(PROJECT 4) Evidence from this program project (PPG) demonstrated that defects in genome maintenance cause premature aging in mice. The contribution of genome maintenance to human longevity, however, remains to be established. The main objective of Project 4 (Previous Project 5) has been to translate the PPG's breakthrough discoveries into the human situation by testing the hypothesis that polymorphic variation at loci involved in genome maintenance relates to longevity and healthy aging phenotypes in humans. Research in Project 4 has led to the discovery of genetic and epigenetic signatures associated with human longevity: (1) enrichment of rare variants predicted to change the function and/or expression of proteins involved in signaling and repair of DNA double strand breaks (DSBs) in centenarians as compared to controls;and (2) upregulated microRNAs (miRNAs) in both immortalized B-cells and plasma of centenarians as compared to controls. Interestingly, some of these miRNAs were found, by Project 1, to induce cell preservation responses and cell death repression in the presence of unrepaired DNA damage. We hypothesize that a cluster of protective (epi)genotypes in the genome maintenance gene regulatory network is necessary to achieve exceptional longevity in humans. To confirm and extend our observations that support this hypothesis, we propose a systematic multidisciplinary approach to validate the longevity-associated (epi)genotype signatures and investigate the underlying molecular mechanisms to ascertain the functional relevance of observed positive associations by testing various parameters of cellular fitness in short-term cell culture studies in collaboration with all other Projects. Functionally relevant gene variants and miRNAs will then be further studied for their in vivo effect during aging by modeling them in the mouse in collaboration with Core B. The information generated in Project 4 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.
(PROJECT 4) Defining the genetic and epigenetic factors that influence longevity in humans may have profound implications for the development of strategies to delay or prevent age-related diseases. Identification of genes that promote longevity and prevent or delay crippling diseases at old age is likely to help us finding novel strategies for prevention and therapy.
|Han, Jeehae; Atzmon, Gil; Barzilai, Nir et al. (2015) Genetic variation in Sirtuin 1 (SIRT1) is associated with lipid profiles but not with longevity in Ashkenazi Jews. Transl Res 165:480-1|
|Raj, Divya D A; Jaarsma, Dick; Holtman, Inge R et al. (2014) Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging 35:2147-60|
|Choi, Yong Jun; Li, Han; Son, Mi Young et al. (2014) Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair. PLoS One 9:e86358|
|Barnhoorn, Sander; Uittenboogaard, Lieneke M; Jaarsma, Dick et al. (2014) Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency. PLoS Genet 10:e1004686|
|Akman, Kemal; Haaf, Thomas; Gravina, Silvia et al. (2014) Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data. Bioinformatics 30:1933-4|
|Jung, Hwa Jin; Suh, Yousin (2014) Circulating miRNAs in ageing and ageing-related diseases. J Genet Genomics 41:465-72|
|Campisi, Judith; Robert, Ladislas (2014) Cell senescence: role in aging and age-related diseases. Interdiscip Top Gerontol 39:45-61|
|Derks, Kasper W J; Hoeijmakers, Jan H J; Pothof, Joris (2014) The DNA damage response: the omics era and its impact. DNA Repair (Amst) 19:214-20|
|Campisi, Judith (2014) Cell biology: The beginning of the end. Nature 505:35-6|
|Reiling, Erwin; Dollé, Martijn E T; Youssef, Sameh A et al. (2014) The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency. PLoS One 9:e93568|
Showing the most recent 10 out of 155 publications