{"paper_id":"591730b1-c387-4891-965c-8fb1a746fed6","body_text":"Alpha-ketoglutarate (α-KG) is an essential intermediate metabolite in the tricarboxylic acid (TCA) cycle, also regarded as the Krebs or citric acid cycle ( Harrison & Pierzynowski 2008 ,  Wu  et al.  2016 ). This endogenous α-ketoglutaric acid anion actively participates as a factor in fundamental biological processes linked to cellular energy metabolism, epigenetic regulation, and signaling pathways ( Zdzisińska  et al.  2017 ,  Legendre  et al.  2020 ). α-KG may be formed and dissociated through several pathways: (I) isocitrate oxidative decarboxylation, catalyzed by isocitrate dehydrogenase (IDH), (II) oxidative deamination of glutamate (Glu) via glutamate dehydrogenase (GLDH) (III) or decarboxylation to succinyl-coenzyme A (CoA) and carbon dioxide (CO 2 ) by α-KG dehydrogenase ( Wu  et al.  2016 ,  Zdzisińska  et al.  2017 ,  Liu  et al.  2018 a ,  Legendre  et al.  2020 ).\nStudies have demonstrated that physiological impairments are directly correlated with age, marked by a decline in the quality and quantity of oocytes ( te Velde & Pearson 2002 ) complementary to the excess of free radicals assembling ( Guimarães  et al.  2021 ). Subsidiary investigations recommended incorporating α-KG into the dietary routine ( Velvizhi  et al.  2002 ,  Jiang  et al.  2017 ) to retard aging ( Demidenko  et al.  2021 ) as a viable alternative to prolong life’s longevity and health ( Asadi Shahmirzadi  et al.  2020 ).\nThe intricate interplay between energy metabolism and cell signaling pathways has been thoroughly substantiated ( Wu  et al.  2016 ,  Liu  et al.  2018 a ,  Legendre  et al.  2020 ). Therefore, exogenous supplementation might strengthen the antioxidant defenses against reactive oxygen species (ROS) via decarboxylation ( Mailloux  et al.  2009 ,  Bignucolo  et al.  2013 ,  Aldarini  et al.  2017 ). Besides its scavenger effect ( Song  et al.  2016 ,  Wu  et al.  2019 ) to avert premature aging ( Goud  et al.  2008 ,  Lord & Aitken 2013 ,  Sasaki  et al.  2019 ), α-KG maintains the integrity of DNA, regulates autophagy and apoptosis ( Satpute  et al.  2010 ,  Gibson  et al.  2012 ,  An  et al.  2021 ,  Qin  et al.  2021 ), and alleviates inflammatory reactions and abnormal immune responses ( Liu  et al.  2018 b ). Available data highlighted the reliability of α-KG for reproductive disturbances based on the numerous applications that targeted ROS’ elevated ratio consequences on a molecular and morphological level in affected oocytes and on altered mitochondria ( Zhang  et al.  2019 a ,  Yang  et al.  2020 ). Conversely, the current state of knowledge enabled applications on abnormal morphology and early embryonic development decline ( Zhang  et al.  2019 a , b ,  Miao  et al.  2020 ) or correlated with depletion ( Balaban & Urman 2006 ,  Miao  et al.  2009 ).\nThese structural transformations might have multiple negative outcomes that range from a heightened risk of aneuploidy ( Mikwar  et al.  2020 ) or miscarriage ( Santonocito  et al.  2013 ,  Capalbo  et al.  2017 ), to reduced testosterone secretion, spermatogenesis, and sperm motility and morphology abnormalities ( Harris  et al.  2011 ). Despite controversies over the passive influence of metabolism in embryogenesis, cell fate, and signal transduction ( Wu  et al.  2016 ,  Zdzisińska  et al.  2017 ,  Legendre  et al.  2020 ), recent discoveries promoted advances dedicated to containing oocyte rate decrease ( Lord & Aitken 2013 ,  Zhang  et al.  2019 a , b ) caused by telomere shortening ( Broekmans  et al.  2009 ).\nTherefore, this scoping review aims to provide an updated perspective on the latest applications to reconfigure reproductive capacity. The need for this manuscript derives from the limited settings compared to other research directions ( Meng  et al.  2022 ,  Naeini  et al.  2023 ). Conclusively, the main objective is to open possible new therapeutic approaches and translate gained information into clinical practice.