N6-Methyladenosine Methylation of mRNA in Cell Senescence.

Cell senescence is the growth arrest caused by the accumulation of irreparable cell damage, which is involved in physiological and pathological processes and regulated by the post-transcriptional level. This regulation is performed by transcriptional regulators and driven by aging-related small RNAs, long non-coding RNAs, and RNA-binding proteins. N6-methyladenosine (m6A) is the most common chemical modification in eukaryotic mRNA, which can enhance or reduce the binding of transcriptional regulators. Increasing studies have confirmed the crucial role of m6A in controlling mRNA in various physiological processes. Remarkably, recent reports have indicated that abnormal methylation of m6A-related RNA may affect cell senescence. In this review, we clarified the association between m6A modification and cell senescence and analyzed the limitations of the current research.

Cell senescence, N6-methyladenosine methylation, mRNAs

Cellular Senescence Cell senescence is a state of growth arrest that occurs when cells encounter stresses. Senescent cells often express a senescence-associated secretory phenotype (SASP), which is composed of pro-inflammatory cytokines, growth factors, chemokines, metalloproteases, and extracellular vesicles (Tchkonia et al. 2013). SASP factors can alter the microenvironment and play a dual role in cellular responses (Tchkonia et al. 2013). Thus, cellular senescence has become a critical cellular process in health and disease, exhibiting both beneficial (such as tumor suppression, embryonic development, tissue regeneration and remodeling, and wound healing) and detrimental (such as inflammation, apoptosis, fibrosis, and oncogenesis) effects (Childs et al. 2015; Muñoz-Espín and Serrano 2014; Campisi 2001; Demaria et al. 2014; Prieur and Peeper 2008; Storer et al. 2013). Shreds of evidence have identified that senescent cells can accelerate atherosclerosis, Parkinson’s and Alzheimer’s disease, hepatic fibrosis, insulin resistance, cancer, and age-related chronic inflammation (Munk, et al. 2021; O’Hara and Russo 2017; Wissler Gerdes et al. 2020; Bloniarz et al. 2021). Cell senescence can be divided into replicative senescence, damage-induced senescence, and tumor-induced senescence. In the 1960s, Hayflick and Moorhead observed that cell arrests their growth when it reaches the maximum number of divisions (Hayflick and Moorhead 1961). This phenomenon is known as the “Hayflick limit” and is caused by the gradual shortening of telomeres as each cell divides (Xu and Teixeira 2019). At present, we define this bio clock as replicative senescence. It is needed to protect organisms from infinite cell proliferation caused by massive stimuli or deregulation. Replicative senescence possesses a high degree of heterogeneity and asynchrony, which facilitates genomic instability and senescence escape (Xu and Teixeira 2019). Damage-induced senescence is triggered by acute stress responses, including oxidants, hypoxia, chemotherapy drugs, and radiation. These endogenous and exogenous factors cause DNA damage and then lead to senescence and even apoptosis of cells if not properly repaired (Nakayama and Yamaguchi 2013). Senescence also can be induced by carcinogenic stress. The activation of oncogenes causes permanent growth stagnation in tumor cells. It functions as a powerful tumor suppressor and prevents the proliferation of seriously damaged cells (Liu et al. 2018; Saretzki 2010). Recently, Childs et al. surprisingly found that senescent cells actively inhibit cell apoptosis and possess tumor-promoting effects (Childs et al. 2014). The existence of β-galactosidase activity at pH 6, induction of tumor suppressor pathways TP53 (p53) and/or CDKN2A (p16), and morphological changes such as cell flattening, cell boundary-blurring, and vacuolation are defining markers of senescence (Casella 2019). Moreover, the most frequently mentioned laboratory markers of aging include cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL) as well as other proteins, such as C-reactive protein (CRP), and the constantly discussed non-epigenetic biomarkers of aging are telomere length, DNA damage severity, Sirtuin 1/6 (SIRT1/6), Growth differentiation factor 15/11 (GDF15/11), and Chemokine (C-X-C motif) Ligand 1 Protein (CXCL1) (Hartmann 2021). Moreover, a newly published study found novel RNA and protein markers of cell senescence, including HIST1H1, HIST1H1D, SRPX, STAT1, CCND3, and