TABLE 2.
Genes showing differential expression changes in CR compared to AL participants during the 24‐month CR intervention.
| Symbol | Name | Characteristics and functions | References |
|---|---|---|---|
| (A) Genes with increased expression under CR (p < 0.01) | |||
| TERF2 | Telomeric repeat binding factor 2 | A component of the telomere nucleoprotein sheltering complex that plays a key role in the protective activity of telomeres | Smogorzewska et al. (2000) |
| ZC3H10 | Zinc finger CCCH‐type containing 10 | DNA‐binding transcription factor that activates UCP1 increases thermogenic gene expressions in BAT and iWAT in vivo | Nguyen et al. (2020) and Yi et al. (2019) |
| SF3A1 | Splicing factor 3a subunit 1 | Spliceosome protein | Rhoads et al. (2018) |
| ATG13 | Autophagy related 13 | An autophagy factor and a target of the TOR kinase signaling pathway. Essential for autophagosome formation and mitophagy | Jung et al. (2009) and Ntsapi and Loos (2016) |
| NACA | Nascent polypeptide associated complex subunit alpha | Regulates postnatal skeletal muscle growth and regeneration | Park et al. (2010) |
| MCM7 | Minichromosome maintenance complex component 7 | Declines with aging in human fibroblasts, prevents genomic instability during replication and its expression is reduced in replicative senescence | Tsitsipatis et al. (2022) |
| KHDRBS1 | KH RNA‐binding domain containing, signal transduction associated 1 | RNA‐binding protein family with many functions including alternative splicing and cell cycle regulation. Upregulated by CR in muscle of adult cynomolgus monkeys (Macaca fascicularis) | Wang et al. (2009) |
| SF3B4 | Splicing factor 3b subunit 4 | Involved in pre‐mRNA splicing as a component of the splicing factor SF3B complex | Qin et al. (2016) |
| PKNOX1 | PBX/knotted 1 homeobox 1 | Improves genomic stability “in vitro” | Iotti et al. (2011) |
| PDP2 | Pyruvate dehydrogenase phosphatase catalytic subunit 2 | Mitochondrial protein that enhances the utilization of pyruvate in oxidative phosphorylation | Wiley and Campisi (2016) |
| PRPF8 | Pre‐mRNA processing factor 8 | Core component of U2‐type and the minor U12‐type spliceosomes | Le Couteur et al. (2021), Rhoads et al. (2018), and Zhang et al. (2019) |
| WBP11 | WW domain‐binding protein 11 | Colocalizes with mRNA splicing factors and intermediate filament‐containing perinuclear networks | Ubaida‐Mohien et al. (2019) |
| RNF185 | Ring finger protein 185 | E3 ubiquitin‐protein ligase that regulates selective mitochondrial autophagy. Protects cells from ER stress‐induced apoptosis by increasing the degradation of misfolded proteins that accumulate in the endoplasmic reticulum (ER) for ubiquitination and subsequent proteasome‐mediated degradation | Tang et al. (2011) |
| TAF4 | TATA‐box binding protein associated factor 4 | Inhibits polysome formation in condition of stress | Molenaars et al. (2018) and Wright et al. (2006) |
| PATL1 | PAT1 homolog 1, processing body mRNA decay factor | Coordinate the assembly and activation of a decapping messenger ribonucleoprotein (mRNP) that promotes 5′‐3′ mRNA degradation | Vindry et al. (2017) |
| PPRC1 | PPARG related coactivator 1 | Similar to PPAR‐gamma coactivator 1 (PGC‐1α) activates mitochondrial biogenesis by interacting with nuclear respiratory factor 1 (NRF1) | Miller et al. (2019) and Shi et al. (2021) |
| PRPF6 | Pre‐mRNA processing factor 6 | A key spliceosome proteins that is upregulated with CR | Le Couteur et al. (2021) |
| PIAS3 | Protein inhibitor of activated STAT 3 | Protects STAT3 from overactivation, and considered a “fine tuning tool” for the modulation of NFκB, SMAD, and MITF | Yagil et al. (2010) |
| PLD6 | Phospholipase D family member 6 | Located in mitochondrial outer membrane enables cardiolipin hydrolase activity and regulates mitochondrial fusion | Brillo et al. (2021) |
| KLF15 | Kruppel like factor 15 | Circadian clock transcription factor regulated by FoxOs that orchestrate the nitrogen metabolism by increasing amino acid catabolism and suppressing lipogenesis during fasting | Mattson et al. (2014) and Takeuchi et al. (2021) |
| KLF9 | Kruppel like factor 9 | Modulates cellular circadian clock and is overrepresented in muscle with CR | Kasai et al. (2020) and Knoedler et al. (2020) |
| USP2 | Ubiquitin‐specific peptidase 2 | A ubiquitin‐specific protease required for TNF‐induced NF‐kB (nuclear factor kB) signaling. Regulates the circadian clock by shuttling PER1 to the nuclei and by repressing the clock transcription factors CLOCK and ARNTL/BMAL1 | Melzer et al. (2020) and Pouly et al. (2016), and Zhang et al. (2014) |
| PRKACA | Protein kinase cAMP‐activated catalytic subunit alpha | This has been found upregulated with aging and downregulated with CR in mice, involved in multiple cellular processes including glucose metabolism and cell division | Bareja et al. (2021) |
| EFTUD2 | Elongation factor Tu GTP binding domain containing 2 | GTPase component of the spliceosome complex, tends to be alternatively spliced with aging | Rodríguez et al. (2016) |