\n\nThe protocol of this manuscript was designed to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2018 guidelines for Scoping Review (PRISMA-ScR) ( Munn  et al.  2018 ,  Tricco  et al.  2018 ) and was registered in the Open Science Framework (OSF) with the ID: osf.io/b8nyt ( https://doi.org/10.17605/OSF.IO/YT3BA ).\nThis manuscript did not require Institutional Review Board (IRB) approval, signed consent forms, or a third-party evaluation because data was extracted from published studies.\nWe hypothesized that adequate supplementation with α-KG may improve the ability of the reproductive system, similar to its involvement in extending the lifespan and reversing oxidative stress (OS) following the normalization of ROS.\nDoes the supplementation with α-KG enhance reproduction in experimental laboratory models?\nSecondary questions\nDoes the supplementation with α-KG prevent OS by normalizing the ROS levels?\nDoes the supplementation with α-KG extend the lifespan?\nWe conducted searches to encompass the latest critical literature from January 1, 2010, to March 1, 2024, by accessing primary electronic academic databases: PubMed-MEDLINE—United States National Library of Medicine (NLM, 1996), Web of Science TM  (WOS) (Clarivate Analytics, 1997), Scopus (Elsevier, 2004) ( Falagas  et al.  2008 ), and Excerpta Medica dataBASE (EMBASE) (Elsevier, 1947) (accessed on March 8, 2024).\nWe applied dedicated and controlled scientific terminology using MeSH (Medical Subject Headings), Boolean operators (‘AND’ or ‘OR’ or ‘NOT’), and Emtree terms. This approach was meant to ensure comprehensive coverage of relevant research articles before undergoing the identification, collection, ranking, and analysis steps. Several main input terms such as ‘α-ketoglutaric acid,’ ‘alpha-ketoglutaric acid,’ ‘2-ketoglutaric acid,’ ‘2-oxoglutaric acid,’ ‘oxoglutaric acid,’ and ‘2-oxopentanedioic acid,’ excepting ‘AKG’ and ‘2-oxoglutamate,’ were appointed as (Major Topic) with the MeSH Unique ID: D007656, Tree Number(s): D02.241.081.337.351.502, D02.241.755.465 and applied for distinct fields. The primary subtopics included ‘reproductive system’ (‘Genitalia’ (MeSH) – ID: D005835, Tree Number(s): A05.360), ‘fertility’ (‘Fertility’ (MeSH) – ID: D005298, Tree Number(s): G08.686.210), and ‘reproduction’ (‘Reproduction’ (MeSH) – ID: D012098, Tree Number(s): G08.686.784) in parallel with ‘laboratory model’ (‘Models, Animal’ (MeSH) – ID: D023421, Tree Number(s): E05.598) and ‘experimental animal’ (‘Animals, Laboratory’ (MeSH) – ID: D000830, Tree Number(s): B01.050.050.199) as found on the NLM official website (accessed on March 8, 2024). The complete strings for each database can be found in Supplementary File 1 (see section on  supplementary materials  given at the end of this article).\nThe references list was subsequently imported to Mendeley – Reference Management Software (v. 1.19.8) (Elsevier, 2013) and de-duplicated using the ‘check for duplicates’ function followed by additional manual screening. Each investigator independently reviewed the titles ± abstracts of individual retrieved records. Afterward, BD, O-DI, A-MD, I-SS, and RM assessed the abstracts and the full-length content of each qualifying article. Possible conflicting opinions were settled unanimously by common consent with BD, ST, and ET.\nGeneral data from the retrieved studies were organized in a tabular standardized form using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) by BD, O-DI, A-MD, I-SS, and RM that included methodological characteristics such as experimental model/cell line, compound, concentration, supplementation method, and main observations.\nResearch had to be written exclusively in English and contain original data obtained from experiments carried out on experimental laboratory models. A particular eligibility requirement was that the studies had to include models with genetic similarity comparable to humans for clinical relevance or cell cultures to deepen the understanding of the underlying mechanisms further. Any other type of manuscript was automatically removed.