m 6A methylation in cellular senescence of age-associated diseases

Abstract

Cellular senescence is a state of irreversible cellular growth arrest that occurs in response to various stresses. In addition to exiting the cell cycle, senescent cells undergo many phenotypic alterations, including metabolic reprogramming, chromatin rearrangement, and senescence-associated secretory phenotype (SASP) development. Furthermore, senescent cells can affect most physiological and pathological processes, such as physiological development; tissue homeostasis; tumour regression; and age-associated disease progression, including diabetes, atherosclerosis, Alzheimer's disease, and hypertension. Although corresponding anti-senescence therapies are actively being explored for the treatment of age-associated diseases, the specific regulatory mechanisms of senescence remain unclear. N ⁶-methyladenosine (m ⁶A), a chemical modification commonly distributed in eukaryotic RNA, plays an important role in biological processes such as translation, shearing, and RNA transcription. Numerous studies have shown that m ⁶A plays an important regulatory role in cellular senescence and aging-related disease. In this review, we systematically summarize the role of m ⁶A modifications in cellular senescence with regard to oxidative stress, DNA damage, telomere alterations, and SASP development. Additionally, diabetes, atherosclerosis, and Alzheimer's disease regulation via m ⁶A-mediated cellular senescence is discussed. We further discuss the challenges and prospects of m ⁶A in cellular senescence and age-associated diseases with the aim of providing rational strategies for the treatment of these age-associated diseases.

Keywords: N -methyladenosine; age-associated diseases; cellular senescence.

Figure 1

The process of m ⁶A RNA methylation and functions of m ⁶A effector proteins in RNA metabolism The m 6A effector proteins include writers, erasers, and readers. The role of writers, including WTAP, RBM15/15B, METTL3, and METTL14, is to catalyze the m 6A methylation modification of RNA. The role of erasers such as FTO and ALKBH5 is to mediate the demethylation modification of RNA. The role of readers, namely, IGF2BP1/2/3, YTHDC1/2/3, YTHDF1/2/3, HNRNPA2B1, and HNRNPC, is to read the m 6A signal on RNA to regulate RNA splicing, processing, decay, stability and translation, and other biological processes.

Figure 2

Regulatory role of m ⁶A (N ⁶-methyladenosine) in cellular senescence-related processes Telomere shortening, increased SASP secretion, DNA damage, and oxidative stress are important factors contributing to cellular senescence.Overall, m 6A plays an important regulatory role in these senescence-related processes. During telomere shortening, alterations in m 6A levels regulate the cell cycle; ultimately, this regulates cellular senescence by affecting telomere length and integrity, thereby causing DNA damage and promoting p53/p21 expression. During SASP secretion, m 6A affects the degree of inflammation primarily by regulating the expressions of pro- and anti-inflammatory cytokines; these cytokines, in turn, affect the progression of cellular senescence by regulating p53/p21 and p16 expression to influence the cell cycle. During DNA damage, m 6A regulates p53/p21 expression by influencing the recruitment of DNA polymerase at the site of damage and regulating DNA break repair, thereby regulating cellular senescence. During oxidative stress, m 6A predominantly acts on oxidative and antioxidant systems to regulate the balance of oxidation and antioxidation in vivo; overall, this further influences the degree of DNA damage and inflammation levels and ultimately regulates the process of cellular senescence via cell cycle regulation.