| CERS3 | Ceramide synthase 3 | Increases of ceramides in skeletal muscle with, probably in conjunction with CERS1 and CERS2 | Obanda et al. (2015) |
| PER1 | Period circadian regulator 1 | A core clock gene that transcriptionally represses the negative limb of the feedback loop and interact with the CLOCK|NPAS2‐ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression | Plank et al. (2012), Small et al. (2020), and Velingkaar et al. (2020) |
| GCN1 | GCN1 activator of EIF2AK4 | Acts as a positive activator of the EIF2AK4/GCN2 protein kinase activity in response to amino acid starvation. Participates in the repression of global protein synthesis and in gene‐specific mRNA translation activation, such as the transcriptional activator ATF4 | Derisbourg et al. (2021) |
| SNRNP200 | Small nuclear ribonucleoprotein U5 subunit 200 | A core component of precatalytic, catalytic, and postcatalytic spliceosome complexes | Yang et al. (2021) |
| AAR2 | AAR2 splicing factor | Component of the U5 snRNP complex required for spliceosome assembly and for pre‐mRNA splicing | Nakazawa et al. (1991) |
| TBC1D14 | TBC1 domain family member 14 | Plays a role in the regulation of starvation‐induced autophagosome formation. Contributes to the regulation of starvation‐induced autophagy | Longatti et al. (2012) |
| PER2 | Period circadian regulator 2 | A core clock gene that transcriptionally represses the negative limb of the feedback loop and interact with the CLOCK|NPAS2‐ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression | Plank et al. (2012), Small et al. (2020), and Velingkaar et al. (2020) |
| ELAVL1 | ELAV like RNA‐binding protein 1 | RNA‐binding proteins that selectively bind AU‐rich elements (AREs) found in the 3′ untranslated regions of mRNAs and protect them from degradation. Resveratrol and CR actively regulate ELAVL1 | Li et al. (2017) |
| TINF2 | TERF1‐interacting nuclear factor 2 | A component of the telomere nucleoprotein sheltering complex that protect telomeres from being exposed as DNA damage | Schmutz et al. (2020) |
| GPX3 | Glutathione peroxidase 3 | Protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides, and organic hydroperoxide, by glutathione | Chang et al. (2020) |
| HSP90AA1 | Heat shock protein 90 alpha family class A member 1 | Participate to the unfolded protein response with other chaperones (e.g., Hsp70) | Collino et al. (2013) |
| SUV39H1 | SUV39H1 histone lysine methyltransferase | Interacts with the circadian target genes such as PER2 itself or PER1, contributes to the conversion of local chromatin to a heterochromatin‐like repressive state through H3 “Lys‐9” trimethylation. Upregulated by oxidative stress and CR in a SIRT1‐dependent manner | Bosch‐Presegué et al. (2011) and Mostoslavsky et al. (2010) |
| BCL6 | B‐cell lymphoma 6 | Inhibits the production of chemokines in macrophages in multiple tissues, and may also contribute to prevent cellular senescence in cardiac muscle cells | Altieri et al. (2012), Sommars et al. (2019), Yoo et al. (2017), and Yu et al. (2005) |
| MEF2D | Myocyte enhancer factor 2D | Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle‐specific and/or growth factor‐related transcription. Also, involved in the circadian rhythm and regulation of sleep behavior as well as sleep and fasting cycle | Chen et al. (2015) and Mohawk et al. (2019) |
| EIF1 | Eukaryotic translation initiation factor 1 | Functionally similar to EIF41A, is upregulated by dietary restriction in obese women and enables translational initiation | Bjedov and Rallis (2020) and Nanda et al. (2009) |
| CHERP | Calcium homeostasis endoplasmic reticulum protein | Regulated alternative mRNA splicing events by interaction with U2 small nuclear ribonucleoproteins and U2 snRNP‐related proteins | Yamanaka et al. (2022) |
| NR0B2 | Nuclear Receptor Subfamily 0 Group B Member 1 | An orphan nuclear receptor that connects nutrient signaling with the circadian clock | Wu et al. (2016) |
| SSRP1 | Structure‐specific recognition protein 1 | Is a histone H2A/H2B chaperone proteins that plays a role in DNA single‐strand breaks repair | Gao et al. (2017) |
| USP11 | Ubiquitin‐specific peptidase 11 | Plays an extremely important role in DNA damage repair | Deng et al. (2018) and Liao et al. (2022) |
| PCBP1 | Poly C binding protein 1 | Has been found to regulate alternative splicing in many cancers | Huang et al. (2021) |
| (B) Under‐expressed genes in CR (p < 0.01) | |||
| IL1R1 | Interleukin 1 receptor type 1 | Upregulated with aging mediates the biological activity of IL‐1β, and plays a role in type 2 diabetes | Grant and Dixit (2013) and Laberge et al. (2015) |
| LURAP1L | Leucine‐rich adaptor protein 1 like | Positively regulates I‐kappaB kinase/NF‐kB signaling | Jing et al. (2010) |
| SKP2 | S‐phase kinase associated protein 2 | SKP2 causes FOXO3 poly‐ubiquitination and proteasomal degradation; thus, the under‐expression of SKP2 protects FOXO3 from degradation | Cangemi et al. (2016) and Wang, Chan, et al. (2012) |
Note: These genes were associated with CR previously or are known to play an important role in aging‐related biological mechanisms and/or muscle health.