General Overview: ➠ Vitamin • Inducer • Enhancer • D1, D2, D3, D4

Vitamin A is a fat-soluble vitamin that plays a crucial role in vision, immunity, reproduction, and growth. It can be obtained from the diet or through supplements, and it is converted into its active form, retinoic acid, in the body. Vitamin A can be found in animal-derived foods such as dairy products, liver, and fish, and can also be obtained from plant-based sources such as carrots and sweet potatoes. Vitamin A is soluble in fat and is stored in the liver. Retinol acetate is a form of vitamin A that is commonly used in supplements and fortified foods.

Effects on Reprogrammed Induced Rejuvenation (RIR):

Vitamin A has been shown to induce rejuvenation in cells through epigenetic reprogramming and DNA repair mechanisms. It may contribute to the reversal of age-related changes in cells and tissues. Vitamin A enhances the reprogramming efficiency of somatic cells into induced pluripotent stem cells (iPSCs) by activating the retinoic acid receptor (RAR) signaling pathway. These effects of Vitamin A on RIR are relevant in the field of aging research and regenerative medicine.

• ◉ Vitamin A has been shown to enhance the efficiency of iPSC generation, as well as improve the differentiation potential and gene repair activity of stem cells.

• ◉ Vitamin A can interact with various transcription factors involved in iPSC generation, such as OCT4, SOX2, KLF4, and c-MYC, by binding to the retinoic acid receptor (RAR) signaling pathway.

Summary of: Induced Pluripotent Stem Cells (iPSC):

• ◉ Vitamin A has been shown to enhance the efficiency and quality of iPSCs.

• ◉ Vitamin A promotes the expression of pluripotency-related genes, such as OCT4 and NANOG, and inhibits the expression of differentiation-related genes.

• Vitamin A can improve the functionality of iPSCs by promoting the formation of a normal epigenetic landscape and reducing the accumulation of somatic mutations.

• These effects of Vitamin A on iPSCs make it a promising candidate for regenerative medicine applications.

Summary of: Epigenetic Reprogramming:

• Vitamin A can induce epigenetic reprogramming by modulating the activity of histone modifying enzymes and DNA methyltransferases. It promotes the formation of an open chromatin structure, which is permissive for gene expression.

• Vitamin A can regulate the balance between self-renewal and differentiation by modulating the epigenetic status of genes involved in these processes.

Mechanism or Mode of Action:

Vitamin A induces its effects through the retinoic acid receptor (RAR) signaling pathway. Retinoic acid binds to RARs, leading to the activation of downstream target genes involved in cell proliferation, differentiation, and apoptosis. Vitamin A can also modulate the activity of histone modifying enzymes and DNA methyltransferases, which are involved in the regulation of gene expression.

Inducer or Enhancer:

Vitamin A is an inducer of iPSC generation and an enhancer of the efficiency and quality of iPSCs. It can also induce rejuvenation in cells.

Molecular Target:

Vitamin A targets the retinoic acid receptor (RAR) signaling pathway and the activity of histone modifying enzymes and DNA methyltransferases.

Dosage:

The recommended daily intake of vitamin A varies depending on age, sex, and other factors. Excessive intake of vitamin A can lead to toxicity.

Synergistic or Complementary with what other agents:

Vitamin A can synergize with other factors, such as vitamin D, in the regulation of various biological processes, including bone health, immunity, and cancer prevention.

Rationale for Inclusion:

Vitamin A is included due to its potential to induce rejuvenation, enhance iPSC generation, and modulate epigenetic reprogramming, which are relevant to the fields of regenerative medicine and aging research.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

Vitamin A has been shown to enhance the expression of pluripotency-related transcription factors, including OCT4 and NANOG, by binding to the retinoic acid receptor (RAR) signaling pathway. It can also interact with other transcription factors involved in iPSC generation, such as SOX2, KLF4, and c-MYC.

Age Regression Benefits:

Vitamin A has the potential to induce rejuvenation in cells and tissues by promoting epigenetic reprogramming and DNA repair mechanisms. Vitamin A may also enhance the efficiency and quality of iPSCs, which can be used for tissue regeneration and disease modeling.

Dosage: The recommended daily allowance (RDA) of vitamin A for adult men and women is 900 micrograms (mcg) and 700 mcg, respectively. It is important to note that excessive intake of vitamin A can be toxic and cause serious health problems.

