APOB
Apolipoprotein B-100 precursor (Apo B-100) [Contains: Apolipoprotein B-48 (Apo B-48)]
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Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.
MeSH Terms
- Animals
- Autophagy
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Caloric Restriction
- Gene Expression Regulation
- Gene Silencing
- Intestinal Mucosa
- Lipase
- Lipolysis
- Lipoproteins
- Longevity
- Lysosomes
- Transcription, Genetic
- Vitellogenesis
- Vitellogenins
Keywords
- C. elegans
- TOR
- apolipoprotein B
- autophagy
- fat storage
- intestine
- life span
- lipid metabolism
- lipoprotein
- vitellogenin
Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5-13) or within individual families (66-156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.
MeSH Terms
- Aged, 80 and over
- Apolipoprotein B-100
- Exome
- Family Health
- Female
- Gene Frequency
- Genetic Variation
- Humans
- Longevity
- Male
Keywords
- apolipoprotein B
- centenarians
- exome sequencing
- longevity
- rare variants
The inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sex-specific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR≤ 75 years = 1.49, P = 7.5 × 10(-4) ) and protective effects at older ages (RR76 years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Alleles
- Apolipoproteins B
- Apolipoproteins E
- Cardiovascular Diseases
- Child
- Child, Preschool
- Cholesterol
- Female
- Gene Frequency
- Gene-Environment Interaction
- Genotype
- Humans
- Lipid Metabolism
- Longevity
- Male
- Middle Aged
- Polymorphism, Genetic
Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, [[CDKN2A]], ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Genetic Variation
- Humans
- Polymorphism, Single Nucleotide
To investigate the association of polymorphisms in the apolipoprotein B gene (APOB) 3'variable number of tandem repeat with natural longevity in the Xinjiang Uighur nationality people. Totally 191 healthy individuals over 90 years and 53 individuals aged 65-70 years were recruited among Xinjiang Uighur population, the nationality, gender and living area were matched. Genotyping was performed using polymerase chain reaction-sequence specific primer(PCR-SSP) and PCR-sequencing. Fourteen alleles were found in the Xinjiang Uighur nationality population. The frequency of HVE36 and HVE42 in the natural longevity group were significantly higher than that in the control group (both P<0.05) and HVE44, HVE46, HVE48 and HVE58 were only found in the natural longevity group. However, the frequency of HVE26, HVE30 and HVE34 were markedly lower in the natural longevity group compared to the control group. Logistic regression analyses revealed that allele L and the genotypes LL were positively associated with age, whereas the allele S and genotype SS were negatively associated with age (both P<0.05). Each allele consists of 15 bp tandem repeats with rich-AT by PCR-sequencing. These results indicate that the S allele, and SS genotype are frail factors in China Uighur natural longevity people, whereas allele L and genotypes LL are protective factors.
MeSH Terms
- Aged
- Aged, 80 and over
- Apolipoproteins B
- Base Sequence
- China
- Female
- Gene Frequency
- Genotype
- Humans
- Longevity
- Male
- Middle Aged
- Minisatellite Repeats
- Molecular Sequence Data
- Polymerase Chain Reaction
- Polymorphism, Genetic
To investigate the differences in serum biochemistry between specific pathogen-free (SPF) and conventional aged Wistar rats. Coulter-JT Analyzer was used to measure the values of serum biochemistry in the two grades of rats. The serum levels of alanine aminotransferase (ALT), total protein (TP), alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), blood urea nitrogen (BUN), creatinine, Fe, P, glucose, uric acid (UA), and low density lipoprotein (LDL) were very significantly different between male and female Wistar rats of either conventional or SPF grade (P<0.01), which also had significant difference in albumin, lactate dehydrogenase (LDH) and apolipoprotein B (ApoB) (P<0.05). Between male aged Wistar rats of the two grades, the differences of TP, albumin, albumin/globulin (A/G) ratio, TC, TG, blood glucose, ApoA1, ApoB, UA, high-density lipoprotein (HDL), LDL, and glutamic oxalacetic transaminase (GOT) were very significant (P<0.01), with also significant differences in ALT, Fe, Mg (P<0.05). Between the female rats of the two grades, the serum levels of ALT, TP, albumin, A/G ratio, ALP, TG, BUN, creatinine, Fe, ApoA1, APOB, HDL, LDL, and bile acids were very significantly different (P<0.01), and Mg was significantly different (P<0.05). Different microbiological profiles affect serum biochemistry of aged Wistar rats.
