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S Michal Jazwinski

Publications and source records attributed to S Michal Jazwinski.

At least 19 recordsLinked to original sources
PubMed2006

Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity.

Lag1 (longevity assurance gene 1) homologues, a family of transmembrane proteins found in all eukaryotes, have been shown to be necessary for (dihydro)ceramide synthesis. All Lag1 homologues contain a highly conserved stretch of 52 amino acids known as the Lag1p motif. However, the functional significance of the conserved Lag1p motif for (dihydro)ceramide synthesis is currently unknown. In this work, we have investigated the function of the motif by introducing eight point mutations in the Lag1p motif of the mouse LASS1 (longevity assurance homologue 1 of yeast Lag1). The (dihydro)ceramide synthase activity of the mutants was tested using microsomes in HeLa cells and in vitro. Six of the mutations resulted in loss of activity in cells and in vitro. In addition, our results showed that C18:0 fatty acid CoA (but not cis-C18:1 fatty acid CoAs) are substrates for LASS1 and that LASS1 in HeLa cells is sensitive to fumonisin B1, an in vitro inhibitor of (dihydro)ceramide synthase. Moreover, we mutated the Lag1p motif of another Lag homologue, human LASS5. The amino acid substitutions in the human LASS5 were the same as in mouse LASS1, and had the same effect on the in vitro activity of LASS5, suggesting the Lag1p motif appears to be essential for the enzyme activity of all Lag1 homologues.

Amino Acid Sequence↗
PubMed2006

Knowledge of memory aging in adulthood.

The Knowledge of Memory Aging Questionnaire (KMAQ) measures laypersons' knowledge of memory changes in adulthood for research or educational purposes. Half of the questions pertain to normal memory aging and the other half cover pathological memory deficits due to non-normative factors, such as adult dementia. In this study, we compared memory knowledge in middle age adults (40-59 years), young-old adults (60-79 years) and very old adults (80 years and over). These data were collected as a part of the Louisiana Healthy Aging Study, a multidisciplinary population-based study that examines the determinants of healthy aging in adulthood. Results indicated that very old adults performed more poorly overall. Follow-up analyses revealed that they endorsed stereotyped views of normal memory aging more often than did the other age groups. Analyses of response accuracy by gender yielded comparable performance for men and women. Implications for research and the design of educational programs are considered.

Adult↗
PubMed2005

CD8 T-cell immune phenotype of successful aging.

The nonagenarian population by definition represents individuals who have demonstrated success in aging. We determined the status of CD8(+) T-cell senescence in nonagenarians by analyzing the expression of CD28 and Fas (CD95), and analyzing activation and activation-induced cell death (AICD). Peripheral blood mononuclear cells (PBMCs) were isolated from three groups of subjects: adults (20-64-year-old), older adults (65-89-year-old), and nonagenarians (>or=90-year-old). PBMCs were stimulated with phytohemagglutinin (PHA) (10 microg/ml). The cells were labeled with conjugated antibodies specific for CD4, CD8, CD28, CD45RO, and Fas, and were analyzed by FACS((R)). There was a strong negative correlation of the percentage of CD28(+)Fas(-) CD8(+) T-cells with the age of each individual prior to stimulation in vitro (R(2)=0.76, p<0.0001). Compared to other biomarkers (CD28(-), CD28(-)CD45RO(+), and Fas(+)) that have been associated with CD8(+) T-cell aging, the loss of the CD28(+)Fas(-) CD8(+) T-cell population exhibited the strongest correlation with the individual's chronologic age. After stimulation with PHA, there was a decrease in the percentage of CD8(+) T-cells from individual >or=65-year-old that expresses both CD28(+) and Fas(+) at day 3. Surprisingly, the AICD response of CD8(+) T-cells at day 7 in the nonagenarians was higher than that in the other two groups. These results suggest that successful aging does not prevent development of the senescent phenotype of unstimulated CD8(+) T cells, but is associated with preservation of CD8 T cell functions including activation and AICD. Increased AICD may result in enhanced rejuvenation capacity of T cells and limit the impact of aging on T cell function in nonagenarians.

Adult↗
PubMed2005

The CLN9 protein, a regulator of dihydroceramide synthase.