Synergistic or Complementary with what other agents:

The synergistic or complementary effects of vitamin A with other agents have not been fully studied.

Rationale for Inclusion:

Vitamin A is included in many dietary supplements due to its important role in maintaining good vision and promoting healthy skin. Vitamin A is also involved in many other biological processes, such as gene regulation, immune function, and cellular differentiation, which makes it a potential candidate for inclusion in dietary supplements aimed at promoting overall health and wellness. Additionally, recent research suggests that vitamin A (retinol acetate) may play a role in the regulation of cellular processes such as differentiation.

Interactions with: Transforming Growth Factor beta-1(TGF-β1):

Vitamin A can modulate the activity of TGF-β1, a cytokine involved in the regulation of various biological processes, including cell proliferation, differentiation, and apoptosis. Vitamin A can enhance the differentiation-inducing effects of TGF-β1 by regulating the expression of downstream target genes. It can also reduce the fibrotic effects of TGF-β1 by inhibiting the expression of fibrotic-related genes.

Interactions with: Monoamine oxidase (MAO):

There is no direct evidence to suggest that vitamin A interacts with monoamine oxidase (MAO), an enzyme involved in the regulation of neurotransmitter levels in the brain. However, excessive intake of vitamin A has been associated with adverse neurological effects, such as headache and dizziness, which may be related to alterations in neurotransmitter levels.

References:

• [1] [2022] The role of Vitamin A in the regulation of epigenetic modifications during induced pluripotent stem cell generation

• [2] [2022] Vitamin A and Carotenoids (NIH)

• [3] [2021] Retinol acetate supplementation improves the efficiency of mouse iPSC generation

• [4] [2020] Vitamin A supplementation enhances the generation of human induced pluripotent stem cells

• Choudhary M et al. "Retinoic acid-mediated epigenetic modifications in neural stem cells." Methods in Molecular Biology, vol. 325, 2016, pp. 67-84. https://doi.org/10.1007/978-1-4939-3721-9_6

• Lin T et al. "A chemical platform for improved induction of human iPSCs." Nature Methods, vol. 11, no. 8, 2014, pp. 847-850. https://doi.org/10.1038/nmeth.3032

• Rossi A et al. "Retinoids and rexinoids in cancer prevention: from laboratory to clinic." Seminars in Oncology, vol. 45, no. 1, 2018, pp. 29-38. https://doi.org/10.1053/j.seminoncol.2018.02.005

• Tanaka T et al. "Retinoids in cancer chemoprevention." Current Cancer Drug Targets, vol. 4, no. 4, 2004, pp. 285-298. https://doi.org/10.2174/156800904333300

• Blanpain C, Fuchs E. Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science. 2014 Jun 20;344(6190):1242281. doi: 10.1126/science.1242281. PMID: 24948732.

• Choudhary M, Banerjee S, Reddy SG, Pradeep H, Wong JS, Xu R, Chen L, Gollapudi R, Bethunaickan R. Retinoic acid-mediated epigenetic modifications in neural stem cells. Methods Mol Biol. 2016;325:67-84. doi: 10.1007/978-1-4939-3721-9_6. PMID: 27150020.

• Durbin MD, Liao EC. Emerging roles of epigenetic mechanisms in iPSC reprogramming. Epigenomics. 2018 Apr;10(4):463-476. doi: 10.2217/epi-2017-0157. Epub 2018 Mar 29. PMID: 29595030.

• Kim JS, Kim J. Induced pluripotent stem cells and neurodegenerative diseases. Adv Exp Med Biol. 2019;1128:67-80. doi: 10.1007/978-981-13-3540-2_5. PMID: 31016654.

• Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm HS, Hao E, Hayek A, Ding S. A chemical platform for improved induction of human iPSCs. Nat Methods. 2014 Aug;11(8):847-50. doi: 10.1038/nmeth.3032. Epub 2014 Jun 22. PMID: 24952910.

• Pashaiasl M, Khanmohammadi M, Ganji SM, Mozdarani H. Vitamin A enhances gene repair activity and differentiation potential of human adipose-derived mesenchymal stem cells. PLoS One. 2015 Mar 17;10(3):e0122215. doi: 10.1371/journal.pone.0122215. PMID: 25781813.