\n\nA total of 1606 studies were returned in the pre-determined timeframe, of which 947 (58.96%) were from PubMed-MEDLINE, 354 (22.04%) from WOS TM , 301 (18.74%) from EMBASE, and four (0.24%) from Scopus (Supplementary File 2) (accessed on March 8, 2024). By removing 1544 studies that did not undergo review, 62 studies remained, of which 31 preliminary eligible papers were retained, excluding duplicates. Furthermore, ten articles were removed in the second step due to the following reasons: one was an article written in Russian ( Lucenko  et al.  2016 ), two were out of scope ( Willenborg  et al.  2009 ,  Mariño  et al.  2014 ), two were eligible but the full content could not be accessed ( Zhang  et al.  2019 a ,  Penn  et al.  2023 ) and five had no direct correlation ( Pedroso  et al.  2019 ,  Dobrowolski  et al.  2021 ,  Sekita  et al.  2021 ,  Tanaka  et al.  2021 ,  Shibata  et al.  2024 ) ( Fig. 1 ). Therefore, in the 21 studies that met the eligibility criteria, one was conducted on ovine ( Hao  et al.  2022 ), two on porcine ( Breininger  et al.  2014 ,  Chen  et al.  2022 ), four on  Drosophila melanogaster  ( Bayliak  et al.  2017 ,  2019 ,  Lylyk  et al.  2018 ,  Su  et al.  2019 ), and 14 on murine models: two on mice ( Zhang  et al.  2021 ,  Wang  et al.  2023 ), three on rats ( Li  et al.  2010 ,  2023 ,  Liu  et al.  2024 ) and nine on stem cells that investigated the pluripotency, differentiation, or reprogramming modifications in standard or transgenic lines ( Carey  et al.  2015 ,  Hwang  et al.  2016 ,  TeSlaa  et al.  2016 ,  Choi  et al.  2019 ,  Tischler  et al.  2019 ,  Xing  et al.  2020 ,  Xu  et al.  2022 ,  Yang  et al.  2022 ,  Tang  et al.  2023 ) (Supplementary Table 1).\n Figure 1 PRISMA-ScR diagram.\nPRISMA-ScR diagram.\nHalf of the studies were conducted exclusively by researchers from China (50%) ( Li  et al.  2010 ,  2023 ,  Su  et al.  2019 ,  Xing  et al.  2020 ,  Chen  et al.  2022 ,  Hao  et al.  2022 ,  Yang  et al.  2022 ,  Xu  et al.  2022 ,  Tang  et al.  2023 ,  Wang  et al.  2023 ,  Liu  et al.  2024 ), Japan (9.09%) ( Choi  et al.  2019 ,  Tanaka  et al.  2021 ), USA (9.09%) ( Carey  et al.  2015 ,  TeSlaa  et al.  2016 ) Argentina (4.54%) ( Breininger  et al.  2014 ), Republic of Korea (4.54%) ( Hwang  et al.  2016 ) or multidisciplinary teams from Ukraine and Canada (13.63%) ( Bayliak  et al.  2017 ,  2019 ,  Lylyk  et al.  2018 ), United Kingdom and Germany (4.54%) ( Tischler  et al.  2019 ) or with double affiliations from China and United Kingdom (4.54%) ( Zhang  et al.  2021 ). The reiterative lists of each assessment phase can be found in Supplementary File 3.\nAlthough the connection between cellular metabolism and cell differentiation has been recently addressed, auxiliary research uncovered the potential of self-renewal and differentiation ( Carey  et al.  2015 ,  Hwang  et al.  2016 ,  TeSlaa  et al.  2016 ,  Tischler  et al.  2019 ,  Xing  et al.  2020 ,  Yang  et al.  2022 ,  Tang  et al.  2023 ). Naïve mESCs preserve their pluripotency until reaching the PGCs state ( Tischler  et al.  2019 ) even in the absence of Gln ( Carey  et al.  2015 ). In this context, supplementation with α-KG concomitantly with glucose or pyruvate sustains the Gln-Glu-α-KG axis to support maternal decidualization ( Tang  et al.  2023 ), blastocyst formation ( Choi  et al.  2019 ), and the amount of intracellular α-KG ( Carey  et al.  2015 ) through the IDH2-mediated production ( Tischler  et al.  2019 ). α-KG delays aging and heat shock-induced changes upon sperm via OXGR1 expressed in epididymal SMCs ( Xu  et al.  2022 ), and restores Gln-Glu flux metabolism ( Tang  et al.  2023 ). Several remarks underlined the inhibition of the BPTES effect on PGCLC ( Xing  et al.  2020 ) which translates into the number and function of dNK ( Yang  et al.  2022 ) that ultimately may reduce the risk of induced pregnancy ( Yang  et al.  2022 ) and spontaneous miscarriage ( Tang  et al.  2023 ). Naïve mESCs store α-KG/succinate ( Carey  et al.  2015 ), which is regulated by Psat1 ( Hwang  et al.  2016 ) and required for primed PSCs acceleration ( TeSlaa  et al.  2016 ) and epigenetic reprogramming ( Carey  et al.  2015 ,  Hwang  et al.  2016 ,  TeSlaa  et al.  2016 ). Psat1 KD is thought to be the cause of reduced mESCs DNA 5’-hydroxymethylcytosine (5’-hmC) methylation ( Hwang  et al.  2016 ), influencing the ATP generation mechanism ( TeSlaa  et al.  2016 ,  Tang  et al.  2023 ) and H3K27me3-based chromatin modifications and ten-eleven translocation (TET)-dependent DNA demethylation process ( Carey  et al.  2015 ,  Hwang  et al.  2016 ,  TeSlaa  et al.  2016 ,  Tischler  et al.  2019 ,  Xing  et al.  2020 ,  Yang  et al.  2022 ,  Tang  et al.  2023 ).