CLDN1 (Rossi and Abdelmohsen 2021) (Fig. 1). Increasing evidence supported that RNA modification participates in the expression of these markers. RNA Modifications Transcriptional and post-transcriptional regulators tightly regulate senescence-associated growth arrest, morphological changes, and SASP. The transcriptional regulation of senescence is performed by transcriptional regulators, including p53, p16, p21, melanogenesis-associated transcription factor (MITF), and enzymes associated with epigenetic modifications, such as DNA (cytosine-5-)-methyltransferase 1(DNMT1) (Liebl and Hofmann 2021; Leon, et al. 2021; Zhang 2021a; Pan et al. 2013). Post-transcriptional regulation of senescence is driven by aging-associated microRNAs, long non-coding RNAs, and RNA-binding proteins (Choi et al. 2017; Panda et al. 2017; D’Amico et al. 2019). These factors integrate into mRNA, interfering with its storage, translation, and cytoplasmic stability. Studies are emerging that specific chemical modifications affect senescence-related mRNA metabolism and protein generation. To date, more than 170 kinds of post-transcriptional modifications have been discovered in the field of life science. N6-methyladenosine (m6A), as the most common chemical modification in eukaryotic mRNA, has attracted extensive attention. RNA Methylation at m6A in Senescence m6A Methylation Related Proteins The m6A modification mainly occurs in the common conserved motif of RRACH ([A/G/U][A/G]AC[A/C/U]), which is dynamically controlled by various functional proteins, including “writers” (m6A methyltransferases), “erasers” (m6A dimethyl transferases), and “readers” (effectors recognizing m6A) (Fu et al. 2014) (Fig. 2). Writers M6A is attached to mRNA through a methyltransferase complex (MTC), consisting of the METTL3 catalytic subunit and other ancillary subunits, including METTL14, WTAP, VIRMA, METTL16, RBM15, and ZC3H13. METTL3, METTL14, and WTAP are the earliest writers discovered, and they form an MTC to jointly bind the m6A-methylated radicals to RNA (Bokar et al. 1997; Wang et al. 2014a; Ping et al. 2014). METTL3 is the main catalytic component of MTC (Liu et al. 2014). Knocking out METTL3 has been reported to cause significant decreases in m6A levels. METTL3 critically targets mRNA, depositing m6A onto nascent RNA rely on its zinc finger motif (Batista et al. 2014). A mechanistic study in adult hematopoietic stem cells (HSC) presented that METTL3 influences the self-renewal of HSC by promoting the expression of static genes (Yao et al. 2018). Both increased and decreased expression of METTL3 lead to elevated translation of WTAP mRNA and contribute to protein stabilization. An increase in METTL3 levels promotes WTAP protein expression by increasing WTAP mRNA translation and protein stabilization, while the decrease of METTLE3 levels causes higher WTAP protein expression by increasing WTAP mRNA levels (Sorci et al. 2018). Moreover, as an intracytoplasmic reader, METTL3 also directly binds RNA and recruits eIF3 to regulate the translation of specific RNA (Lin et al. 2016). METTL14 plays a crucial role in substrate recognition and structural stability (Bujnicki et al. 2002). A recent study of mouse embryonic stem cells (mESCs) showed that arginine methylation of METTL14 promotes global m6A modification and mESCs endoderm differentiation by stabilizing the binding of the m6A methyltransferase complex to its substrate RNA (Liu et al. 2021a). Furthermore, METTL14 interferes with the self-renewal of female germline stem cells by altering the m6A modification of circRNA and increasing its output to the cytoplasm (Li et al. 2021). WTAP does not have methylation transferase activity and its role is to anchor the complex formed by METTL3–METTL14 to the target RNA and accelerate its accumulation in the nucleus (Ping et al. 2014). In myocardial infarction, WTAP alters m6A modification of ATF4 mRNA to increase endoplasmic reticulum stress and apoptosis, thereby exacerbating myocardial ischemia/reperfusion injury (Wang et al. 2021a). As a newly discovered independent RNA methyltransferase, METTL16 specifically recognizes RNA triple helices and methylates MAT2A transcript encoding S-adenosylmethionine (SAM) synthetase and U6 small nuclear RNA (U6 snRNA). Both substrates contain a conservative UACAGAGAA motif. In addition, METTL16 controls a significant portion of the m6A transcriptome by affecting SAM homeostasis (Ruszkowska 2021). ZC3H13, also named Flacc, is