MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

Abstract

The pathways that regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to longevity, a two-stage case-control study in two independent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 candidate SNPs identified in stage 1 (π markers 0 0.1) were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p01.1×10 −3 and p01.4×10 −3 , respectively). Interestingly, both genes are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmental and internal stresses.

Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs

“…Hence, the finding of HSD17B8 as a hub gene strengthens the hypothesis of a regulatory role in androstenone synthesis. GSTZ1 was found as a hub gene in the lightgreen module and as a DE gene in liver which encodes a member of the GSTs 95 . Other hub genes included SERPINC1 (Fig.…”

Age-associated changes in GSH S-transferase gene/proteins in livers of rats

“…GSTs are crucial enzymes in anti-aging processes. For example, mitochondrial protein levels of the GSTK1 and GSTM4 are significantly higher in dwarf mice and are regulated by growth hormones [28]; GSTK1 is implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging [33]. Aging affects the metabolic capacity of GSTZ1 to detoxify Dichloroacetate (DCA) [34], and GSTs are crucial enzymes in the cell detoxification process catalyzing the nucleophilic attack of GSH on toxic electrophilic substrates and to produce a less dangerous compound, especially by alpha and mu classes of GST [32], and the zeta class of GST received more attention from a therapeutic perspective [31].…”

Longevity: Lesson from Model Organisms

“…A high level of oxidative stress is also an important risk factor of other age-related diseases such as hypertension, atherosclerosis, and diabetes. SNP (single nucleotide polymorphisms) studies have identified Tp53, coding for tumor suppressor p53 [140,141,142], EXO1 [143], GPX1 (glutathione peroxidase1) [144], SOD2 (manganese superoxide dismutase) [145], heat shock proteins genes HSPA1A, HSPA1B, and HSPA1L [146,147,148], GSTZ1 (glutathione S-transferase zeta 1) [149], NOS1, NOS2 (nitric oxide synthase 1 and 2) [150], and UCPs (uncoupling proteins) [147,151,152] as susceptibility genes.Genes involved in telomeres length: they have been found to be associated with human longevity such as TERT and TERC (telomerase reverse transcriptase, telomerase RNA component) [153], SIRT1, and SIRT3 (sirtuins) [154,155]. The first discoveries were made in yeasts and tetrahymena by Elizabeth Blackburn, finding the role of TERT and TERC ([156] and references within).…”

“…These findings have been replicated in other model organisms [161], but their role in longevity is not consistent for all species, and therefore is still under debate [162]. Genes involved in metabolism and cellular division: APOE (apolipoprotein E) [163], TXNRD1 (thioredoxin reductase 1), XDH (xanthine dehydrogenase) [163], MAP3K7 (mitogen-activated protein kinase kinase kinase 7) [149], AKT kinase, and TOR [164]. The association of APOE with human longevity have been replicated in different populations: [165,166,167].…”