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-ε4 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.
Highlights
Aging is a complex biological process that is characterized by overall decline in health, vigor, cognition, and increased vulnerability to numerous diseases
During enrollment to Women’s Health Initiative Memory Study (WHIMS), participants were over 65 years old and free of dementia
Our main motivation to test the mitochondrial ribosomal proteins (MRPs) comes from studies carried out in model organisms showing that mutations in members of this gene family contribute to aging and longevity
Summary
Aging is a complex biological process that is characterized by overall decline in health, vigor, cognition, and increased vulnerability to numerous diseases. Mitochondrial Ribosomal Proteins and Aging (C. elegans) indicate that imbalances in protein translation between mitochondrial and nuclear genes can trigger lifeextending signaling pathways (Houtkooper et al, 2013; Mouchiroud et al, 2013). Protein synthesis in mitochondria is exquisitely regulated by a translational machinery that is attuned to nuclear protein turnover (Poyton and McEwen, 1996). Components of the translational system, including the mitochondrial ribosomal proteins (MRPs), are encoded by the nuclear genome and subsequently translocated into the mitochondria. Mutations in the Mrp genes that reduce gene expression have a conserved life-extending effect in both mice and C. elegans (Houtkooper et al, 2013; Mouchiroud et al, 2013). In this study we evaluate if this effect seen in experimental settings in model organisms translates to aging and lifespan traits in humans
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