crucial to m6A methylation. Its’ diminish mainly affects m6A methylation at 3′-UTR of mRNA. Previous studies demonstrated that ZC3H13 knockdown leads to the transportation of WTAP, Virilizer, and Hakai from the nucleus to the cytoplasm, which means that ZC3H13 anchors WTAP, Virilizer, and Hakai in the cell nucleus to enhance methylation (Jiang et al. 2021; Liu et al. 2021b). RBM15 and RBM15B (collateral homolog of RBM15) regulate the m6A methylation level of lncRNA. They combine with the m6A-methylated complex and recruit it to specific RNA regions. In addition, RBM15 and RBM15B also combined with METTL3 in a WTAP-dependent manner (Patil et al. 2016; Balacco and Soller 2019). Erasers FTO and ALKBH5 have been identified as the two significant demethylases in eukaryotes. They are escherichia coli Fe (II)/αKG-dependent dioxygenases that reverse DNA alkylation damage (Fedeles et al. 2015). In a biochemical study in 2011, m6A in nuclear RNA was found as a substrate for FTO and further supported by partial colocalization of FTO with the nuclear spot. The C-terminal of FTO has a unique long loop structure capable of removing m6A from single-stranded DNA or RNA in an iron (II)- and α-KG-dependent manner (Jia et al. 2011). Furthermore, FTO preferentially binds to pre-mRNAs in introns, poly (A) sites, and near alternatively splicing exons (Bartosovic et al. 2017). Some studies have confirmed that FTO is a pivotal regulator of m6A-labeled transcripts. It affects lipogenesis through regulating the alternative splicing and 3’-end processing of lipogenic transcription factors in an m6A-dependent manner (Bartosovic et al. 2017; Zhao et al. 2014). However, recent studies support the physiological preference of FTO to demethylate 2-O-dimethyladenosine (m6Am) instead of m6A, and FTO decreases the stability of m6Am mRNA (Mauer et al. 2017). Unlike the m6A modification located inside RNA, m6Am is mainly located at the first base after the m7G cap at the 5′-end of eukaryotic mRNA (Xie et al. 2020). FTO is mainly existed in the nucleus, while mRNA is merely present in the nuclear during transcription, indicating that FTO can only demethylate m6A in mRNA within a concise time window. Therefore, FTO can hardly dynamically regulate cytosolic mRNA (Mauer and Jaffrey 2018). ALKBH5 is a ribosomal RNA m6A eraser that demethylates and modifies mRNA in the nucleus (Lan et al. 2019). The unique coiled-coil structure at the N-terminal facilitates the function of this demethylase. ALKBH5 expresses higher in mouse testis than other tissues and alters germ cell splitting and long 3′-UTR mRNAs stability in an m6A-dependent manner (Tang et al. 2018). The silence of ALKBH5 properly eliminated m6A in the spermatogenic cell nuclei, reducing the quantity and quality of sperm in male mice and even leading to infertility (Tang et al. 2018). In addition, ALKBH5 plays a pivotal role in biological processes, including invasion, metastasis, proliferation, and ossification (Li et al. 2019; Jin et al. 2020; Chao et al. 2020; Wang et al. 2020). A novel m6A demethylase ALKBH3 preferentially acts on m6A in tRNA rather than m6A in mRNA or rRNA (Ueda et al. 2017). Readers After finishing the dynamic regulation of methylation or demethylation, readers activate downstream pathways. It identifies bases modified with m6A to improve translation efficiency, mediate mRNA degradation, and control mRNA stability, splicing, and export. The earlier identified readers are YTH domain family proteins, including YTHDC1/2 and YTHDF1/2/3. YTHDC1 is mainly present in the nucleus and involved in mRNA splicing and nuclear transporting. A recent study indicated that YTHDC1 recruits the pre-mRNA splicing factor SRSF3 (SRP20) and simultaneously blocks the gene binding of SRSF10 (SRP38) to help exon inclusion of targeted mRNAs and thus alters splicing (Xiao et al. 2016). Besides, YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, integrating target mRNA into the nuclear export pathway and transferring RNA to the splice and adaptor proteins (Roundtree, et al. 2017). YTHDC2 exists in both the nucleus and the cytoplasm, controlling RNA translation and decay. A study of human bone marrow mesenchymal stem cells presented that YTHDC2 knockdown supported osteogenic differentiation and inhibited adipogenic differentiation (Wen et al. 2021). Another study exhibited that the expression of YTHDC2 was up-regulated in the testis at the beginning of meiosis, indicating that YTHDC2 may play an essential