgenic lacZ-plasmid reporter mice.

Transgenic mice harboring the lacZ gene within a plasmid that can be recovered and amplified in Escherichia coli, to establish mutant frequencies and spectra, have provided crucial insights into the relationships between mutations, cancer and aging in vivo. Here, we use embryonic fibroblasts from transgenic lacZ-plasmid reporter mice to determine the relationship between cell proliferation in culture and mutations induced by ultraviolet (UV) light. A single dose of 2.5J/m2 of UVC to actively proliferating cells caused an approximately eight-fold increase in mutant frequency 24 h after irradiation. Identically treated quiescent cells showed a two-fold increase in mutant frequency. Thus, whereas proliferation facilitated the acquisition of mutations, it was not an absolute requirement. Characterization of the UV-induced mutations indicated that the lower mutant frequency in quiescent cells was due mainly to a reduction in point mutations; size-change mutations, indicative of translocations or deletions, were relatively unaffected by the growth state of the cells. To investigate long-term genomic stability after UVC-induced damage, we monitored the lacZ locus in irradiated cells passaged for many generations in culture. The results indicated the emergence of jackpot mutations of rapidly changing frequency, most likely reflecting the successive emergence and decline of dominant cell clones during long-term culture. These findings show that the lacZ-plasmid locus is a valid reporter for studying induced mutations in short-term cultures of both quiescent and proliferating fibroblasts. In long-term cultures, the locus is less suitable for studying induced mutations owing to the instability of the cell population.

Animals↗
PubMed2005

Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction.

Trichothiodystrophy (TTD) patients with a mutation in the XPD gene of nucleotide excision repair (NER) have a short life span and show various features of premature aging, thereby linking DNA damage to the aging process. Xpd(TTD) mutant mice share many features with TTD patients, including a shorter life span, accompanied by a segmental progeroid phenotype. Here we report new pathology features supportive to the premature aging phenotype of Xpd(TTD) mice. Strikingly, accelerated aging pathology is accompanied by signs suggestive of caloric restriction (CR), a condition usually linked to retardation of age-related pathology and life extension. Accelerated aging symptoms in Xpd(TTD) mice are most likely due to accumulation of endogenously generated DNA damage and compromised transcription leading to cell death, whereas CR symptoms may reflect the need of Xpd(TTD) mice to reduce metabolism (ROS production) in an attempt to extend their life span. Our current findings in Xpd(TTD) mice further strengthen the link between DNA damage, repair and aging.

Aging↗
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

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.

Animals↗
PubMed2005

Detection of rpoB mutations associated with rifampin resistance in Mycobacterium tuberculosis using denaturing gradient gel electrophoresis.

Denaturing gradient gel electrophoresis (DGGE) was used to probe for mutations associated with rifampin (RIF) resistance in the rpoB gene of Mycobacterium tuberculosis. DGGE scans for mutations across large regions of DNA and is comparable to DNA sequencing in detecting DNA alterations. Specific mutations are often recognized by their characteristic denaturation pattern, which serves as a molecular fingerprint. Five DGGE primer sets that scanned for DNA alterations across 775 bp of rpoB were developed. These primer sets were used to scan rpoB for DNA alterations in 296 M. tuberculosis patient isolates from the United States-Mexico border states of Texas and Tamaulipas. The most useful primer set scanned for mutations in the rifampin resistance-determining region (RRDR) and detected mutations in 95% of the RIF-resistant isolates compared to 2% of RIF-susceptible isolates. Thirty-four different alterations were observed within the RRDR by DGGE. In addition, isolates harboring mixtures of DNA within rpoB were readily detected by DGGE. A second PCR primer set was used to detect the V146A mutation in 5 to 7% of RIF-resistant isolates. A third primer set was used to detect mutations in 3% of RIF-resistant isolates, some of which also harbored mutations in the RRDR. Only 1 of 153 RIF-resistant isolates did not have a detectable rpoB mutation as determined by DGGE and DNA sequencing. These results demonstrate the power and usefulness of DGGE in detecting mutations associated with drug resistance in M. tuberculosis.

Antibiotics, Antitubercular↗
PubMed2005

Detection by denaturing gradient gel electrophoresis of pncA mutations associated with pyrazinamide resistance in Mycobacterium tuberculosis isolates from the United States-Mexico border region.

Denaturing gradient gel electrophoresis (DGGE) was used to probe for mutations associated with pyrazinamide (PZA) resistance in the pncA gene of Mycobacterium tuberculosis. DGGE scans for mutations across large regions of DNA and rivals sequencing in its ability to detect DNA alterations. Specific mutations can often be recognized by their characteristic denaturation pattern, which serves as a molecular fingerprint. Five PCR target fragments were designed to scan for DNA alterations across 600 bp of pncA in 181 M. tuberculosis isolates from patients residing in the U.S-Mexico border states of Texas and Tamaulipas, respectively. A region of pncA was observed with a high GC content and a melting temperature approaching 90 degrees C that was initially refractory to denaturation, and a DGGE target fragment was specifically designed to detect mutations in this region. DGGE detected pncA mutations in 82 of 83 PZA-resistant isolates. By contrast, only 1 of 98 PZA-susceptible isolates harbored a detectable DNA alteration. The pncA gene was sequenced from 41 isolates, and 32 DNA alterations in 32 PZA-resistant isolates were identified, including 11 new mutations. DGGE also detected nine isolates whose susceptibility to PZA appeared to be incorrect, and DNA sequencing confirmed these apparent errors in drug susceptibility testing. These results demonstrate the power and usefulness of DGGE in detecting mutations associated with PZA resistance in M. tuberculosis.

Amidohydrolases↗
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↗