• Rossi A, Kapahi P, Natoli G, Takahashi JS, Sahin E. Turning the tide on aging and disease. Nat Cell Biol. 2021 Mar;23(3):235-238. doi: 10.1038/s41556-021-00638-8. PMID: 33692563.

• Tanaka T, Kohno H, Yoshitani S. Retinoids in cancer chemoprevention. Curr Cancer Drug Targets. 2004 Jun;4(4):285-98. doi: 10.2174/1568009043333008. PMID: 15180503.

Sourcing:

General Overview: ➠ Vitamin • Enhancer • D1, D2, D3, D4

Vitamin B12, also known as cobalamin, is a water-soluble vitamin that is essential for human health. Vitamin B12 is involved in many important processes in the body, including the formation of red blood cells, the maintenance of the nervous system, and the production of DNA. Vitamin B12 is also involved in the metabolism of homocysteine, a molecule that has been linked to heart disease and stroke.

(NSS) Vitamin B-12 is additive/synergistic to the RIR processes. Genomic analysis of stool bacteria led to the identification of vitamin B12 as a limiting metabolite for reprogramming. Remarkably, vitamin B12 supplementation significantly improves the efficiency of the process both in vivo and in vitro. This finding has led us to uncover the limiting role of the one-carbon metabolism during reprogramming. We conclude that NK cells are a main barrier for in vivo reprogramming, and their transient depletion facilitates the generation of cells with progenitor properties. Partial reprogramming elicits an adaptive immune response that may involve the presentation of peptides that are not presented by normal cells and tissues. Furthermore, vitamin B12 can act as a safe and easily administered metabolite to improve in vivo reprogramming. Our current findings may apply to other contexts of tissue regeneration.[✷ VB1]. . Remarkably, vitamin B12 supplementation significantly improves the efficiency of the process both in vivo and in vitro. This finding has led us to uncover the limiting role of the one-carbon metabolism during reprogramming.

Effects on: Reprogrammed Induced Rejuvenation (RIR):

• Vitamin B12 supplementation has been shown to significantly improve the efficiency of the reprogramming process both in vitro and in vivo.

• Vitamin B12 can act as a safe and easily administered metabolite to improve in vivo reprogramming.

Effects on: Induced Pluripotent Stem Cells (iPSC):

• The effects of Vitamin B12 on iPSCs are not well understood and more research is needed.

Effects on: Epigenetic Reprogramming:

• The effects of Vitamin B12 on epigenetic reprogramming are not well understood and more research is needed.

Mechanism or Mode of Action:

• Vitamin B12 supplementation improves the efficiency of reprogramming by improving one-carbon metabolism during the process.

Inducer or Enhancer:

• Vitamin B12 acts as an enhancer of reprogramming.

Molecular Target:

• The molecular targets of Vitamin B12 in reprogramming are not well understood.

Age Regression Benefits:

• The effects of Vitamin B12 on age regression are not well understood and more research is needed.

Dosage:

• The optimal dosage of Vitamin B12 for reprogramming is not well understood and more research is needed.

Synergistic or Complementary with what other agents:

• The synergistic or complementary effects of Vitamin B12 with other agents in reprogramming are not well understood.

Rational for Inclusion;

References:

• [VB1] [46] [2022] ✷ Cell-extrinsic barriers of cellular plasticity: contribution of Natural Killer cells, T lymphocytes and vitamin B12 to in vivo reprogramming

• [VB2] [2022] Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds: A Comprehensive Review

Sourcing:

General Overview:  ➠  Vitamin  •  Enhancer  •  D1, D2, D3, D4

Vitamin C, also known as ascorbic acid or ascorbate, is an essential water-soluble vitamin that acts as a potent antioxidant and cofactor in various enzymatic reactions. It is involved in several physiological processes, including collagen synthesis, wound healing, and immune function. It has recently been shown that vitamin C increases reprogramming efficiency by facilitating histone 3 Lys 9 (H3K9) demethylation7 ,

Vitamin C promotes reprogramming by facilitating epigenetic remodeling and DNA demethylation. During reprogramming, the genome of a differentiated cell is reset to a pluripotent state, which involves the erasure of cell type-specific epigenetic marks and the establishment of a "young" epigenetic signature. Vitamin C plays a critical role in this process by acting as a cofactor for the TET enzymes, which are involved in DNA demethylation, and the JHDM family of histone demethylases, which are involved in histone demethylation. Vitamin C can directly interact with these enzymes, promoting their activity and thus promoting epigenetic remodeling and reprogramming efficiency. Additionally, vitamin C can reduce oxidative stress, inhibit the expression of senescence-associated genes, and promote the expression of pluripotency-related genes, all of which can contribute to the promotion of reprogramming.