role in spermatogenesis (Hsu et al. 2017). YTHDF1/2/3 functions mainly in the cytoplasm. YTHDF1 was initially observed to unite to the region near the stop codon of the m6A-modified transcript (Wang et al. 2015). Subsequent studies suggested that YTHDF1 interacts with translation initiation factor eIF3 to encourage the translation efficiency of m6A-modified RNA substrates (Wang et al. 2015). YTHDF2 can alter the stability of target mRNA. In 2014, YTHDF2 was first reported to mediate the decay of mRNA with m6A (Wang et al. 2014b). The carboxy-terminal domain of YTHDF2 binds to the m6A RNA and the amino-terminal domain localizes the YTHDF2 mRNA complex to the RNA decay site and initiates the degradation of m6A RNA (Wang et al. 2014b). In addition, YTHDF2 relies on the recruitment of the CCR4–NOT deadenylase complex to accelerate the decay of m6A-modified transcripts (Du et al. 2016). The primary function of YTHDF3 is to adjust the translation and decay of mRNA. Similar to YTHDF1, the binding site of YTHDF3 is also mainly located at the 3′UTR. YTHDF3 could improve the translation efficiency of target genes shared by YTHDF1 and YTHDF3, indicating that YTHDF3 and YTHDF1 coordinate the translation efficiency of mRNA (Li et al. 2017a). Another study revealed that YTHDF3 could mediate mRNA degradation through direct interaction with YTHDF2 (Shi et al. 2017). IGF2BPs are single-stranded RNA-binding proteins that recognize a conserve GG(m6A)C sequence on target mRNA transcripts. Contrary to the fact that YTHDC2 promotes mRNA decay, IGF2BPs recruit RNA stabilizers to stabilize the m6A-modified mRNA under normal conditions and transfer to stress particles to store the m6A-modified mRNA under stress conditions, thereby affecting gene expression output (Huang et al. 2018; Xu et al. 2019). IGF2BP1 is mainly expressed in fetal tissues and cancer but is rarely expressed in normal adult tissues (Bell et al. 2013; Hammer et al. 2005). This gene plays a crucial role in embryogenesis, tumorigenesis, and chemotherapy resistance via affecting mRNAs localization, stability, or translatability (Fakhraldeen et al. 2015; Mahaira et al. 2014). IGF2BP1 knockout mice exhibited impaired intestinal development, growth and development limitations, and raised mortality. In addition, IGF2BP1 affects neuronal behavior partially by controlling the synthesis of related proteins during neuronal development (Perycz et al. 2011; Fabrizio et al. 2008). Other studies have shown that IGF2BP1 could regulate testicular stem cells and control neuronal differentiation (Donnelly et al. 2011; Boylan 2008). IGF2BP2 has been involved in various metabolic diseases and cancers by affecting the localization, stabilization, and translation of miRNA, mRNA, and lncRNA (Wang et al. 2021b). In diabetic nephropathy, IG2BP2 recognizes m6A-modified lamb2 mRNA in the actin skeleton to modulate the expression of lamb2 (Schaeffer et al. 2012). Moreover, this gene can regulate the signal transduction to affect the regeneration and survival of podocytes (Fu et al. 2015). Using transgenic mice, Beate Czepukojc et al. have discovered that IGF2BP2 enhances bile duct response leading to cirrhosis and short-term survival in a model of steatohepatitis (Czepukojc et al. 2019). Besides, overexpression of IGF2BP2 causes short survival time and poor prognosis in patients with various cancers, including acute myeloid leukemia, hepatocellular carcinoma, esophageal carcinoma, and gallbladder carcinoma. IGF2BP3 and IGF2BP1 have 73% homologous amino acid sequences and have many identical or similar functions. It also functions in embryonic regulation and cancer. The Vg1-RBP in Xenopus laevis is orthologous to IGF2BP3 and has 84% amino acid homology with human IGF2BP3. The absence of Vg1-RBP leads to the bending of nerve tubes, abnormal intestinal morphology, and loss of pancreatic organs in Xenopus laevis, indicating that IGF2BP3 plays a vital role in neurodevelopment and organ maturation. Overexpression of IGF2BP3 in mice revealed extensive remodeling of the exocrine pancreas. This remodeling results in increased acinar cell proliferation, reduced compartment size, and the emergence of double-differentiated mesenchymal cells. These changes are the primary source of precancerous pancreatic lesions. In addition, excessive expression of IGF2BP3 was detected in other precancerous lesions, such as atypical endometriosis, Barrett’s esophageal dysplasia, and pancreatic ductoma. m6A mRNA Methylation