The Epigenetics of Aging in Invertebrates

Abstract

Aging is an unstoppable process coupled to the loss of physiological function and increased susceptibility to diseases. Epigenetic alteration is one of the hallmarks of aging, which involves changes in DNA methylation patterns, post-translational modification of histones, chromatin remodeling and non-coding RNA interference. Invertebrate model organisms, such as Drosophila melanogaster and Caenorhabditis elegans, have been used to investigate the biological mechanisms of aging because they show, evolutionarily, the conservation of many aspects of aging. In this review, we focus on recent advances in the epigenetic changes of aging with invertebrate models, providing insight into the relationship between epigenetic dynamics and aging. conserved in both insects and mammals, where it regulates the rate of aging [11]. Therefore, this review will summarize recent advances in the roles of epigenetic changes in aging in these two invertebrates. DNA Methylation in Invertebrate AgingDNA methylation is a covalent chemical modification, which usually occurs at 5-methyl cytosine (5mC) and which is enriched in cytosine phosphate guanine (CpG) dinucleotides [12]. CpG methylation within promoters leads to transcriptional repression through the formation of compact chromatin structures such as heterochromatin. Conversely, promoters of genes that are highly expressed are devoid of DNA methylation, hence their name-CpG islands [13]. The dynamic changes in DNA methylation can impact aging and health. The local methylation level increases while the global methylation level decreases with aging [14]. Age-related DNA methylation changes are also correlated with human age-related diseases, such as cancer and sarcopenia [15,16]. Cytosine methylation is catalyzed by three DNA methyltransferases (DNMTs): DNMT1, DNMT3a, and DNMT3b. Three ten-eleven translocation (TET) proteins initiate the specific demethylation of 5mC residues in DNA: TET1, TET2, and TET3 [17]. The schematic diagram of DNA methylation and demethylation is shown in Figure 1. Worms do not encode a conventional DNA methyltransferase to silence DNA repeats, which led to the prevailing view that DNA methylation does not occur in C. elegans [18]. Similarly, in adult D. melanogaster, only a low level of DNA methylation was confirmed [19,20]. In Drosophila, overexpression of the DNA methyltransferase gene, dDnmt2, extends lifespan in a small heat shock protein-dependent way [21]. However, although 5mC methylation is rare, methylation on N6 adenine (6mA) is prevalent in C. elegans and D. melanogaster [22,23]. Recent studies have confirmed that NMAD-1 (MT-A70 family) and DMAD (DNA 6mA demethylase, TET ortholog) are 6mA demethylases in C. elegans and D. melanogaster, respectively. DAMT-1 (AlKB family) is likely a 6mA methyltransferase in C. elegans [24]. NMAD-1 and DAMT-1 can regulate 6mA levels and control the epigenetic inheritance of phenotypes associated with the loss of the H3K4me2 demethylase spr-5 [22]. The worm mutant of spr-5 displayed a transgenerational increase in H3K4me...

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

“…Meanwhile, epigenetic regulation in cooperation with transcriptional regulators influence the functions of cells and the fate of organisms, and could act as markers of aging ( 51 ). Epigenetic regulation involves DNA methylation, chromatin remodeling, post-translational modifications (PTMs) of histones, and non-coding RNA transcription ( 28 ). Here we discuss longevity mechanisms related to transcriptional regulators of metabolic networks and epigenetic regulation in C. elegans .…”

“…AMPK is another crucial metabolic energy sensor that links nutrient availability to lifespan by binding and phosphorylating a set of transcriptional (co)activators. The mTOR pathway is another critical pathway that links nutrient availability and metabolism to longevity; however, its mechanism remains to be fully elucidated ( 18 , 28 – 49 ).…”

“…Besides, LncRNAs with a variable length spanning from 200 base pairs up to several kilobases are important for cell function, because it can target classic signal pathways such as IIS. For example, the LncRNA tts-1 extends lifespan by reducing ribosome levels in the daf-2 mutant C. elegans ( 28 ). IIS conserved in both insects and mammals; the genetic and biological characteristics of the IIS pathway in aging were successfully translated to mammals and humans ( 67 ).…”

“…Histone modification can regulate lifespan by acting on mTOR signaling pathways. In C. elegans , COMPASS H3K4me3 methyltransferase (methylation of Lys 4 of histone H3) deficiency promotes fat accumulation and extends lifespan by targeting RSKS-1 (S6K) in the mTOR complex ( 28 ). H3K4me3 methyltransferases have homologs in humans.…”

Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus

“…Epigenetic regulations are essential for cell differentiation, development, an d protection against viruses. The y are critical for the integration of endogenous an d environmental signals during the life [12][13][14]. Dysregulations of epigenetic mechanisms have been associated with a number of age related disorders including cancers an d autoimmunity [15,16].…”