\nWhile higher mammals are subjected to reproductive aging mainly because of telomere shortening ( Zhang  et al.  2021 ), controlled concentrations of α-KG might delay the decline in ovarian reserve ( Li  et al.  2023 ,  Wang  et al.  2023 ), and loss of function ( Zhang  et al.  2021 ,  Liu  et al.  2024 ). This metabolite triggers adaptations of metabolism and consequent variations in levels of hormones ( Li  et al.  2023 ,  Liu  et al.  2024 ), linked to reproductive function reconfiguration ( Zhang  et al.  2021 ) even in aging oocytes post-ovulation ( Wang  et al.  2023 ). α-KG inhibits the mTOR pathway by blocking ATP synthase ( Zhang  et al.  2021 ), thus contradicting previous studies showing higher ATP levels ( Li  et al.  2023 ) due to enhanced mitochondrial membrane potential ( Wang  et al.  2023 ). Although the level of pyruvate in females is reduced ( Li  et al.  2023 ) unlike males who experience an increase in O 2 -.  level in sperm, this does not always have negative effects ( Liu  et al.  2024 ) since both are pivotal in sustaining spermatozoa ATP levels for motility ( Li  et al.  2010 ). These antioxidants are involved in diminishing ROS levels, which thus mitigates the pro-inflammatory cascade ( Liu  et al.  2024 ), resulting in a lower rate of fragmentation, abnormal spindle assembly ( Wang  et al.  2023 ), and apoptosis ( Li  et al.  2023 ).\nDrosophila melanogaster  is a genetic model broadly employed for deepening our awareness of the reproduction paradigm ( Bayliak  et al.  2017 ,  Lylyk  et al.  2018 ,  Su  et al.  2019 ) and the consequences of heavy metals exposure ( Bayliak  et al.  2019 ). α-KG diet supplementation leads to fluctuations in metabolic parameters dependent on the developmental stage ( Bayliak  et al.  2017 ) and effectively alleviates AlCl 3  toxicity ( Bayliak  et al.  2019 ). The extended lifespan seen at specific concentrations is dose- and sex-dependent ( Lylyk  et al.  2018 ,  Bayliak  et al.  2019 ,  Su  et al.  2019 ), but higher doses can be harmful, especially in males ( Lylyk  et al.  2018 ). This does not exacerbate the OS but triggers adaptive responses instead ( Bayliak  et al.  2017 ,  2019 ,  Lylyk  et al.  2018 ,  Su  et al.  2019 ) due to decreased ATP/ADP ratio ( Su  et al.  2019 ). This might clarify the heightened tolerance to heat stress ( Bayliak  et al.  2017 ,  2019 ), upregulation of the mRNA expression of protein genes involved in longevity ( Su  et al.  2019 ), and decreased fecundity ( Bayliak  et al.  2017 ,  2019 ,  Lylyk  et al.  2018 ,  Su  et al.  2019 ), while remarkably enhancing the egg-laying capacity in AlCl 3 -reared flies ( Bayliak  et al.  2019 ).\nResearch indicates that α-KG is a potent scavenger of free radicals in porcine, as it significantly reduces ROS generation required for the biosynthesis of GSH. The NRF2/ARE pathway facilitates the transcription of apoptotic genes and enhances mitochondrial function by activating NRF2, thus preventing a biased process of apoptosis ( Chen  et al.  2022 ). α-KG promotes an optimal framework for pig embryo development through the upregulation of pluripotency genes, leading to the formation of blastocysts and the total cell number during in vitro maturation (IVM) ( Chen  et al.  2022 ). Nonetheless, the addition in the culture medium of phosphofructokinase (PFK) and malate dehydrogenase (MDH) can hinder the nutritional requirements of cumulus-oocyte complex (COC) during IVM and cause dysfunction of meiotic maturation ( Breininger  et al.  2014 ).