in Senescence To date, there is little research has been done on senescence and m6A, while the current studies of this aspect mainly focus on the relationship between METTL3/METTL14 and senescence. Only a few articles have examined the relationship between eraser/reader and aging. In 2017, Li et al. reported the connection between m6A and cell senescence. Using TP53-deficient human colon carcinoma cells (HCT116 p53−/−) and HeLa cells, they demonstrated that METTL3/METTL14 catalyzed the formation of m6A in p21 3'UTR. Interestingly, knocking out METTL3/METTL14 did not affect the overall mRNA level but reduced the protein level of p21, indicating that the modification of m6A affected the translation efficiency of p21 (Li et al. 2017b). Moreover, METTL3/METTL14 induced m6A modification of p21 mRNA in HCT116 p53−/−, meaning that this change in p21 expression was independent of p53. Meanwhile, in H2O2-treated HCT116 p53−/− cells, the expression of p21, METTL3, and METTL14 exceeded and the percentage of cells expressing aging-related β-galactosidase also go up, further proving that METTL3 and METTL14 had effects independent of p53 in cell senescence (Li et al. 2017b). The intervention of sulforaphane (SFN) on three breast cancer cells MCF-7, MDA-MB-231, and SK-BR-3 resulted in cell cycle arrest, senescence, apoptosis, and autophagy. SFN treatment raised protein expression of p53, p21, and p27 without a significant effect on RNA levels. In addition, SFN medication contributed to a decrease in overall m6A levels in three breast cancer cells. The specific mechanism is unclear, but SFN may promote senescence by reducing overall m6A levels (Lewinska et al. 2017). In 2018, Min et al. analyzed the m6A modification spectrum of human peripheral blood mononuclear cells from the young and aged cohorts and testified to an overall decrease in m6A levels in the aged population. In the cell model of aging human diploid fibroblasts, the expression of METTL3 decreased and the methylation and expression of AGO2 mRNA also reduced. This connection suggests that m6A methylation increased the expression of AGO2. AGO2 can speed senescence by affecting the expression of mature miRNA (Min 2018). HMNA gene is often expressed in patients with Hutchinson-Gilford premature aging syndrome (HGPS) and the Lamin A this gene encodes is a component of nuclear speckles. The interaction between Lamin A and METTL3/METTL14 ensured the correct positioning in the nuclear speckles and protein stability. With the later passage of HGPS cells and normal cells, METTL14 was down-regulated. Indeed, overexpression of METTL14 weakens senescence in normal and HGPS cells (Zhang 2020). Lately, some scholars have explored the role of m6A modification in regulating the senescence of premature stem cells using homologous human mesenchymal stem cells (hMSCs) with LMNA mutation and WRN knockout as HGPS and WS models. They proved that the m6A modification in METTL3-knockout hMSCs reduced and the cells showed a state of accelerated senescence. Meanwhile, hMSCs cells overexpress METTL3, accompanied by enhanced m6A transformation and decreased aging phenotype. Further mechanical studies indicated that METTL3 inhibited hMSC senescence through m6A modification of the MIS12 transcript and m6A reader IGF2BP2 was vital to the recognition and stabilization of m6A-modified MIS12 mRNA. Thus, the authors determined that m6A modification was associated with premature senescence (Wu et al. 2020). Endogenous retroviruses (ERVs) affect genomic regulation and cellular physiology by affecting the RNA-centric life cycle (Johnson 2019). Failure limitation of ERVs is associated with senescence (Tam et al. 2019). Chelmicki et al. revealed that m6A RNA methylation could restrict ERVs using unbiased genome-scale CRISPR knockout screening in mouse embryonic stem cells (Chelmicki et al. 2021). The absence of METTL3–METTL14 and its accessory subunits WTAP and ZC3H13 increased mRNA abundance of intracisternal A-particle (IAPs) and related ERVK elements. In-depth research found that m6A RNA methylation reduced the half-life of IAP mRNA by recruiting the YTHDF family of m6A reader proteins. These results suggest that m6A may affect senescence by the failure restriction of ERVs. Low back pain, the most common chronic pain, is closely related to intervertebral disc degeneration (IVDD), of which abnormal nucleus pulposus (NP) is the leading cause (Wu 2021). Zhu et al. approved that methylation levels of m6A in