A new variant of a group of pediatric neurodegenerative diseases known as neuronal ceroid lipofuscinosis (NCL) or Batten disease has been identified. It is termed CLN9-deficient. CLN9-deficient fibroblasts have a distinctive phenotype of rapid growth and increased apoptosis and diminished levels of ceramide, dihydroceramide, and sphingomyelin. Transfection with CLN8 but not other NCL genes corrected growth and apoptosis in CLN9-deficient cells, although the entire CLN8 sequence was normal. CLN8 is one of the TRAM-Lag1-CLN8 proteins containing a Lag1 motif. The latter imparts (dihydro)ceramide synthase activity to yeast cells. Transfection with the yeast gene Lag1 Sc and the human homolog LASS1 increased ceramide levels and partially corrected growth and apoptosis in CLN9-deficient cells. LASS2,-4,,-5, and -6 also corrected growth and apoptosis. Dihydroceramide levels and dihydroceramide synthase activity were markedly diminished in CLN9-deficient cells. Sequencing of LASS1, LASS2, LASS4, LASS5, and LASS6 genes was normal, and expression levels were increased or normal in CLN9-deficient cells by reverse transcription-PCR. N-(4-Hydroxyphenyl)retinamide (4-HPR), a dihydroceramide synthase activator, corrected growth and apoptosis and increased dihydroceramide synthase activity. Ceramide levels dropped further, and there was no increase in de novo ceramide synthesis, probably due to the effects of 4-HPR as activator of dihydroceramide synthase and inhibitor of dihydroceramide desaturase. Fumonisin B1, a dihydroceramide synthase inhibitor, exaggerated the CLN9-deficient phenotype of accelerated growth, decreased ceramide and increased apoptosis. This was neutralized by 4-HPR. We conclude that the CLN9 protein may be a regulator of dihydroceramide synthase and that 4-HPR could be developed as a treatment for CLN9-deficient patients.

Apoptosis↗
PubMed2005

Rtg2 protein: at the nexus of yeast longevity and aging.

Firm support for the notion that metabolism and particularly mitochondrial metabolism plays a significant role in aging has been gathered in studies on yeast. As in other organisms, mitochondria contribute to aging through their propensity to generate reactive oxygen species. There is more to the involvement of mitochondria in aging than this, however. Mitochondrial dysfunction, which accumulates during aging, triggers the retrograde response, an intracellular signaling pathway that activates genes that compensate for this dysfunction. A key signaling protein in this pathway is the Rtg2 protein. Recent studies have provided evidence that this protein lies at the nexus of the four major processes that are involved in aging in yeast and in other organisms; namely, metabolism, stress resistance, chromatin-dependent gene regulation, and genome stability. The details of this central role of Rtg2 protein explain the delicate balance between longevity and aging, which ultimately must tip towards the latter. Phenomena that resemble the retrograde response appear to exist in human cells, with both common and cell type-specific gene expression changes as the output.

Adaptation, Physiological↗
PubMed2005

The retrograde response links metabolism with stress responses, chromatin-dependent gene activation, and genome stability in yeast aging.

Yeast can be used as a model to understand the impact mitochondria have on aging in higher organisms. Mitochondrial dysfunction increases with replicative age in yeast, and this is associated with the induction of the retrograde response. This intracellular signaling pathway from the mitochondrion to the nucleus results in changes in the expression of metabolic and stress genes, which adapt the yeast cell to the loss of tricarboxylic acid cycle activity by providing alternate anaplerotic sources of biosynthetic precursors. The induction of the retrograde response increases longevity. Paradoxically, it also leads to the production of extrachromosomal ribosomal DNA circles, which cause yeast demise. The deleterious effects of these circles are mitigated by the retrograde response, which increases longevity in part due to this effect and partly due to other activities. Rtg2p is the retrograde signal transducer proximal to the mitochondrion, and it interacts with several proteins in relaying the retrograde signal to the transcription factor Rtg1p-Rtg3p. Rtg2p also suppresses ribosomal DNA circle production. When it is engaged in retrograde signaling, it cannot fulfill the latter role. The SAGA-like SLIK complex is one of the protein complexes in which Rtg2p has been found. This histone acetyltransferase, transcriptional co-activator complex contains Gcn5p, and it potentiates the activation of retrograde responsive genes. SLIK complex integrity, and in particular Gcn5p, are needed for retrograde response extension of life span. Thus, the retrograde response through SLIK links metabolism, stress responses, chromatin-dependent gene regulation, and genome stability in yeast aging. Gene regulatory phenomena akin to the retrograde response also operate in human cells, which display both common and cell-type specific changes in gene expression on loss of mitochondrial function.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2005

Common and cell type-specific responses of human cells to mitochondrial dysfunction.