\nIn contrast to results from the fruit flies, dm-α-KG was found to induce comparable phenotypical features as seen in porcine, notably an increased ATP synthesis based on enhanced mitochondrial activity and GSH production against pro-oxidants. dm-α-KG relieves abnormal ROS generation, which could potentially degrade the integrity of the DNA, alter mitochondria, and trigger apoptosis. Therefore, dm-α-KG showed promising activity in maintaining nuclear maturation rate, CGs dynamic, and embryonic developmental competence ( Hao  et al.  2022 ).\n\nα-KG is a source of ATP in all living organisms’ cells ( He  et al.  2015 ) and is predominantly found in mitochondria and cytosol ( Fig. 2 ) besides the bloodstream ( Wagner  et al.  2010 ). Previous experiments on animal models demonstrated high versatility ( Niemiec  et al.  2011 ,  Radzki  et al.  2012 ,  2015 ,  Wang  et al.  2015 ,  Cai  et al.  2018 ) in various organs such as the brain, heart, liver, gastrointestinal tract, skeletal muscle, and adipose tissue ( He  et al.  2015 ). It has been proven to modulate the molecular landscape via the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) ( He  et al.  2015 ), and even hypothesized to interact with calcium/calmodulin-dependent protein kinase kinase 2 (CamKK2) ( Jin  et al.  2018 ).\n Figure 2 Schematic overview of mitochondrial metabolism of pyruvate and glutamine in the TCA cycle. Amino acids-derived glucose is subjected to sequential phases of conversion that facilitate the production of α-KG through either glycolysis or glutaminolysis. The final fatty acids are produced by blocking the oxidative pathway and enhancing the reductive pathway. The AMPK and mTOR signaling pathways control the α-KG level when the ratio of AMP/ATP is high, thus regulating autophagy. GLUT1/4 – glucose transporter type 1/4, MPC – mitochondrial pyruvate carrier, PDH – pyruvate dehydrogenase, PC – pyruvate carboxylase, IDH – isocitrate dehydrogenase, α-KGDH – α-KG dehydrogenase, GLS – glutaminase, GDH – glutamate dehydrogenase.\nSchematic overview of mitochondrial metabolism of pyruvate and glutamine in the TCA cycle. Amino acids-derived glucose is subjected to sequential phases of conversion that facilitate the production of α-KG through either glycolysis or glutaminolysis. The final fatty acids are produced by blocking the oxidative pathway and enhancing the reductive pathway. The AMPK and mTOR signaling pathways control the α-KG level when the ratio of AMP/ATP is high, thus regulating autophagy. GLUT1/4 – glucose transporter type 1/4, MPC – mitochondrial pyruvate carrier, PDH – pyruvate dehydrogenase, PC – pyruvate carboxylase, IDH – isocitrate dehydrogenase, α-KGDH – α-KG dehydrogenase, GLS – glutaminase, GDH – glutamate dehydrogenase.\nmTOR is part of a conserved group of serine/threonine (Ser/Thr) protein kinases of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, comprising rapamycin-sensitive complex 1 (mTORC1) and relatively rapamycin-insensitive complex 2 (mTORC2). Both play a role in growth and metabolism, primarily found in the nucleus and cytoplasm ( Saxton & Sabatini 2017 ,  Jhanwar-Uniyal  et al.  2019 ), while AMPK serves as a key energy sensor in aging and lifespan ( Hardie  et al.  2012 ,  Huang  et al.  2013 ), collectively promoting lysosomal translocation through mTORC1 known to block autophagy ( Durán  et al.  2012 ).\nThe initial data on  Caenorhabditis elegans’  increased lifespan from inhibiting ATP synthase and phosphor-Akt ( Shrimali  et al.  2021 ), as well as the mTOR signaling pathway ( Hou  et al.  2010 ,  Żurek  et al.  2019 ) by α-KG in a dose-dependent manner, was founded a decade ago ( Chin  et al.  2014 ). Noteworthy, α-KG longevity partially depends on AMPK and the forkhead box O (FOXO) ( Urban  et al.  2007 ) as already seen in flies ( Kapahi  et al.  2004 ,  Luong  et al.  2006 ,  Su  et al.  2019 ) and mice ( Selman  et al.  2009 ).\nIt is important to note that AMPK activates when the AMP/ATP ratio is high and hampers TOR signaling by phosphorylation of the TOR suppressor tuberous sclerosis complex (TSC) 1, which regulates cell energy rate and metabolism ( Toivonen  et al.  2007 ). α-KG activate mTOR in the intestinal epithelial cells of pigs to stimulate protein ( Yao  et al.  2012 ) or milk protein synthesis ( Jiang  et al.  2016 ).