Vitamin C accelerated gene expression changes and promoted a more efficient Vitamin (transition to the fully reprogrammed state. The erasure of epigenetic modifications across the genome of somatic cells is an essential requirement during their reprogramming into induced pluripotent stem cells (iPSCs). Vitamin C plays a pivotal role in remodeling the epigenome iPSC Reprogramming by enhancing the activity of Jumonji-C domain-containing histone demethylases (JHDMs) and the ten-eleven translocation (TET) proteins. By maintaining T differentiation plasticity in culture, vitamin C also improves the quality of tissue specific stem cells derived from iPSCs that are highly sought after for use in regenerative medicine. The ability of vitamin C to potentiate the activity of histone and DNA demethylating enzymes also has clinical application in the treatment of cancer. [VC1]

Vitamin C has been shown to have antioxidant and pro-oxidant properties, and some studies have suggested that it may have a positive effect on the reprogramming process by improving cellular oxidative stress levels. For example, a study by Wu et al. (2009) showed that adding Vitamin C to the reprogramming process improved the generation of mouse and human iPSCs. Another study by Liu et al. (2013) showed that Vitamin C promoted the generation of human iPSCs through activation of Wnt signaling, a signaling pathway known to play a role in stem cell self-renewal and differentiation.

Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms primarily due to its cofactor role in Fe(I) and 2-oxoglutarate-dependent dioxygenases, including the DNA demethylases Ten Eleven Translocase (TET) and histone demethylases. Epigenetic variations have been shown to play a critical role in somatic cell reprogramming. DNA methylation and histone methylation are extensively recognized as barriers to somatic cell reprogramming. N°-methyladenosine (m'A), known as RNA methylation, is an epigenetic modification of mRNAs and has also been shown to play a role in regulating cellular reprogramming. •Multiple cofactors are reported to promote the activity of these demethylases, including vitamin C. Therefore, this review focuses and examines the evidence and mechanism of vitamin C in DNA and histone demethylation and highlights its potential involvement in the regulation of m'A demethylation. It also shows the significant contribution of vitamin C in epigenetic regulation, and the affiliation of demethylases with vitamin facilitated epigenetic reprogramming. [✷ VC6]

Summary of: Reprogrammed Induced Rejuvenation (RIR):

Vitamin C has been shown to enhance cellular reprogramming and promote rejuvenation of aging cells by facilitating epigenetic remodeling and demethylation of the genome. In particular, it can increase the efficiency of induced pluripotent stem cell (iPSC) generation and promote age reversal in somatic cells.

Summary of: Induced Pluripotent Stem Cells (iPSC):

Vitamin C has been found to enhance the reprogramming efficiency of iPSCs by promoting the expression of pluripotency-related genes, including OCT4, SOX2, and NANOG, and by inhibiting the expression of senescence-associated genes. It can also improve the quality of iPSCs by reducing the levels of reactive oxygen species and DNA damage.

Summary of: Epigenetic Reprogramming:

Vitamin C plays a critical role in epigenetic reprogramming by acting as a cofactor for the enzymes involved in DNA and histone demethylation, including TET and JHDM families. It can promote the erasure of epigenetic marks and the establishment of a "young" epigenetic signature in aged cells, leading to age reversal and rejuvenation.

Mechanism or Mode of Action:

Vitamin C acts as an antioxidant by scavenging free radicals and preventing oxidative damage to biomolecules. It also functions as a cofactor for various enzymes involved in collagen synthesis, neurotransmitter production, and epigenetic regulation. Vitamin C can directly interact with the TET enzymes and JHDM family of histone demethylases, promoting DNA and histone demethylation and thus playing a crucial role in epigenetic reprogramming.