MeSH Terms
- Aging
- Animals
- Blood Chemical Analysis
- Female
- Male
- Rats
- Rats, Wistar
- Sex Factors
- Specific Pathogen-Free Organisms
The contribution of 17 polymorphisms within 13 candidate genes on lipid trait variability was investigated by a multiplex assay in 772 men and 780 women coming for a health checkup examination. The studied genes were APOE, APOB, APOC3, CETP, LPL, PON, MTHFR, FGB, GpIIIa, SELE, ACE, and AGT. We found that APOB-Thr71Ile, APOE-(112/158), APOC3-1100C/T, and SELE-98G/T polymorphisms had a significant effect on lipid traits (P < or = 0.001 to P < or = 0.01). Genetic effects accounted for 3.5-5.7% of variation in apolipoprotein B (apoB)-related traits among men, and for 5.7-9.0% among women. The contribution of APOE polymorphism on apoB-related traits variability was two to three times more important in women than in men. We found suggestive evidence for interactive effects between genetics and age, smoking status, and oral contraceptives. Increase of LDL-cholesterol and apoB concentrations with age was stronger among the epsilon4 carriers in women, and apolipoprotein A-I (apoA-I) concentration decreased with age in epsilon4 male carriers. The effect of epsilon2 allele on LDL-cholesterol was more important in the oral contraceptive users. In nonsmokers only, the APOC3-1100C allele in women was related to lower apoB-related traits concentrations, and in men to higher apoA-I and HDL-cholesterol concentrations. In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors. The newly observed relationships between E-selectine gene and lipid concentrations support the hypotheses of multiple metabolic pathways contributing to the complexity of lipids variability.
MeSH Terms
- Adult
- Aging
- Alleles
- Apolipoprotein A-I
- Apolipoprotein C-III
- Apolipoproteins B
- Apolipoproteins C
- Apolipoproteins E
- Cholesterol, LDL
- Codon
- Cohort Studies
- Contraceptives, Oral
- Female
- Genetic Variation
- Humans
- Lipid Metabolism
- Lipids
- Male
- Middle Aged
- Polymorphism, Genetic
- Sex Characteristics
- Smoking
Differentiating FH from other causes of hypercholesterolemia has important clinical and therapeutic implications but is often not possible by standard clinical criteria. As accumulation of cholesterol in tendon is generally considered as pathognomonic of FH, we evaluated the sensitivity and specificity of clinical and ultrasonographic tendon characteristics using the data of 127 genetically ascertained FH and 160 controls with various lipid profiles. Upon clinical examination, none of the controls and 29% of FH individuals (17% FH women and 38% FH men) presented with xanthomata in Achilles tendons, but no female and only 6% of male FH patients also showed xanthomata in the extensor tendon of the hand. Amongst all possible quantitative parameters (thickness, breadth, section and roundness) of Achilles tendon (AT) measured by ultrasonography, the thickness presented the best receiver operating curves. AT thickness above 5.8 mm was the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85%. Analysis of variation of AT thickness with age and sex indicated that this clinical criterion performed better in females older than 45 and in males under 45. In patients carrying the APOB-R3500Q mutation, AT-thickness appeared significantly less important compared with those carrying LDLR mutations. In conclusion, this study recommends identification of possible FH individuals amongst hypercholesterolemic patients using a criteria of AT-thickness over 5.8 mm eventually associated with a specific genetic test for APOB-R3500Q mutation.