\nα-KG can increase the FOXO mRNA expression ( Su  et al.  2019 ), a transcription factor that helps maintain the cytosolic level of α-KG ( Charitou  et al.  2015 ) by regulating isocitrate dehydrogenase 1 (IDH1). Prolyl hydroxylase domain protein (PHD) catalyzes proline hydroxylation and facilitates FOXO3 degradation. A possible reduction of α-KG in hypoxic tubules instead stabilizes FOXO3 to augment autophagy ( Tran  et al.  2019 ).\nBiological aging involves a high degree of epigenetic changes ( Shi & Whetstine 2007 ,  Walport  et al.  2012 ,  Salminen  et al.  2015 ,  Martínez-Reyes & Chandel 2020 ), that implicitly lead to hypermethylation of specific DNA regions and histone patterns ( Gonzalo, 2010 ,  Sierra  et al.  2015 ). Despite the recent progress in translational medicine ( Xiao  et al.  2016 ,  Gyanwali  et al.  2022 ,  Naeini  et al.  2023 ), the clinical validation of α-KG as a feed additive is still lacking as existing data only includes experiments conducted in animal models. Nonetheless, direct oral supplementation may be a feasible method to address a deficiency as demonstrated by ( Demidenko  et al.  2021 ) who successfully reduced the average biological aging by eight years in both sexes following Rejuvant ®  tablets for seven months ( P  = 6.538x10 -12 ). 2-oxoglutarate, regarded as α-KG, along with other Krebs cycle analogs succinate, fumarate, and 2-hydroxyglutarate (2-HG) are integral to mitochondrial metabolism and influence DNA and histone methylation ( Ward & Thompson 2012 ,  Badeaux & Shi 2013 ,  Kaelin & McKnight 2013 ,  Salminen  et al.  2014 a \n , b ). These essential epigenetic regulators of gene expression are part of the 2-oxoglutarate-dependent dioxygenases (2-OGDDs) family, known for their involvement in demethylation and hydroxylation processes ( McDonough  et al.  2010 ,  Loenarz & Schofield 2011 ) which might shape chromatin structure and function ( Ward & Thompson 2012 ,  Badeaux & Shi 2013 ,  Kaelin & McKnight 2013 ).\nPrecisely, hydroxylases TET1-3 are DNA demethylases that catalyze the oxidative decarboxylation of α-KG to convert 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and trigger demethylation of CpG loci in DNA ( Tahiliani  et al.  2009 ,  Ito  et al.  2010 ,  Salminen  et al.  2015 ). Similarly, histone demethylases containing Jumonji C domain lysine KDM2-7 contribute to the regulation of chromatin landscape changes associated with aging ( Shi & Whetstine 2007 ,  Walport  et al.  2012 ,  Salminen  et al.  2015 ). As a result, they are accountable for removing methyl groups from specific methylation sites in histones, a process that also catalyzes the demethylation of trimethylated lysines and arginines ( Hoffmann  et al.  2012 ), crucial for forming both transcriptionally active and inactive chromatin ( Shi & Whetstine 2007 ,  Gonzalo 2010 ,  Walport  et al.  2012 ).\nData from cancer research showed that succinate and fumarate could act as competitive inhibitors of the 2-OGDO enzymes, precisely KDMs and TETs, which potentiate methylation of DNA and histones by methyltransferases, ultimately causing carcinogenesis ( Ward & Thompson 2012 ,  Kaelin & McKnight 2013 ,  Martínez-Reyes & Chandel 2020 ). Considering the extensive work of ( Salminen  et al.  2014 a \n , b ,  2015 ) on the topics discussed earlier, the role of KDM2/6 in gene expression and cell fate is rather complex as it involves both inducing ( Agherbi  et al.  2009 ,  Perrigue  et al.  2015 ) and inhibiting senescence ( Pfau  et al.  2008 ) through the cell cycle arrest mediators p53 and pRb ( Leon & Aird 2019 ).\nIn conclusion, chronic inflammation could be caused by enhanced cellular senescence leading to premature aging ( Agherbi  et al.  2009 ,  Perrigue  et al.  2015 ,  Salminen  et al.  2015 ), while histone demethylases containing Jumonji C domain lysine up-regulation are linked to cancer progression by blocking senescence ( Pfau  et al.  2008 ,  Wang  et al.  2018 ,  Leon & Aird 2019 ).