Buffering Mechanisms in Aging: A Systems Approach Toward Uncovering the Genetic Component of Aging

Department of Pathology, Albert Einstein College of Medicine, New York, New York, United States of America.
PLoS Computational Biology (Impact Factor: 4.62). 09/2007; 3(8):e170. DOI: 10.1371/journal.pcbi.0030170
Source: PubMed


An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the "oldest old" Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.

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Available from: Gil Atzmon, Oct 08, 2015
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    • "These disease traits include cardiac diseases such as cardiomyopathy and arrhythmia that increase the risk of sudden cardiac death as well as metabolic diseases such as diabetes, hypercholesterolemia, and obesity. One explanation for the presence of disease alleles in centenarians might be that these variants have incomplete penetrance as a result of complex interplay between modifying genetic and environmental factors (Bergman et al. 2007; Cooper et al. 2013). However, for some variants the published evidence may be viewed as too weak to uphold their classification as pathogenic. "
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    ABSTRACT: To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30× coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as “pathogenic” or “likely pathogenic” based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.
    09/2014; 2(5). DOI:10.1002/mgg3.86
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    • "With regard to the enrichment of deleterious genotypes in long-lived females, it might be partially interpreted by the Buffering Mechanisms in Aging hypothesis proposed recently by Bergman and colleagues who reasoned that in a subpopulation endowed with a favorable longevity genotype(s), the prevalence of a deleterious genotype is expected not to vary or even increase with age because the longevity genotype may buffer out or modulate the harmful effect of deleterious ones, while in a subpopulation lacking longevity genotypes, the prevalence of a deleterious genotype will decrease with age since subjects with this genotype are weeded out due to mortality [28,29]. Therefore, screening for potential longevity genotypes such as CETP (VV) (rs5882), APOC3 (CC) (rs2542052), AdipoQ (del/del APM1 + 2019) (rs56354395), and FOXO3a (GG), which have been demonstrated in other populations [30-33], will be one of our next efforts in the near future. "
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    ABSTRACT: Background Variants in the Methylenetetrahydrofolate reductase (MTHFR) gene may result in a lowered catalytic activity and associate with subsequent elevated serum homocysteine (Hcy) concentration, abnormal DNA synthesis and methylation, cardiovascular risk, and unhealthy aging. Several investigations on the relationship of MTHFR C677T polymorphism with serum lipid profile and longevity have been conducted in some populations, but the findings remain mixed. Herein, we sought to look at the association between MTHFR C677T and lipid profile in a longevous cohort in Bama, a well-known home of longevity in China. Methods Genotyping of MTHFR C677T was undertaken in 516 long-lived inhabitants (aged 90 and older, long-lived group, LG) and 493 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Correlation between MTHFR genotypes and lipids was then evaluated. Results T allele and TT genotype were significantly more prevalent in LG (P = 0.001 and 0.002, respectively), especially in females, than in non-LG. No difference in the tested lipid measures among MTHFR C677T genotypes was observed in LG, non-LG and total population (P > 0.05 for all). However, female but not male T carriers exhibited higher TC and LDL-C levels than did T noncarriers in the total population and in LG after stratification by sex (P < 0.05 for each). These differences did not however remain through further subdivision by hyperlipidemia and normolipidemia. Conclusion The higher prevalence of MTHFR 677 T genotypes and its modest unfavorable impact on lipids in Bama long-lived individuals may imply an existence of other protective genotypes which require further determination.
    Lipids in Health and Disease 06/2014; 13(1):104. DOI:10.1186/1476-511X-13-104 · 2.22 Impact Factor
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    • "CETP V405 homozygosity was associated with slower memory decline and lower incidence of dementia and Alzheimer disease risk in healthy older adults compared with controls in the Einstein Aging Study (Sanders et al., 2010). In Ashkenazi Jews from the Longevity Gene Study, high levels of HDL and its large lipoprotein sizes were over represented in centenarians, as well as the prevalence of homozygosity for I405V-CETP and 641C-APOC3 in both centenarians and their offspring than in the controls (Barzilai et al., 2006; Bergman et al., 2007). We also found high levels of HDL and a borderline higher prevalence of homozygosity for 641C-APOC3 (rs2542052: p = 0.06) in the healthy LLFS subjects as compared to an independent data from the Family Heart Study (N = 3794 European-Americans) that has approximately half families CVDselected and the other half families randomly-selected. "
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    ABSTRACT: The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease, and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4,114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p< 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly LLFS subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in ENCODE; however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
    Frontiers in Genetics 06/2014; 5:159. DOI:10.3389/fgene.2014.00159
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