Transcriptional and epigenetic regulation of autophagy in aging

Abstract

Macroautophagy is a major intracellular degradation process recognized as playing a central role in cell survival and longevity. This multistep process is extensively regulated at several levels, including post-translationally through the action of conserved longevity factors such as the nutrient sensor TOR. More recently, transcriptional regulation of autophagy genes has emerged as an important mechanism for ensuring the somatic maintenance and homeostasis necessary for a long life span. Autophagy is increased in many long-lived model organisms and contributes significantly to their longevity. In turn, conserved transcription factors, particularly the helix-loop-helix transcription factor TFEB and the forkhead transcription factor FOXO, control the expression of many autophagy-related genes and are important for life-span extension. In this review, we discuss recent progress in understanding the contribution of these transcription factors to macroautophagy regulation in the context of aging. We also review current research on epigenetic changes, such as histone modification by the deacetylase SIRT1, that influence autophagy-related gene expression and additionally affect aging. Understanding the molecular regulation of macroautophagy in relation to aging may offer new avenues for the treatment of age-related diseases.

Keywords: AMPK, AMP-activated protein kinase; Atg, autophagy related; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CaN, calcineurin; HDAC, histone deacetylase; FOXO; HAT, histone acetyltransferase; LC3, microtubule-associated protein 1 light chain 3; MITF, microphthalmia-associated transcription factor; PDPK1/2, 3-phosphoinositide dependent kinase 1/2; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; SIRT1; TFEB; TFEB, transcription factor EB; TOR, target of rapamycin; TSC, tuberous sclerosis complex; UVRAG, UV radiation resistance associated.; acetyl-CoA, acetyl coenzyme A; autophagy; epigenetics; longevity; miRNA; transcription..

Figure 1.

Regulation of autophagy-related gene expression associated with longevity. The process of autophagy and the transcriptional regulation of autophagy genes by the action of specific transcription factors, epigenetic modifications, and miRNAs have emerged as important conserved mechanisms to ensure longevity. (A) The autophagy process is initiated by cytoplasmic nucleation of the phagophore with double-membrane structures. The phagophore then elongates and sequesters cellular components until it matures into an autophagosome, which then docks and fuses with lysosomes to form an autolysosome. Upon fusion, the cargo and inner membrane of the autolysosome are degraded. (B) The nutrient sensor MTORC1 is a major regulator of the autophagy process. MTORC1 inhibits autophagy and positively regulates growth, mRNA translation, and ribosomal and lipid biogenesis. The nutritional status of the cell (e.g., amino acid levels) dictates the recruitment of MTORC1 to the lysosomal membrane and its subsequent activation. Active MTORC1 phosphorylates several targets, including the transcription factors TFEB and FOXO. Phosphorylation of TFEB, and possibly of FOXO, occurs at the lysosomal membrane and leads to their retention in the cytosol. (C) The nuclear translocation of transcription factors TFEB and FOXO, as well as activation of FOXA induces the expression of multiple autophagy-related and lysosomal genes (for FOXA, which is constitutively nuclear; only the C. elegans ortholog PHA-4 has so far been shown to regulate autophagy gene transcription and modulate longevity). TFEB and FOXO are regulators of longevity in several species. (D) Autophagy gene expression can also be regulated epigenetically by histone modifications such as acetylation (Ac) and methylation (Me), which affect the chromatin state thus altering expression of specific genes. For example, the deacetylation of histone mark H4K16 by SIRT1 leads to transcriptional repression of various autophagy-related genes (the acetylation reactions occurs by the acetyltransferase KAT8). High levels of acetyl-CoA can inhibit the expression of autophagy gene ATG7, and conversely, histone hypoacetylation via spermidine treatment can increase gene expression of ATG11, ATG7, and ATG15. The dimethylation of H3K9 through the methyltransferase EHMT2 leads to the repression of autophagy gene transcription. The deacetylase SIRT1, spermidine treatment and levels of nucleocytosolic acetyl-CoA are associated with the regulation of longevity in several species. Mammalian gene names are used exclusively in the figure. See text for reference to specific model systems and for further details.