NP tissues of patients with IVDD were mediated by METTL14 and positively correlated with TNF-A. METTL14 knockdown significantly inhibited TNF-a-induced cell cycle arrest and cell senescence. Further study on its mechanism revealed that METTL14 accelerates the processing of pri-miR-34a by DGCR8 in an m6A manner, and miR-34a-5p promoted cell cycle arrest and senescence by targeting Silencing information regulator 2 related enzyme 1(SIRT1) (Zhu 2021). In recent research on ovarian aging, the authors compared FTO levels and m6A content in the follicular fluid between the young and the aged. They observed that the youth cohort had higher FTO levels and lower m6A levels than the old cohort. In animal studies, older mice also have decreased FTO and increased m6A levels (Sun et al. 2021). In conclusion, the existing studies support that the methylation modification of m6A may directly affect cell senescence by regulating the protein levels of p53 and p21 or control cell cycle arrest and senescence by regulating the expression of miRNA targeting SIRT1 and regulating the expression of MIS12. However, whether the m6A modification affects the expression of p16 has not been elaborated (Fig. 3). m6A Methylation and Cell Senescence in the Central Nervous System It has been reported that more m6A sites are observed in mouse and humans as age increase, suggesting that m6A plays a vital role in aging and neurodegenerative diseases (Shafik et al. 2021). m6A Methylation and Cell Senescence in Microglia Microglia play a prominent role in the inflammatory process of the central nervous system. Microglial alterations as reduced motility and capacity for phagocytosis, mitochondrial DNA damage, and excess iron storage and these changes are related to senescence phenotypes. Overactivated microglia may release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-18, etc.), causing cell senescence and accelerating neurodegeneration. When treating the microglia with lipopolysaccharide to establish the inflammation model, microglia showed increased expression of METTL3, inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-18), and inflammatory proteins (TRAF6 and NF-κB). The potential mechanism may be that the overexpression of METTL3 promotes the activation of the TRAF6-NF-κB pathway in an m6A-dependent manner, causing massive release of inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-18) and the expression of SASP (Wen 2020). In another study, the researchers treated BV2 cells with OGD/R and observed that microRNA-421-3p targets YTHDF1, which specifically binds to the m6A site of p65 mRNA to facilitate its translation (Zheng 2020). m6A Methylation and Cell Senescence in Astrocytes Astrocytes are the largest glial cell population in the central nervous system and m6A is involved in astrocyte production (Wang et al. 2021c). The destruction of astrocyte function manifested as DNA damage, lysosomal dysfunction, morphological changes (flattened cells), decreased proliferation, and mitochondrial dysfunction accompanied by oxidative stress. All these pathological changes are related to senescence. In Alzheimer’s disease (AD), astrocytes often exhibit a senescence phenotype. Using streptozotocin-treated astrocytes as AD models, the researchers observed that streptozotocin-treated astrocytes possessed significantly higher expression of FTO and YTHDF1. When decreasing the expression of FTO, oxidative stress and mitochondrial dysfunction are also inhibited in astrocytes. The findings of this study indicated that m6A may promote the development of AD by impairing the physiological function of astrocytes (Cockova, et al. 2021). m6A Methylation and Cell Senescence in Neurons Neurons are the basic structural and functional unit of the nervous system and the m6A participates in its development, differentiation, regeneration, and cell cycle regulation (Yoon et al. 2017; Angelova et al. 2018). Numerous studies demonstrated that neuron usually shows an aging phenotype in Parkinson’s disease (PD) and AD (Kritsilis, et al. 2018; Han et al. 2020a). The previous study has shown that the generation and development of neurons were severely affected when Ythdf2 was missing in the embryonic neocortex (Li et al. 2018). In a pathological study of AD, Han et al. constructed an AD mouse model using APP/PS1 transgenic mice and C57BL/6 mice as the control. Quantitative results of RNA m6A methylation indicated that the m6A methylation in the cortex and hippocampus of APP/PS1 transgenic mice increased. Meantime, high-throughput sequencing results showed increased expression of METTL3 and decreased expression of FTO in AD mice. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the different genes constructed pathways that might be related to neuronal development and growth (Han et al. 2020b). Similarly, Zhao et al. studied the expression of m6A modifications and m6A regulatory factors in brain tissue of AD patients. The data indicated decreased levels of neuronal m6A and reduced METTL3 expression in the brain of AD patients. In another study, the expression profiles of known m6A regulatory genes were investigated using a public RNA-seq dataset. The results showed that the expression of METTL3 was up-regulated and the expression of RBM15B was down-regulated in the hippocampus of AD patients (Huang, et al. 2020). PD is an age-related neurological disease that manifests as early senescence and death of dopaminergic neurons. Chen et al. established cellular and rat models of PD using 6-OHDA to detect the variation of m6A mRNA modification levels. The data indicated that the global m6A modification of mRNAs decreased in both models. Then when they overexpressed FTO to reduce the m6A level, they found significantly reduced apoptosis of dopaminergic neurons. These results suggest that the m6A modification may play a vital role in the death of dopaminergic neurons (Chen et al. 2019).

and Perspectives Epitranscriptomic changes, including RNA chemical modifications, are important factors in regulating gene expression programs. Among them, m6A is the most extensive chemical modification in mRNA in eukaryotes (Roundtree et al. 2017). In recent years, due to the technical progress in mass spectrometry and sequencing, the research on mRNA base modification has been deepened gradually (Schwartz and Motorin 2017). The current studies on mRNA modification mainly focus on the contribution of mRNA methylation in cancer and metabolic diseases (Lang 2021; Zhang 2021b; Wang et al. 2021d; Sun and Zhang 2021; Luo et al. 2021). Indeed, accumulating studies have shown that mRNA modification is closely related to physiological senescence. This paper reviews the most common chemical modification m6A in eukaryotes, regulating aging in different cell models through various mechanisms. METTL3 and METTL14 have been shown to alter the expression of senescence-associated proteins P21, P27, and P53 by conferring methylation radicals on P21, P27, and P53 mRNAs (Li et al. 2017b; Lewinska et al. 2017). Meanwhile, METTL3-induced AGO2 mRNA degradation can affect the expression of many mature miRNAs, thus regulating cell senescence (Min 2018). In addition, another study testified that FTO expression was higher in the elderly population (Sun et al. 2021). Given the increasing evidence of m6A controlling the expression of the critical aging regulator, a comprehensive analysis of mRNA methylation in different aging models is necessary (Casella 2019). Specific animal models are also essential for studying aging-related mRNA methylation in vivo (Casella 2019). However, there is a paucity of literature regarding the role of m6A modification in aging. Meanwhile, the current studies of m6A in senescence focus only on METTL3 and METTL14, whereas clues toward the “erasers” and “readers” are scarce. In addition, most current studies on m6A and aging remain in the phenotype, and the research on m6A methylation-related protein targeting genes is still insufficient. Therefore, it is crucial to deeply decipher the roles and mechanisms of m6A methylation-related proteins in mediating m6A signal transduction. The participation of m6A in cell senescence provides a new potential therapeutic target for treatment. However, the role of m6A in aging is still well beyond our understanding. There is a great demand for in-depth study of how m6A signals regulate the physiology and pathology of cell senescence. Funding No financial support has been received for this article. Declarations Conflict of interest All authors declare no conflict of interest. Ethical Approval This article does not contain any studies with human participants or animals performed by any of the authors. Research Involving Human and/or Animal Participants This article does not contain any studies with animals or human participants performed by any of the authors. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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