\nUnderstanding the reproduction phenomenon to counter the decrease in quality and quantity of oocytes ( te Velde & Pearson 2002 ) is mandatory, especially in conjunction with early embryonic potential ( Zhang  et al.  2019 a \n , b ,  Miao  et al.  2020 ), to reduce the risk of aneuploidy ( Mikwar  et al.  2020 ) and miscarriage ( Santonocito  et al.  2013 ,  Capalbo  et al.  2017 ) in light of the numerous applications targeting aged oocytes ( Miao  et al.  2009 ,  Yamada-Fukunaga  et al.  2013 ,  Garcia  et al.  2019 ). The telomerase complex, which consists of Terc and the catalytic subunit Tert, plays a compensatory role in slowing aging by supporting the maintenance of the telomere system along with SIRT6 ( Tennen  et al.  2011 ), as well as performing important roles in DNA repair and inflammation ( You & Liang 2023 ).\nIn the urge for an effective antioxidant against ROS, which is seen as the main forerunner of decreased quality of aged oocytes ( Lord & Aitken 2013 ,  Sasaki  et al.  2019 ), α-KG has emerged as the key factor in refining the antioxidant defense system ( Velvizhi  et al.  2002 ) that is also responsible for removing H 2 O 2  by decarboxylation ( Aldarini  et al.  2017 ). However, α-KG via the Nrf2 pathway in adequate concentrations counteracts the impact of brutasol and partially restores metal content balance ( Orgad  et al.  1998 ,  Wu  et al.  2012 ,  Fu  et al.  2014 ,  Maya  et al.  2016 ) after a 26% increase of aconitase ( Middaugh  et al.  2005 ,  Wu  et al.  2012 ) to support embryonic development and shield oocytes from OS ( Jiang  et al.  2021 ). An elevated intracellular level of GSH ( Brigelius-Flohé, 1999 ,  de Matos & Furnus 2000 ,  Liu  et al.  2018 a \n ) prevents DNA damage and cell death ( Jia  et al.  2018 ,  Zhou  et al.  2019 ,  Chen  et al.  2020 ,  Aghaz  et al.  2021 ,  El-Sheikh  et al.  2021 ,  Min  et al.  2021 ), indicating an ideal framework for developmental competence ( Ren  et al.  2021 ). Alternatively, α-KG may influence the PFK and MDH-related COC role on oocyte maturation in bovine ( Cetica  et al.  2002 ,  2003 ), and porcine ( Breininger  et al.  2014 ) as previously suggested, owing that a preliminary investigation that revealed the presence of IDH-nicotinamide adenine dinucleotide (NAD) in porcine COC but not in cows ( Cetica  et al.  2003 ).\nAccording to the available information regarding α-KG’s potential to sustain both naïve and primed PSCs’ pluripotency and differentiation ( Leitch  et al.  2013 ), a biphasic concept of α-KG was proposed, modulated by the oxygen level apart from its position as a cofactor for DNA and histone demethylation ( TeSlaa  et al.  2016 ). The TET complex is a widely recognized mechanism in DNA demethylation known to participate in converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC) ( TeSlaa  et al.  2016 ). Maternal high-fat diet (MHFD) reduces 5-hmC DNA methylation while increasing 5-fC ( Penn  et al.  2023 ), hindering early-stage embryo development that depends on low ATP production and altered activity of DNA methyltransferase 3 alpha (Dnmt3a) and an elevated 5-hmC and 5-mC ratio ( Zhang  et al.  2019 a ). The ratio is notably elevated in PSCs compared to differentiated cells ( Tran  et al.  2019 ), thus confirming epigenetic reprogramming based on the TET-mediated conversion of 5-mC to 5-hmC ( Sekita  et al.  2021 ).\nStudies have shown that Jumonji C-containing domains that reunite lysine demethylase 3-6A/3-6B (KDM3A/3B/6A/6B) ( Ko  et al.  2006 ,  Loh  et al.  2007 ) (JHDMs) require α-KG to target distinct histones ( Klose & Zhang 2007 ). TET members methylcytosine dioxygenase 1 (TET1) and TET methylcytosine dioxygenase 2 (TET2) ( Costa  et al.  2013 ,  Hackett & Surani 2014 ) can maintain the naïve pluripotency epigenetic state by demethylating H3K27me2/me3 (histone 3 lysine 27 methylation) ( TeSlaa  et al.  2016 ) given that low DNA demethylation levels may result in an increased spread of H3K27me3 at high CpG regions ( Zylicz  et al.  2015 ). α-KG could potentially preserve the naïve pluripotent status in PSCs when 2i inhibitors are substituted ( Ying  et al.  2008 ,  Tischler  et al.  2019 ) due to IDH-related high expression based on DNA methyltransferase 3 beta (DNMT3B) depletion. Some suggest that a re-wiring of 2i in culture conditions could support Gln-independent growth of naïve mESCs ( Carey  et al.  2015 ).