MeSH Terms
- Achilles Tendon
- Adult
- Aging
- Apolipoproteins B
- Female
- Hand
- Humans
- Hyperlipoproteinemia Type II
- Male
- Middle Aged
- Muscular Diseases
- Mutation
- ROC Curve
- Receptors, LDL
- Sensitivity and Specificity
- Tendons
- Ultrasonography
- Xanthomatosis
Apolipoprotein E (APOE) E4, apolipoprotein B-100 (APOB) Q3611 allele, the angiotensin converting enzyme (ACE) deletion (D) allele and glycoprotein IIIa (GP3A) P33 mutant allele are reported to predispose to early-onset coronary heart disease (CHD). These associations were not all confirmed in more recent studies. To determine the impact of these alleles on CHD, we examined the prevalence of these mutations in patients presenting with early-onset CHD and compared them to those manifesting CHD later in life. The delayed-onset was considered a sign of longevity and would serve as a comparative group to assess prevalence of the biochemical and genetic risk factors. 300 patients with a history of myocardial infarction or angina pectoris and angiographically documented CHD were studied. Patients were divided into two groups: group 1 (G1 = 150 patients) presenting with these findings under the age of 50 years; while group 2 (G2 = 150 patients) were patients presenting for the first time over the age of 65 years. Prevalence of the alleles of APOE, APOB, ACE and GP3A was assessed by molecular analysis. An association of any of these genotypes with early onset CHD could lead to a higher prevalence in the younger age group. None of the suspected alleles namely APOB Q3611 [G1: 10.7% vs. G2: 9.0%, p = 0.57], ACE D (G1: 52.0% vs. G2: 49.7%, p = 0.57), or the GP3A P33 (G1: 17.3% vs. G2: 15.7%; p = 0.58) showed any significant difference between the two groups. Subjects with APOE E4 were more frequent in the younger age group (G1: 18.3% vs. G2: 13.7%; p = 0.047), while APOE E2 was more frequent in G2 (G2: 10.0% vs. G1: 2.7%; p = 0.0002). Multivariate analysis showed an odds ratio of APOE E2 allele in G1 of 0.27 with a confidence interval of 0.10-0.73.
MeSH Terms
- Adult
- Age of Onset
- Aged
- Analysis of Variance
- Apolipoprotein B-100
- Apolipoproteins B
- Apolipoproteins E
- Coronary Disease
- Female
- Genetic Predisposition to Disease
- Humans
- Longevity
- Male
- Middle Aged
- Peptidyl-Dipeptidase A
- Platelet Glycoprotein GPIIb-IIIa Complex
- Polymorphism, Genetic
- Risk Factors
- Survival Rate
To identify possible genetic factors affecting human longevity we compared allele pools at two candidate loci for longevity between a sample of 143 centenarians (S) and a control sample of 158 individuals (C). The candidate loci were APOB and TPO, which code for apolipoprotein B and thyroid peroxidase, respectively. Both restriction fragment length (RFL) (XbaI2488 and EcoRI4154) and variable number of tandem repeat (VNTR) (3'APOB-VNTR) polymorphisms were analysed at the APOB locus; the TPO-VNTR polymorphism (intron 10) was analysed at the TPO locus. The main result of the investigation was that there is an association between the APOB locus and longevity that is revealed only when multiallelic polymorphisms are considered. In particular: (i) the frequency of 3'APOB-VNTR alleles with fewer than 35 repeats is significantly lower in cases than in controls; (ii) the linkage disequilibrium between the XbaI-RFLP and the EcoRI-RFLP is significantly different from 0 in cases but not in controls; (iii) the EcoRI-RFLP and XbaI-RFLP allele frequencies do not discriminate between cases and controls. The differences observed between case and control allele pools are specific to the APOB locus, since no significant difference was observed at the TPO locus.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Apolipoproteins B
- Female
- Haplotypes
- Humans
- Iodide Peroxidase
- Longevity
- Male
- Middle Aged
- Minisatellite Repeats
- Polymorphism, Restriction Fragment Length