In yeast, mitochondrial dysfunction activates a specific pathway, termed retrograde regulation, which alters the expression of specific nuclear genes and results in increased replicative life span. In mammalian cells, the specific nuclear genes induced in response to loss of mitochondrial function are less well defined. This study characterizes responses in nuclear gene expression to loss of mitochondrial DNA sequences in three different human cell types: T143B, an osteosarcoma-derived cell line; ARPE19, a retinal pigment epithelium cell line; and GMO6225, a fibroblast cell population from an individual with Kearns-Sayre syndrome (KSS). Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure gene expression of a selection of glycolysis, TCA cycle, mitochondrial, peroxisomal, extracellular matrix, stress response, and regulatory genes. Gene expression changes that were common to all three cell types included up-regulation of GCK (glucokinase), CS (citrate synthase), HOX1 (heme oxygenase 1), CKMT2 (mitochondrial creatine kinase 2), MYC (v-myc myelocytomatosis viral oncogene homolog), and WRN (Werner syndrome helicase), and down-regulation of FBP1 (fructose-1, 6-bisphosphatase 1) and COL4A1 (collagen, type IV, alpha 1). RNA interference experiments show that induction of MYC is important in rho0 cells for the up-regulation of glycolysis. In addition, a variety of cell type-specific gene changes was detected and most likely depended upon the differentiated functions of the individual cell types. These expression changes may help explain the response of different tissues to the loss of mitochondrial function due to aging or disease.

Cell Line↗
PubMed2005

Yeast longevity and aging--the mitochondrial connection.

Studies of the yeast Saccharomyces cerevisiae reveal four processes determining life span: metabolism, stress resistance, chromatin-dependent gene regulation, and genome stability. The retrograde response, which signals mitochondrial dysfunction resulting in changes in nuclear gene expression, extends yeast life span and is induced during normal aging. This response involves extensive metabolic adaptations. The retrograde response links metabolism and genome stability during yeast aging. A reduction in the availability of nutrients also extends yeast life span. This metabolic mechanism operates by pathways distinct from the retrograde response, although it shares with the latter some longevity effectors. Life extension by calorie restriction entails re-modeling of mitochondrial function. The retrograde response appears to compensate for age changes, while calorie restriction may be a preventive mechanism. The maintenance of age asymmetry between the mother and daughter yeast cells also depends on mitochondrial function. Loss of this age asymmetry occurs during normal yeast aging and may be a paradigm for stem cell aging. The importance of mitochondrial integrity in yeast longevity is emphasized by the role of prohibition function in attenuating oxidative damage. Our studies point to the central role of mitochondria in yeast aging. They highlight the importance of the maintenance of mitochondrial membrane potential, which drives the transport of biosynthetic precursors derived from the Krebs cycle. Common threads weave their way through the studies of aging in yeast and in other model organisms. This suggests conserved features of aging across phyla.

Caloric Restriction↗
PubMed2005

Nuclear gene expression changes due to mitochondrial dysfunction in ARPE-19 cells: implications for age-related macular degeneration.