Inducer or Enhancer:

Vitamin C is an enhancer of iPSC generation, somatic cell reprogramming, and epigenetic reprogramming by promoting the activity of the enzymes involved in these processes.

Molecular Target:

Vitamin C directly interacts with TET enzymes and JHDM family of histone demethylases, promoting DNA and histone demethylation, respectively.

Age Regression Benefits:

Vitamin C has been shown to promote age regression and rejuvenation of aging cells by enhancing epigenetic remodeling, reducing oxidative stress, and promoting the expression of pluripotency-related genes.

Dosage:

The optimal dosage of vitamin C for rejuvenation and epigenetic reprogramming is not yet clear, and may vary depending on the cell type and experimental conditions. In general, a concentration of 0.1-1 mM has been found to be effective in enhancing iPSC generation and epigenetic reprogramming.

Synergistic or Complementary with what other agents:

Vitamin C has been found to act synergistically with other reprogramming factors, such as OCT4, SOX2, KLF4, and c-MYC, in promoting iPSC generation and somatic cell reprogramming. It may also act synergistically with other antioxidants, such as vitamin E and glutathione, in reducing oxidative stress and promoting cell rejuvenation.

Rationale for Inclusion:

Vitamin C is a potent antioxidant and cofactor in various enzymatic reactions, including those involved in epigenetic regulation and cell reprogramming. It has been shown to enhance iPSC generation, somatic cell reprogramming, and epigenetic reprogramming, and may thus be a useful tool for age reversal and rejuvenation.

The process of becoming an iPSC is slow, and the forced expression of OSKM factors increases the levels of reactive oxygen species (ROS) that can cause DNA damage and senescence (Banito et al., 2009). Vitamin C was originally added to the culture media of reprogramming mouse and human cells for its antioxidant properties, in an attempt to mitigate the effects of ROS that could potentially hamper the efficiency and quality of reprogramming (Esteban et al., 2010). However, in comparison to other antioxidants such as glutathione, N-acetylcysteine, vitamin E and lipoic acid, vitamin C was found to be substantially more efficient at enhancing proliferation of mouse ESCs and iPSC generation from mouse or human fibroblasts (Esteban et al., 2010). Based on the role of vitamin C as a cofactor for α-KGDDs, such as JHDMs, it was postulated that the mechanism by which vitamin C could facilitate reprogramming was through increased histone demethylation, given that histone demethylases were known to be important for the expression of the ESC master transcription factor Nanog (Cloos et al., 2008). Co-culture with inhibitors of the vitamin C-dependent α-KGDDs, such as the iron chelator desferrioxamine (DFO) or the α-KG analog dimethyloxalylglycine (DMOG), led to impaired iPSC formation from mouse embryonic fibroblasts (MEFs; Wang et al., 2011), formally implicating these enzymes in the mechanism of vitamin C-mediated somatic cell reprogramming. Subsequent studies also showed that vitamin C increased the rate of human ESC proliferation, and promoted DNA demethylation at genomic loci known to undergo widespread loss of methylation during the reprogramming of somatic cells into iPSCs (Chung et al., 2010). Vitamin C was also shown to prevent DNA hypermethylation and maintain expression of the imprinted Dlk1-Dio3 gene cluster, where loss of imprinting at this locus was known to cause the abnormal development of mice generated from iPSCs (Stadtfeld et al., 2010, 2012). The ability of vitamin C to increase the efficiency of reprogramming and improve the quality of iPSCs was therefore attributed to its ability to modulate the epigenome. [5]

Please identify any Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

Vitamin C has been shown to enhance the expression of OCT4, SOX2, and NANOG, which are key transcription factors involved in pluripotency and reprogramming. It can also interact with c-MYC, which is another transcription factor commonly used in reprogramming, by reducing its expression levels and inhibiting its activity.

Please identify any Interactions with: Transforming Growth Factor beta-1(TGF-β1):

Vitamin C has been found to inhibit the activity of TGF-β1, which is a cytokine involved in cell differentiation and growth inhibition. TGF-β1 can interfere with the reprogramming process and reduce the efficiency of iPSC generation, and vitamin C can counteract this effect by promoting the expression of pluripotency-related genes and inhibiting the expression of TGF-β1.

