Identifying the Genes and Genetic Interrelationships Underlying the Impact of Calorie Restriction on Maximum Lifespan: An Artificial Intelligence-Based Approach

Abstract

Novel artificial intelligence methodologies were applied to analyze gene expression microarray data gathered from mice under a calorie restriction (CR) regimen. The data were gathered from three previously published mouse studies; these datasets were merged together into a single composite dataset for the purpose of conducting a broader-based analysis. The result was a list of genes that are important for the impact of CR on lifespan, not necessarily in terms of their individual actions but in terms of their interactions with other genes. Furthermore, a map of gene interrelationships was provided, suggesting which intergene interactions are most important for the effect of CR on life extension. In particular our analysis showed that the genes Mrpl12, Uqcrh, and Snip1 play central roles regarding the effects of CR on life extension, interacting with many other genes (which the analysis enumerates) in carrying out their roles. This is the first time that the genes Snip1 and Mrpl12 have been identified in the context of aging. In a follow-up analysis aimed at validating these results, the analytic process was rerun with a fourth dataset included, yielding largely comparable results. Broadly, the biological interpretation of these analytical results suggests that the effects of CR on life extension are due to multiple factors, including factors identified in prior theories of aging, such as the hormesis, development, cellular, and free radical theories.

Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import

“…Similarly, Drosophila MRPL12 is required for cyclin-dependent growth signaling (34). Last, an in silico study identified MRPL12 as one of a small set of interacting genes that might be responsible for the longevity-promoting effects of caloric restriction (35). We speculate that the dynamic nature of the two forms of MRPL12 and the instability of POLRMT when MRPL12 levels are perturbed might contribute to these unique properties.…”

GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging

“…Employing the 400 nM concentration of level of GIT2 siRNA to reduce cellular GIT2 levels, we were able to recapitulate selected expression data generated from our microarray analysis, with specific relevance to beta cell function, metabolism, diabetes, and aging (Table S15 in Supplementary Material: Figures 8 B–I). Hence acute siRNA; mediated reduction of cellular GIT2 caused increased expression of Dcx [doublecortin, Figure 8 C ( 88 )], Glo1 [glyoxylase I, Figure 8 D ( 89 )], Ndufb10 [NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10, Figure 8 E ( 90 )) as well as a decreased expression of Mrpl12 [mitochondrial ribosomal protein L12, Figure 8 F ( 91 )], Atm [ataxia telangiectasia mutated, Figure 8 G ( 18 )], Reg3b [regenerating islet-derived 3 beta, Figure 8 H ( 92 )], and Sesn1 [sestrin 1, Figure 8 I ( 93 )].…”

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

“…MRPL12 is the first mitochondrial ribosomal protein to be characterized in mammals ( Frei et al., 2005 ), and its mutations lead to growth retardation, neurological deterioration, and mitochondrial translation deficiency ( Serre et al., 2013 ). In addition, an artificial intelligence analysis showed that MRPL12 plays central roles regarding the effects of calorie restriction on life extension ( An et al., 2008 ). And MRPL12 was identified as one of the significant down-regulation mitochondrial proteins in prenatal stress-related mitochondrial biogenesis in the frontal cortex and hippocampus ( Olszanecki and Basta-kaim, 2015 ).…”