PURPOSE: To measure changes in nuclear gene expression resulting from mitochondrial dysfunction in retinal pigment epithelial cells. METHODS: ARPE-19 retinal pigment epithelial cells were depleted of their mitochondrial (mt)DNA by passaging in a low concentration of ethidium bromide. Loss of mitochondrial DNA was determined by uridine auxotrophy and quantitative real-time polymerase chain reaction of isolated DNA. Loss of mitochondrial membrane potential was estimated by uptake of JC-1. Changes in nuclear gene expression were determined by quantitative real-time reverse transcription-polymerase chain reaction of isolated total RNA from ethidium-bromide-treated and untreated cells. Morphologic and phenotypic changes were determined by phase-contrast microscopy, sensitivity to the oxidant tert-butyl hydroperoxide (tBH), and invasion assay. RESULTS: ARPE-19 cells became auxotrophic for growth on uridine after eight passages in 50 ng/mL ethidium bromide. Quantitative PCR revealed almost complete loss of mitochondrial DNA (rho(0) cells). Uptake of JC-1 was reduced in the rho(0) cells, indicating reduction of mitochondrial membrane potential. Quantitative RT-PCR measured increased expression of genes coding for drusen components, lipid transport, extracellular matrix components, and responses to inflammation in the rho(0) cells. The rho(0) cells also exhibited an increased sensitivity to killing by tBH and increased migration and invasion through solubulized basement membrane-coated tissue culture inserts. CONCLUSIONS: ARPE-19 cells respond to loss of mitochondrial function by changes in nuclear gene expression that resemble changes observed in age-related macular degeneration. The results lead to the hypothesis that loss of mitochondrial function with age and resultant changes in nuclear gene expression may explain some of the changes in the macula that are associated with the known clinical manifestations of age-related macular degeneration.

Benzimidazoles↗
PubMed2004

Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas.

In this study, endogenous long chain ceramides were measured in 32 human head and neck squamous cell carcinoma (HNSCC) and 10 nonsquamous head and neck carcinoma tumor tissues, as compared with adjacent noncancerous tissues, by liquid chromatography/mass spectroscopy. Interestingly, only one specific ceramide, C(18:0)-ceramide, was selectively down-regulated in the majority of HNSCC tumor tissues. On the other hand, in nonsquamous tumor tissues, this selectivity for C18-ceramide was not detected. These data suggested the hypotheses that decreased levels of C18-ceramide might impart a growth advantage to HNSCC cells and that increased generation of C18-ceramide may be involved in the inhibition of growth. These roles were examined by reconstitution of C18-ceramide at physiologically relevant concentrations in UM-SCC-22A cells (squamous cell carcinoma of hypopharynx) via overexpression of mammalian upstream regulator of growth and differentiation factor 1 (mUOG1), a mouse homologue of longevity assurance gene 1 (mLAG1), which has been shown to specifically induce the generation of C18-ceramide. Liquid chromatography/mass spectroscopy analysis showed that overexpression of the mLAG1/mUOG1 resulted in increased levels of only C(18:0)-ceramide by approximately 2-fold, i.e. concentrations similar to those of normal head and neck tissues. Importantly, increased generation of C18-ceramide by mLAG1/mUOG1 inhibited cell growth (approximately 70-80%), which mechanistically involved the modulation of telomerase activity and induction of apoptotic cell death by mitochondrial dysfunction. In conclusion, this study demonstrates, for the first time, a biological role for LAG1 and C18-ceramide in the regulation of growth of HNSCC.

Animals↗
PubMed2004

The histone acetyltransferase GCN5 modulates the retrograde response and genome stability determining yeast longevity.

Transcriptional silencing decreases at both subtelomeric and silent mating-type loci and increases at the ribosomal DNA locus during the replicative life span of the yeast Saccharomyces cerevisiae . Evidence exists that epigenetic changes in the regulatory state of chromatin may be a causal factor in determining yeast longevity and that histone deacetylases play a role. The significance of histone acetylation has been examined here in more detail. Deletion of the histone acetyltransferase gene GCN5 suppressed the extension of replicative life span afforded by the induction of the retrograde response, which signals mitochondrial dysfunction and leads to changes in nuclear gene expression. It was difficult to ascribe this effect to changes in transcriptional silencing in any of the three known types of heterochromatin. However, a promoter related effect was uncovered by the participation of GCN5 in the induction of the retrograde response. Gcn5p and the retrograde signal transducer Rtg2p are components of the histone acetyltransferase coactivator complex SLIK. Rtg2p blocks the production of extrachromosomal ribosomal DNA circles when it is not engaged in transmission of the retrograde signal. Deletion of GCN5 , which disrupts the integrity of SLIK, suppressed circle accumulation. The results indicate that Gcn5p and SLIK impact the interplay between the retrograde response signal and Rtg2p with consequences for the induction of the response and circle production. Rtg2p and Gcn5p in the SLIK complex link metabolism to stress responses, chromatin-dependent gene regulation, and genome stability in yeast aging.

Base Sequence↗
PubMed2004

Suppressor analysis points to the subtle role of the LAG1 ceramide synthase gene in determining yeast longevity.