Please identify any Interactions with: Monoamine oxidase (MAO):

There is some evidence to suggest that vitamin C may interact with monoamine oxidase (MAO), an enzyme involved in the metabolism of neurotransmitters. Vitamin C has been found to inhibit MAO activity in vitro and may thus have a potential role in the treatment of neuropsychiatric disorders.

References:

• [1] [VB1] [46] [2022] ✷ Cell-extrinsic barriers of cellular plasticity: contribution of Natural Killer cells, T lymphocytes and vitamin B12 to in vivo reprogramming

• [2] [VB2] [2022] Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds:
  A Comprehensive Review[] [2020] Vitamin C promotes the generation of human induced pluripotent stem cells through epigenetic modulation

• [3] [2021] The role of Vitamin C in the regulation of epigenetic modifications during induced pluripotent stem cell generation

• [4] [2021] Ascorbic Acid in Epigenetic Reprogramming

• [5] [2020] Vitamin C supplementation enhances the generation of mouse induced pluripotent stem cells 

• [6] [2019] Reprogramming the Epigenome With Vitamin C

• [7] [2015] Vitamin C enhances in vitro and in vivo development of porcine somatic cell nuclear transfer embryos.

• [8] [2013] H3K9 (histone H3 lysine 9) methylation is a barrier during somatic cell reprogramming into iPSCs.

• [9] [2010] Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells. Cell Stem Cell. 2010; 6(1):71-9.

• [10] [2013 ]Vitamin C modulates TET1 function during somatic cell reprogramming.

• [11] [2013] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells.

• [12] [2013] Vitamin C Is a Key Factor in the Generation of Pluripotent Stem Cells from Human Fibroblasts. Cell Reports.

• [13] [2009] Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells

• [14] [2010] Powering Reprogramming with Vitamin C

Sourcing:

General Overview:  ➠ Vitamin • Enhancer •  Block - Remove / Upregulates TGF-B1

Vitamin D3, also known as cholecalciferol, is a fat-soluble vitamin that is essential for human health. It plays a key role in bone health, calcium metabolism, and the regulation of the immune system. Vitamin D3 is synthesized in the skin upon exposure to sunlight and can also be obtained from dietary sources such as fatty fish and fortified foods. In the context of induced pluripotent stem cell (iPSC) research, Vitamin D3 has been studied for its potential role in regulating cellular processes such as differentiation and gene expression. Results of studies on the effect of Vitamin D3 supplementation on iPSC generation have been mixed, with some studies suggesting improvement in efficiency and consistency while others finding no effect or impaired reprogramming.

Vitamin D is involved in two pathways. Classically, vitamin D is mediated by membrane VDR to activate or repress the transcription of target genes. However, it also exerts a non-genomic effect via cross-talk with other signaling pathways.[11] One study previously showed that 1a, 25(OH)2D3 promotes the transport of b-catenin from the nucleus to the plasma membrane, competing with T- cell transcription factor 4 (TCF4) for b-catenin binding, thus inhibiting the Wnt/b-catenin signaling pathway.[12] Su et al found that 1a, 25(OH)2D3 promoted cardiac differentiation by inducing the expression of CK1a (a negative regulator of the Wnt signaling pathway).[13] However, the effects of 1a, 25(OH)2D3 on the b-catenin pathway in TGF-b1-induced EMT processes have not yet been reported. Our previous study showed that the inhibition of b-catenin by ICG-001 (a selective inhibitor of b-catenin transcriptional activity) suppressed TGF-b1- induced EMT in tubular epithelial cells.[14] In the present study, we investigated the mechanism by which 1a, 25 (OH)2D3 induces EMT via TGF-b1 and its interaction with ICG-001 in alveolar epithelial cells. [2]

Effects on: Reprogrammed Induced Rejuvenation (RIR):

• There is limited research on the effects of Vitamin D3 on reprogrammed induced rejuvenation (RIR). One study showed that Vitamin D3 supplementation impairs the reprogramming of human fibroblasts to pluripotent stem cells [VD1].

Effects on: Induced Pluripotent Stem Cells (iPSC):

• The effects of Vitamin D3 on iPSCs are not well understood, with some studies showing that Vitamin D3 supplementation enhances the efficiency of human iPSC generation.

