Genome-Wide Scan for a Healthy Aging Phenotype Provides Support for a Locus Near D4S1564 Promoting Healthy Aging

Reed, Terry; Dick, Danielle M.; Uniacke, Sean K.; Foroud, Tatiana; Nichols, William C.

doi:10.1093/gerona/59.3.b227

Cited by 45 publications

(33 citation statements)

References 22 publications

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“…FOXO3a, a homolog of the C. elegans longevity gene DAF-16, represses NF-B nuclear translocation and transcriptional activity (Lin et al 2004). Intriguingly, the human NFKB1 gene maps within a genetic locus on chromosome four that has been repeatedly associated with human longevity (Reed et al 2004). Recent studies in model organisms have suggested that target hub proteins that receive input from multiple upstream pathways are likely key integration and control points in morphogenetic pathways (Borneman et al 2006).…”

Section: Nf-b Enforcement Of Agingmentioning

confidence: 99%

Motif module map reveals enforcement of aging by continual NF-κB activity

Adler¹,

Sinha²,

Kawahara³

et al. 2007

Genes Dev.

433

389

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Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-B. Inducible genetic blockade of NF-B for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-B blockade and orthogonal cell cycle interventions revealed that NF-B controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-B is continually required to enforce many features of aging in a tissue-specific manner.[Keywords: Aging; NF-B; epidermis; functional genomics; computational biology] Supplemental material is available at http://www.genesdev.org.

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Section: Nf-b Enforcement Of Agingmentioning

confidence: 99%

Motif module map reveals enforcement of aging by continual NF-κB activity

Adler¹,

Sinha²,

Kawahara³

et al. 2007

Genes Dev.

433

389

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show abstract

“…In addition, in our in vivo work we have observed a distinctive biphasic pattern of NF-B activation in atrophic muscles of old rats [54,55] . Interestingly, the human NFKB1 gene maps within a genetic locus on chromosome 4 that has been repeatedly associated with human longevity [56] .…”

Section: Is Nuclear Factor Kappa B a Signaling Mediator Of Aging?mentioning

confidence: 99%

The Evolutionary Theories of Aging Revisited – A Mini-Review

Ljubuncic

Reznick²

2009

Gerontology

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This short review portrays the evolutionary theories of aging in the light of the existing discoveries from genomic and molecular genetic studies on aging and longevity. At the outset, an historical background for the development of the evolutionary theories of aging is presented through the works of August Weismann (programmed death and the germ plasm theories) including his exceptional theoretical postulation, later experimentally validated by the existence of cell division limits. Afterwards, the theory of mutation accumulation of Peter Medawar and the theory modification by Charlesworth (late-life mortality plateau) are presented as well as the antagonistic pleiotropy hypothesis of George Williams, and the disposable soma theory of Kirkwood and Holliday. These theories are discussed in the light of the different research studies, which include studies on insulin signaling and longevity, the possibility that nuclear factor kappa B may be a major mediator of aging, studies of anti-aging Sirtuins and studies on heat shock proteins and longevity and on gene sets as biomarkers of aging. Finally, the proposals for future research in biogerontology, such as studies on the control of protein synthesis, validation of biomarkers of aging, understanding the biochemistry of longevity and research in the field of gerontologic pathology are presented. Likewise, further attention is suggested regarding the work on telomere shortening, stem cells and studies on understanding the biochemical and molecular basis for longevity in centenarians.

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“…2 -4 Recent studies performed a genome-wide linkage scan in long-lived individuals and provided evidence for a locus for longevity at chromosome 4 near microsatellite marker D4S1564. 5,6 Fine mapping of the region identified Microsomal Triglyceride Transfer Protein (MTP) as the gene responsible for the chromosome 4 linkage peak, 7 although a confirmatory study in a French population did not confirm this observation. 7 The two SNPs found to account for the majority of the variation at the locus were rs2866164Fa SNP in complete linkage disequilibrium with rs1800591 (À493G/T), an MTP promoter mutationFand MTP Q/HFa semiconservative mutation in exon 3 of MTP (glutamine to histidine at aminoacid 95).…”

Section: Introductionmentioning

confidence: 98%

No evidence for an association between extreme longevity and Microsomal Transfer Protein polymorphisms in a longitudinal study of 1651 nonagenarians

et al. 2005

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Previous studies have reported two SNPs and a haplotype marker within the Microsomal Transfer Protein gene associated with extreme longevity. Here, we test this finding in a longitudinal study of nonagenarians and in an association study. Participants in the Danish 1905 cohort study (1651 participants aged 92 -93 years) were genotyped for the two SNPs (rs2866164 and Q95H) in the Microsomal Transfer Protein gene recently reported to be associated with longevity. The 1905 Cohort has been followed for 6.5 years, during which period 83% of the cohort has died. Furthermore, a group of 575 middle-aged Danish twins (mean age 53.7 years) were tested as a younger control group. The risk haplotype had no significant survival disadvantage (P-values: 0.56, 0.31 and 0.97 in the total population of nonagenarians, males and females, respectively) after 6.5 years of follow-up. The distributions of the suggested risk alleles (rs2866164-G and Q95) and the resulting haplotypes are very similar and not statistically different between the two age cohorts. The frequency for rs2866164-G is in the middle-aged compared to the nonagenarians 25.4 and 23.6% in males and 23.0 and 26.1% in females. The frequency for the risk haplotype is in the middle-aged compared to the nonagenarians 22.7 and 19.2% in males and 18.1 and 21.8% in females. In conclusion, our longitudinal study of survival in the 10th decade of life and an association study in a genetically homogeneous population provided no support for an association between the Microsomal Transfer Protein gene and extreme longevity.

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Genome-Wide Scan for a Healthy Aging Phenotype Provides Support for a Locus Near D4S1564 Promoting Healthy Aging

Cited by 45 publications

References 22 publications

Motif module map reveals enforcement of aging by continual NF-κB activity

Motif module map reveals enforcement of aging by continual NF-κB activity

The Evolutionary Theories of Aging Revisited – A Mini-Review

No evidence for an association between extreme longevity and Microsomal Transfer Protein polymorphisms in a longitudinal study of 1651 nonagenarians

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