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Genetic Analysis of Mitochondrial Ribosomal Proteins and Cognitive Aging in Postmenopausal Women.

ABSTRACT: Genes encoding mitochondrial ribosomal proteins (MRPs) have been linked to aging and longevity in model organisms (i.e., mice, Caenorhabditis elegans). Here we evaluated if the MRPs have conserved effects on aging traits in humans. We utilized data from 4,504 participants of the Women's Health Initiative Memory Study (WHIMS) who had both longitudinal cognitive data and genetic data. Two aging phenotypes were considered: (1) gross lifespan (time to all-cause mortality), and (2) cognitive aging (longitudinal rate of change in modified mini-mental state scores). We tested genetic association with variants in 78 members of the MRP gene family. Genetic association tests were done at the single nucleotide polymorphism (SNP) level, and at gene-set level using two distinct procedures (GATES and MAGMA). We included SNPs in APOE and adjusted the tests for the APOE-?4 allele, a known risk factor for dementia. The strongest association signal is for the known cognitive aging SNP, rs429358, in APOE (p-value = 5 × 10-28 for cognitive aging; p-value = 0.03 for survival). We found no significant association between the MRPs and survival time. For cognitive aging, we detected SNP level association for rs189661478 in MRPL23 (p-value < 9 × 10-6). Furthermore, the gene-set analysis showed modest but significant association between the MRP family and cognitive aging. In conclusion, our results indicate a potential pathway-level association between the MRPs and cognitive aging that is independent of the APOE locus. We however did not detect association between the MRPs and lifespan.

SUBMITTER: Mozhui K

PROVIDER: S-EPMC5613226 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Genetic Analysis of Mitochondrial Ribosomal Proteins and Cognitive Aging in Postmenopausal Women.

Mozhui Khyobeni K Snively Beverly M BM Rapp Stephen R SR Wallace Robert B RB Williams Robert W RW Johnson Karen C KC

Frontiers in genetics 20170921

Genes encoding mitochondrial ribosomal proteins (MRPs) have been linked to aging and longevity in model organisms (i.e., mice, Caenorhabditis elegans). Here we evaluated if the MRPs have conserved effects on aging traits in humans. We utilized data from 4,504 participants of the Women's Health Initiative Memory Study (WHIMS) who had both longitudinal cognitive data and genetic data. Two aging phenotypes were considered: (1) gross lifespan (time to all-cause mortality), and ( ...[more]

PMID: 28983317

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Project description:ImportanceMenopause is associated with biological aging, and hormone therapy (HT) is associated with health outcomes in postmenopausal women.ObjectiveTo evaluate the association between HT use and discrepancies between chronological and biological age in postmenopausal women as well as the potential modifying role of socioeconomic status (SES).Design, setting, and participantsThis population-based, retrospective cohort study included postmenopausal women registered in the UK Biobank. A baseline survey on HT use and biological aging biomarkers was conducted from March 2006 to October 2010. Data analyses were conducted in December 2023.ExposuresInformation regarding HT use, the age at starting HT, and HT duration was collected via a touchscreen questionnaire. SES was evaluated by education, family income, occupation, and the Townsend Deprivation Index.Main outcomes and measuresBiological aging discrepancy was evaluated using validated phenotypic age, which was calculated using chronological age and 9 biomarkers measured at baseline. All-cause and cause-specific mortality were also assessed.ResultsAmong the 117 763 postmenopausal women (mean [SD] age, 60.2 [5.4] years), 47 461 (40.3%) ever used HT. The mean phenotypic age was 52.1 (7.9) years. Ever use of HT was associated with a smaller biological aging discrepancy than never use of HT (β, -0.17 years; 95% CI, -0.23 to -0.10 years). This smaller aging discrepancy was more evident in those who started HT at age 55 years or older (β, -0.32 years; 95% CI, -0.48 to -0.15 years) and in those who used HT for 4 to 8 years (β, -0.25 years; 95% CI, -0.35 to -0.15 years). The association between HT and a smaller aging discrepancy was more evident in women with low SES, with a significant interaction observed for education (higher education: β, -0.08 years [95% CI, -0.17 to 0.01]; other education: β, -0.23 [95% CI, -0.32 to -0.14] years; P for interaction = .02). Phenotypic aging discrepancy mediated 12.7% (95% CI, 6.3% to 23.9%) of the association between HT and all-cause mortality and cause-specific mortality.Conclusions and relevanceIn this study, postmenopausal women with historical HT use were biologically younger than those not receiving HT, with a more evident association observed in those with low SES. The biological aging discrepancy mediated the association between HT and decreased mortality. Promoting HT in postmenopausal women could be important for healthy aging.

Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

Dataset Information

Genetic Analysis of Mitochondrial Ribosomal Proteins and Cognitive Aging in Postmenopausal Women.

Publications

Genetic Analysis of Mitochondrial Ribosomal Proteins and Cognitive Aging in Postmenopausal Women.

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