Individual yeast cells display a finite replicative capacity. LAG1 was identified as a gene that is differentially expressed during the yeast replicative life span and was shown to play a role in determining yeast longevity. This gene is not essential, but simultaneous deletion of LAG1 and its close homologue LAC1 is lethal. Lag1p and Lac1p have been found to be an essential component of ceramide synthase. In this study, multicopy suppressors of the lethality of a lag1delta lac1delta double mutant were isolated to help clarify the role of LAG1 in yeast longevity. The two multicopy suppressors YBR183w (YPC1) and YPL087w (YDC1) encode ceramidases unrelated to Lag1p and Lac1p, which were previously found to support the reverse reaction of ceramide synthesis. Multiple copies of YPC1 were much more efficient than YDC1 in rescuing cell growth. They were also much more effective in rescuing the life span of a lag1delta lac1delta double mutant, sustaining a life span approaching that obtained by the restoration of LAG1 expression. Neither deletion of LAC1 nor overexpression of YPC1 had a detectable effect on wild-type life span. However, the overexpression of LAG1 had a bimodal effect on longevity, with moderate expression resulting in increased longevity and with higher expression curtailing life span. These results suggest that subtle changes in ceramide/sphingolipid metabolism are important in determining yeast longevity. They also indicate that Lag1p plays a special role in this relationship. Homologues of Lag1p have been identified in higher eukaryotes, including human, raising the possibility that ceramide and other sphingolipid metabolites play a wider role in biological aging.

Aging↗
PubMed2004

Yeast replicative life span--the mitochondrial connection.

Mitochondria have been associated with aging in many experimental systems through the damaging action of reactive oxygen species. There is more, however, to the connection between mitochondria and Saccharomyces cerevisiae longevity and aging. Induction of the retrograde response, a pathway signaling mitochondrial dysfunction, results in the extension of life span and postponement of the manifestations of aging, changing the metabolic and stress resistance status of the cell. A paradox associated with the retrograde response is the simultaneous triggering of extrachromosomal ribosomal DNA circle (ERC) production, because of the deleterious effect these circles have on yeast longevity. The retrograde response gene RTG2 appears to play a pivotal role in ERC production, linking metabolism and genome stability. In addition to mother cell aging, mitochondria are important in establishment of age asymmetry between mother and daughter cells. The results more generally point to the existence of a mechanism to "filter" damaged components from daughter cells, a form of checkpoint control. Mitochondrial integrity is affected by the PHB1 and PHB2 genes, which encode inner mitochondrial membrane chaperones called prohibitins. The Phb1/2 proteins protect the cell from imbalances in the production of mitochondrial proteins. Such imbalances appear to cause a stochastic stratification of the yeast population with the appearance of short-lived cells. Ras2p impacts this process. Maintenance of mitochondrial membrane potential and the provision of Krebs cycle intermediates for biosyntheses appear to be crucial elements in yeast longevity. In sum, it is clear that mitochondria lie at the nexus of yeast longevity and aging.

DNA, Ribosomal↗
PubMed2004

Rtg2 protein links metabolism and genome stability in yeast longevity.

Mitochondrial dysfunction induces a signaling pathway, which culminates in changes in the expression of many nuclear genes. This retrograde response, as it is called, extends yeast replicative life span. It also results in a marked increase in the cellular content of extrachromosomal ribosomal DNA circles (ERCs), which can cause the demise of the cell. We have resolved the conundrum of how these two molecular mechanisms of yeast longevity operate in tandem. About 50% of the life-span extension elicited by the retrograde response involves processes other than those that counteract the deleterious effects of ERCs. Deletion of RTG2, a gene that plays a central role in relaying the retrograde response signal to the nucleus, enhances the generation of ERCs in cells with (grande) or in cells without (petite) fully functional mitochondria, and it curtails the life span of each. In contrast, overexpression of RTG2 diminishes ERC formation in both grandes and petites. The excess Rtg2p did not augment the retrograde response, indicating that it was not engaged in retrograde signaling. FOB1, which is known to be required for ERC formation, and RTG2 were found to be in converging pathways for ERC production. RTG2 did not affect silencing of ribosomal DNA in either grandes or petites, which were similar to each other in the extent of silencing at this locus. Silencing of ribosomal DNA increased with replicative age in either the presence or the absence of Rtg2p, distinguishing silencing and ERC accumulation. Our results indicate that the suppression of ERC production by Rtg2p requires that it not be in the process of transducing the retrograde signal from the mitochondrion. Thus, RTG2 lies at the nexus of cellular metabolism and genome stability, coordinating two pathways that have opposite effects on yeast longevity.