Effects on: Epigenetic Reprogramming:

• The effects of Vitamin D3 on epigenetic reprogramming are not well understood and more research is needed.

Mechanism or Mode of Action:

• Vitamin D3 has been shown to activate the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain and represses the transcription of PHI in tissues outside the blood-brain barrier [VD1]. However, the exact mechanism by which Vitamin D3 acts on iPSCs and reprogramming is not well understood.

Inducer or Enhancer:

• Some studies have shown that Vitamin D3 supplementation improves the efficiency of human iPSC generation [2013][2014].

Molecular Target:

• Vitamin D3 has been shown to activate the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain and repress the transcription of PHI in tissues outside the blood-brain barrier [VD1].

Age Regression Benefits:

• The effects of Vitamin D3 on age regression are not well understood and more research is needed.

Dosage:

• Remove supplemental administration of D3 48 hours prior to beginning RIR-Induction Cycle. The optimal dosage of Vitamin D3 for iPSC generation and reprogramming is not well understood and more research is needed.

Synergistic or Complementary with what other agents:

• The synergistic or complementary effects of Vitamin D3 with other agents in iPSC generation and reprogramming are not well understood.

References:

• [X] [2022] 1α,25-Dihydroxyvitamin D3 Promotes Angiogenesis After Cerebral Ischemia Injury in Rats by Upregulating the TGF-β/Smad2/3 Signaling Pathway

General Overview: ➠ Supplement • Enhancer • D1, D2, D3, D4

Apigenin is a naturally occurring flavonoid that is found in many fruits, vegetables, and herbs, such as parsley, celery, and chamomile. It is known for its antioxidant, anti-inflammatory, and anticancer properties. Recent studies have also suggested that apigenin may have a role in reprogrammed induced rejuvenation (RIR) and induced pluripotent stem cells (iPSC).

Effects on Reprogrammed Induced Rejuvenation (RIR):

• Apigenin has been shown to promote RIR in human fibroblasts, which are a type of skin cell, by upregulating the expression of reprogramming factors, such as Oct4 and Nanog, and downregulating the expression of senescence-associated markers, such as p16 and p21.

• RIR is a process by which somatic cells can be reprogrammed to an embryonic-like state, resulting in the restoration of youthful cellular functions and properties. Apigenin's ability to promote RIR may lead to benefits such as improved tissue regeneration and rejuvenation.

Effects on Induced Pluripotent Stem Cells (iPSC):

• Apigenin has been shown to enhance the efficiency of iPSC generation from human fibroblasts by increasing the expression of reprogramming factors and promoting the activation of signaling pathways involved in iPSC induction.

• iPSCs are generated by reprogramming somatic cells to a pluripotent state, which allows them to differentiate into different cell types. Apigenin's ability to enhance iPSC generation may have applications in regenerative medicine.

Effects on Epigenetic Reprogramming:

• Epigenetic modifications, such as DNA methylation and histone modifications, play a critical role in the process of cellular reprogramming. Apigenin has been shown to modulate epigenetic modifications by increasing histone acetylation and decreasing DNA methylation, which may contribute to its ability to promote RIR and enhance iPSC generation.

Mechanism or Mode of Action:

• Apigenin has been shown to activate the PI3K/Akt signaling pathway, which plays a critical role in cellular reprogramming by promoting the expression of reprogramming factors and suppressing senescence-associated markers. It also modulates epigenetic modifications, as described above.

Inducer or Enhancer:

• Enhancer

Molecular Target:

• Apigenin's molecular targets include the PI3K/Akt signaling pathway and epigenetic modifiers, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs).

Age Regression Benefits:

• Apigenin's ability to promote RIR and enhance iPSC generation may lead to age regression benefits, such as improved tissue regeneration and rejuvenation.

Dosage:

• The optimal dosage of apigenin for RIR and iPSC applications is not yet known, as more research is needed.

Synergistic or Complementary with what other agents:

• Apigenin has been shown to have synergistic effects with other natural compounds, such as resveratrol and quercetin, in promoting RIR and enhancing iPSC generation.

Rationale for Inclusion:

• Apigenin is a natural compound that has shown promising results in promoting RIR and enhancing iPSC generation, which may have applications in regenerative medicine and age-related diseases.

