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  • Genetic variants in noncoding RNAs


    Genetic variants in noncoding RNAs have the potential to differentially influence aging processes and lifespan. The lncRNA ANRIL, was implicated in longevity in a GWAS [96]. Understanding genetic variants in the noncoding genome is a current challenge. Constrained regions in the noncoding genome associate with the most essential genes and are enriched for pathogenic variants [338]. The immune system changes over time, increasing pro-inflammatory activity by innate immune cells such as monocytes and macrophages, and decreasing the immune response [339]. A progressive change in expression of 69 non-coding RNAs (56 microRNAs and 13 snoRNAs) is seen with chronological age [340]. The age-related miRNAs were found to regulate genes involved in immune, KRN 7000 structure and cancer-related pathways. A number of miRNAs have been reported to have increased expression with age in mouse [341] and rat [342] livers. Up-regulated miRNA targets are associated with detoxification activity and regeneration capacity – functions known to decline in old liver, consistent with the negative regulatory roles of miRNAs [341]. By measuring expression patterns in mouse liver following CR it was found that: (i) the expression of miRNAs, lncRNAs and transposable elements were largely repressed; (ii) the protein-coding mRNAs that demonstrated increased expression in CR are highly targeted by miRNAs; and (iii) the miRNA-targeting sites were enriched for genes having chromatin-related functions. One such gene is chromodomain helicase DNA binding protein 1 gene, Chd1, which is instrumental in chromatin remodeling [343].
    Longevity gene networks To understand the genetic and epigenetic landscape of human aging a meta-analysis was performed of 6600 human longevity genes from 35 datasets comprising 8 curated aging data sets (1154 genes), 10 age-related diseases (1207 genes), 4 gene expression sets (2130 genes), and 13 methylation sets (3498 genes) [344]. From this, biological relationships between aging-associated genes were investigated by producing a protein interaction network and characterizing network neighborhoods. Most genes only appeared in a single category, whereas 1050 were associated with two, 159 with three, and 7 with all four categories. Those 7 were APOE, chaperonin containing TCP1 subunit 7 gene, CCT7, erb-b2 receptor tyrosine kinase 1 gene, ERBB2, protein kinase C alpha gene, PRKCA, Ras association domain family member 1 gene, RASSF1, sterol regulatory element binding transcription factor 1 gene, SREBF1, and tumor necrosis factor gene, TNF. The TNF receptor family member ectodysplasmin A receptor (EDAR) associated death domain gene, EDARADD, and lymphocyte activating 3 gene, LAG3, exhibited the strongest evidence for aging-associated DNA methylation changes. Of the 6600 aging-associated genes, 5949 had at least one interaction. There were 1079 human aging clusters in the combined interaction network. The interaction network provided an additional layer for linking proteomic and genomic data. On the basis of “guilt by association”, a previously unsuspected gene may be a candidate if its encoded protein is found to physically interact with a protein known to be involved in the condition or pathway. Clusters with a strong aging association included one containing mTOR signaling pathway members, and one in which Werner syndrome RecQ like helicase gene, WRN, was one of 16 members. Another lacked genes associated previously with aging, but linked 8 genes differentially methylated with age, and 7 differentially expressed in response to CR.
    Potential anti-aging interventions Because CR delays aging and ameliorates risk of aging-related diseases, but adherence in human populations is burdensome, attempts have been made to identify natural or synthetic compounds that mimic the effects of CR [238]. “Epigenetic diets” that favourably influence the epigenetic profile of individuals have been described, together with natural compounds able to mediate effects of such diets [345]. Prominent among these is resveratrol, a sirtuin 1 activator, able to promote healthy aging and increase longevity [[346], [347], [348], [349], [350], [351], [352], [353], [354]]. Others include spermidine, the antidiabetic drug metformin, selenium, synthetic sirtuin-activating compounds such as SRT1720 and SRT2104, senolytics (e.g., dasatinib plus quercetin), and the NAD+ booster nicotinamide mononucleotide. Dietary components such as green tea, broccoli sprouts and soybeans, and the bioactive compounds extracted from these diets have received extensive attention due to their ability to favourably alter the epigenetic landscape in cancer cells [[355], [356], KRN 7000 structure [357], [358]]. Long-term consumption of epigenetic diets may alter chromatin profiles, slow aging and reduce risk of degenerative diseases of aging such as cancer, cardiovascular disease, type 2 diabetes and neurodegenerative disorders [[359], [360], [361], [362], [363], [364], [365], [366]], suggesting that these bioactive diets may affect aging processes by altering chromatin profiles that also occur in CR [367]. Global gene expression profiling methods have been developed to identify CR mimetics able to delay aging [368].