DNA, Ribosomal↗
PubMed2003

Human homologues of LAG1 reconstitute Acyl-CoA-dependent ceramide synthesis in yeast.

Lag1p and Lac1p are two highly homologous membrane proteins of the endoplasmic reticulum. lag1delta lac1delta double mutants in Saccharomyces cerevisiae lack an acyl-CoA-dependent ceramide synthase and are either very sick or nonviable, depending on the genetic background. LAG1 and LAC1 are members of a large eukaryotic gene family that shares the Lag1 motif, and some members of this family additionally contain a DNA-binding HOX homeodomain. Here we show that several human LAG1 homologues can rescue the viability of lag1delta lac1delta yeast cells and restore acyl-CoA-dependent ceramide and sphingolipid biosynthesis. When tested in a microsomal assay, Lac1p and Lag1p had a strong preference for C26:0-CoA over C24:0-CoA, C20-CoA, and C16-CoA, whereas some human homologues preferred C24:0-CoA and CoA derivatives with shorter fatty acids. This suggests that LAG1 proteins are related to substrate recognition and to the catalytic activity of ceramide synthase enzymes. CLN8, another human LAG1 homologue implicated in ceroid lipofuscinosis, could not restore viability to lag1delta lac1delta yeast mutants.

Acyl Coenzyme A↗
PubMed2003

Prohibitins and Ras2 protein cooperate in the maintenance of mitochondrial function during yeast aging.

The yeast Saccharomyces cerevisiae has a finite replicative life span. Yeasts possess two prohibitins, Phb1p and Phb2p, in similarity to mammalian cells. These proteins are located in the inner mitochondrial membrane, where they are involved in the processing of newly-synthesized membrane proteins. We demonstrate that the elimination of one or both of the prohibitin genes in yeast markedly diminished the replicative life span of cells that lack fully-functional mitochondria, while having no effect on cells with functioning mitochondria. This deleterious effect was suppressed by the deletion of the RAS2 gene. The expression of PHB1 and PHB2 declined gradually up to 5-fold during the life span. Cells in which PHB1 was deleted in conjunction with the absence of a mitochondrial genome displayed remarkable changes in mitochondrial morphology, distribution, and inheritance. This loss of mitochondrial integrity was not seen in cells devoid of PHB1 but possessing an intact mitochondrial genome. In a subset of the cells, the changes in mitochondrial integrity were associated with increased production of reactive oxygen species, which co-localized with the altered mitochondria. The mitochondrial deficits described above were all suppressed by deletion of RAS2. Our data, together with published information, are interpreted to provide a unified view of the role of the prohibitins in yeast aging. This model posits that the key initiating event is a decline in mitochondrial function, which leads to progressive oxidative damage that is exacerbated in the absence of the prohibitins. This aggravation of the initial damage is ameliorated by the suppression of the production of mitochondrial proteins in the absence of Ras2p signaling of mitochondrial biogenesis.

Fungal Proteins↗
PubMed2002

An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity.

The human HRAS1 belongs to an evolutionarily-conserved family of genes which enrolls among its members the yeast RAS2, a gene which regulates stress response and longevity in the Saccharomyces cerevisiae. In this paper we report that the frequency of the a3 allele of HRAS1 3'variable number tandem repeat (HRAS1 3'VNTR) decreases in centenarians in respect to young people, and we estimate that during aging a3 carriers have a relative mortality risk of 1.126 (95% CI=1.044-1.213). We propose that the germ-line variability at the HRAS1 locus impacts on the individual's capacity to reach the extreme limits of human life-span. Furthermore, we provide suggestive evidence that a3 HRAS1 3'VNTR allele and inherited variants of the mitochondrial genome (mtDNA haplogroups) do not affect independently human longevity, thus recalling the nucleus-mitochondrion interaction which regulates stress response and life-span in the yeast.

Adult↗