SIRT7 in the aging process

Abstract

Aging is the result of the accumulation of a wide variety of molecular and cellular damage over time. This has been associated with a number of features termed hallmarks of aging, including genomic instability, loss of proteostasis, telomere attrition, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and impaired intercellular communication. On the other hand, sirtuins are enzymes with an important role in aging and life extension, of which humans have seven paralogs (SIRT1 to SIRT7). SIRT7 is the least studied sirtuin to date, but it has been reported to serve important functions, such as promoting ribosomal RNA expression, aiding in DNA damage repair, and regulating chromatin compaction. Several studies have established a close relationship between SIRT7 and age-related processes, but knowledge in this area is still scarce. Therefore, the purpose of this review was to analyze how SIRT7 is associated with each of the hallmarks of aging, as well as with some of age-associated diseases, such as cardiovascular diseases, obesity, osteoporosis, and cancer.

Keywords: Aging-associated diseases; Hallmarks of aging; Nucleolus; Ribosomal RNA; Sirtuins.

Fig. 1

General characteristics of SIRT7. A The human SIRT7 gene is located on chromosomal region 17q25.3, spans a 6238 bp region of the reverse strand, and generates a 1725 bp transcript that encodes a 400 amino acid protein with a molecular weight of 44.9 KDa. B SIRT7 has been shown to carry out several enzymatic activities, all of which occur on lysine residues and require the presence of the co-substrate NAD+. NAD+ is consumed to generate nicotinamide (NAM). SIRT7 enzymatic activities are: (1) deacetylation, (2) debutyrylation, (3) decrotonylation, (4) desuccinylation, and (5) defatty-acylation that share a common mechanism of action where reaction intermediates are generated with the ADP-ribose group of NAD+ bound to SIRT7. Subsequent reactions regenerate SIRT7 and release the ADP-ribose and the functional group that was removed. (6) ADP-ribosylation in which NAD+ acts as a donor of the ADP-ribose moiety for target proteins. C SIRT7 can localize to the nucleus and is the only sirtuin highly enriched in nucleolar compartments. Only a small proportion of SIRT7 remains in the cytoplasm

Fig. 2

Association of SIRT7 with the hallmarks of aging

Fig. 3

SIRT7 cooperates to maintain genomic stability. A SIRT7 is recruited to DNA damage sites in a PARP1-dependent manner and, in the early phase of the damage response, modulates H3K18ac and H3K122succ levels and interacts with the B-WICH complex to transiently compact chromatin and enhance DDR signaling. SIRT7 egress from damaged sites occurs in response to increased DICER levels, allowing chromatin to relax and components of the repair machinery (either homologous recombination or non-homologous end-joining machinery) to enter and perform their function. B In the final stage of repair, SIRT7 deacetylates ATM to promote its dephosphorylation by WIP1 and subsequent dimerization. In this way, the damage is resolved and the components of the repair machinery are removed. C SIRT7 also reduces the levels of H3K18ac in retrotransposons such as LINE-1 and promotes its association with lamin A/C in peripheral nuclear heterochromatin, thus preventing its expression and reducing the cumulative DNA damage it could generate

Fig. 4

SIRT7 regulates rRNA levels. SIRT7 promotes the association of Pol I with rDNA by associating with the transcription factor UBF and deacetylating PAF53. Fibrillarin deacetylation by SIRT7 is also required to promote methylation of histone H2A (H2AQ104me), allowing chromatin to remain decondensed. On the other hand, SIRT7 helps in the cleavage of pre-rRNA by associating with the U3 snoRNP complex and deacetylation of its U3-55k subunit. To maintain a balance in rRNA levels, SIRT7 is responsible for deacetylation of H3K36ac at rDNA sequences and for anchoring the WICH complex at rDNA promoters, contributing to heterochromatin silencing and stability. B-WICH protects RPA194, the largest subunit of Pol I, from degradation

Fig. 5

Participation of SIRT7 in the detection of glucose availability. A Liver SIRT7 is involved in the regulation of circadian glucose homeostasis and rhythmic hepatic gluconeogenesis. During the dark phase, SIRT7 deacetylates CRY1 and promotes its ubiquitination by FBXL3 and subsequent degradation. During the light phase, HSP70 levels increase and interact with SIRT7 to promote its ubiquitination and degradation. B When glucose levels are high, PRMT6 methylates SIRT7 to reduce its deacetylase activity and increase H3K18ac in PGK1 and mitochondrial biogenesis. During glucose deprivation, REGγ regulates the redistribution of SIRT7 from the nucleolus to the nucleoplasm and also promotes degradation in an AMPK phosphorylation-dependent manner. In this way, rRNA transcription is reduced and H3K18ac is increased in G6PC. C During metabolic stress, SIRT7 self-monoADP-ribosylates to interact with mH2A1.1. and modify the expression of a subset of genes, mainly second messengers

Fig. 6

Role of SIRT7 in mitochondrial function. A SIRT7 promotes the transcription of nuclear-encoded mitochondrial genes by deacetylating GABPβ1 and facilitating the formation of the GABPα/GABPβ heterotetramer. B Under conditions of nutritional stress, SIRT7 specifically binds and suppresses NRF1 activity at the promoters of mitochondrial ribosomal proteins and mitochondrial translation factors