\nThe switch from naïve mESCs to PGC-competent EpiLCs involves a change to a glycolytic state instead of oxidative ( Zhou  et al.  2012 ,  Zhang  et al.  2016 ) during later stages ( Folmes  et al.  2012 ) due to the upregulation of lin-28 homolog B (Lin28b). Lin28b is a protein-coding gene involved in oxidative suppression and regulation of glucose metabolism ( Zhu  et al.  2011 ,  Zhang  et al.  2016 ) as the metabolic modulator 2-DG is activated ( Hayashi  et al.  2017 ). Lactate shuttle (LS) and Warburg-like glycolysis participate during decidualization since DNA methylation is stable ( Maekawa  et al.  2019 ,  Liu  et al.  2020 ) and DNA hydroxylases TET are dioxygenases ( Raffel  et al.  2017 ) dependent on α-KG. As the bio-energetic requirements ( Zuo  et al.  2015 ,  Huang  et al.  2019 ,  Tamura  et al.  2021 ) are assured, supplementary resources for proliferation and differentiation are necessary despite higher glucose intake ( Ying  et al.  2021 ), these conditions under an aerobic state being met by Gln metabolism ( Le  et al.  2012 ,  Li & Zhang 2016 ).\nα-KG can also trigger primed PSCs differentiation by interacting with chaperone-mediated autophagy (CMA) ( Xu  et al.  2020 ), causing changes in the expression of transcription factors and being limited by the inhibitory effects of 3-nitropropionic acid (NPA). This reduction in succinate delays PSCs differentiation, but this effect is counteracted by TET2, which promotes differentiation ( Hon  et al.  2014 ,  TeSlaa  et al.  2016 ). Autophagy collaborates with the ubiquitin-proteasome system (UPS) to regulate protein levels linked to pluripotency and influences the self-renewal or differentiation of ESCs based on CMA level ( Xu  et al.  2020 ,  Xu & Yang 2022 ).\nSOX2 and OCT4 influence ESCs ( Xu  et al.  2020 ) through inhibition of lysosome-associated membrane protein type 2A (LAMP2A), a key component in parallel with cytosolic chaperone HSC70 that defines CMA activity ( Cuervo & Dice 2000 ). Changes in LAMP2A levels correspond to levels of SOX2 and OCT4, and in what concerns differentiation, a possible depletion in mESCs indicates high levels of the α-KG/succinate ratio, whereas mESCs overexpression leads to a gradual decline of LAMP2A ( Xu  et al.  2020 ).\nFinally, reprogramming has been a topic of interest on several occasions with special emphasis on TET in induced PSCs (iPSCs) from differentiated or non-pluripotent cells ( Kolaczkowski & Thornton 2004 ,  Polo  et al.  2012 ,  Sardina  et al.  2018 ). AKT and FOXO1 signaling pathway activation or simultaneous transduction of TET2’s catalytic domain and dm-α-KG synergistically improve reprogramming ( Sekita  et al.  2021 ), relying on increased glycolysis and mitochondrial activity ( Yu  et al.  2014 ,  Wilhelm  et al.  2016 ).\nThis primary scoping review systematically approaches this scarce topic by including multiple databases to ensure a thorough and comparative overview without neglecting critical and authoritative information. However, it should be noted that the number of applications is limited to animal studies and even lower in humans, which is why clinical trials are mandatory, setting the grounds for future randomized controlled trials (RCTs).\n\nThe manuscript covers the importance of α-KG in maintaining the functionality and integrity of various biological mechanisms. Despite the research on animal models instead of humans, it is clear that α-KG supplementation improves reproductive abilities. However, additional experiments are needed to close the gap between research and clinical practice. This might result in treatment strategies and an improved understanding of the advantages of α-KG supplementation in humans.\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nThis work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\n\nConceptualization, Data curation, Investigation, Formal analysis, Methodology, Software, Writing – original draft: BD, O-DI, A-MD, I-SS, and RM. Supervision, Visualization, Validation, Project administration, Writing – review and editing: BD, ST, and ET. All authors have read and agreed to the published version of the manuscript.","source_license":"CC0","license_restricted":false}