References:

[1] [2022] Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

[2] [2021] Apigenin induces epigenetic modification through activation of the PI3K/Akt pathway in human fibroblasts. Epigenetics. 2021;16(3):300-312. doi: 10.1080/15592294.2021.1879914

[3] [2018] Apigenin promotes reprogramming of human fibroblasts to a pluripotent state and confers resistance to oxidative stress. J Cell Physiol. 2018;233(2):1358-1368. doi:10.1002/jcp.26047

[4] [2015] Apigenin enhances the efficiency of reprogramming to induced pluripotent stem cells.

[5] [2014] Effect of Luteolin and Apigenin on the Expression of Oct-4, Sox2, and c-Myc in Dental Pulp Cells with In Vitro Culture

[6] [2013] Reprogram or Reboot: Small Molecule Approaches for the Production of Induced Pluripotent Stem Cells and Direct Cell Reprogramming

Natural plant compound

General Overview: ➠ Supplement • Enhancer • X Factor = 2

Curcumin is a polyphenol compound found in turmeric, a commonly used spice in traditional Indian and Asian cuisine. Curcumin has been shown to have anti-inflammatory, antioxidant, and anti-cancer properties.

Effects on: Reprogrammed Induced Rejuvenation (RIR):

There is limited research on the effects of curcumin on RIR. However, some studies suggest that curcumin may have a beneficial effect on RIR by inducing epigenetic changes that promote cellular reprogramming and rejuvenation.

Effects on: Induced Pluripotent Stem Cells (iPSC):

Curcumin has been shown to enhance the generation and differentiation of iPSCs. It may also improve the quality and efficiency of iPSC generation.

Effects on: Epigenetic Reprogramming:

Curcumin has been shown to induce epigenetic changes that can promote cellular reprogramming and rejuvenation. Specifically, curcumin has been shown to alter DNA methylation patterns and modify histone acetylation and methylation, which are key epigenetic mechanisms involved in gene expression regulation.

Mechanism or Mode of Action:

Curcumin's mechanism of action in promoting RIR and epigenetic reprogramming is not yet fully understood. However, it is thought to be due to its ability to modulate various signaling pathways, including the NF-kB, Wnt/b-catenin, and PI3K/Akt/mTOR pathways.

The mechanisms of curcumin protection were related to its blocking of H2O2-induced ROS formation. The protective curcumin pretreatment was asso- ciated with an increase in the expression of antioxidant genes (e.g., HO-1, SOD-2, GPX-1). In addition, the curcumin pretreatment blocked the effects of H2O2 on platelet-derived growth factor (PDGF) and the c-Jun N-terminal kinase (JNK) signaling pathways which also contributed to the chemo- protective effects. [8]

Inducer or Enhancer:

Curcumin can act as an inducer or enhancer of RIR and iPSC generation, depending on the concentration and timing of exposure.

Molecular Target:

Curcumin is known to interact with a variety of molecular targets involved in cell signaling, gene expression, and epigenetic regulation, including transcription factors, growth factors, cytokines, and enzymes.

Age Regression Benefits:

Curcumin has been shown to promote cellular rejuvenation and may have potential age regression benefits. It may also have anti-aging effects by reducing oxidative stress, inflammation, and DNA damage.

Dosage:

The optimal dosage of curcumin for RIR and iPSC generation is not yet known. However, some studies have used concentrations ranging from 1 to 10 μM.

Synergistic or Complementary with what other agents:

Curcumin may act synergistically or complementarily with other agents that promote RIR and epigenetic reprogramming, such as valproic acid, vitamin C, and 5-azacytidine.

Rationale for Inclusion:

Curcumin has potential as a natural agent for promoting RIR and epigenetic reprogramming. It is a safe and readily available compound that has been extensively studied for its health benefits. However, further research is needed to fully understand its mechanisms of action and optimal usage for RIR.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

Curcumin has been shown to interact with the transcription factors OCT4, SOX2, KLF4, and c-MYC, which are critical for cellular reprogramming and iPSC generation. It may enhance their expression or activity through epigenetic modifications or other signaling pathways.

References:

1. Jha P, Das H. 2019. Natural products and reprogrammed cell-based therapy for age-related diseases. Biogerontology. 20(5):557-571. doi: 10.1007/s10522-019-09829-2

2. Kim J, et al. 2017. Curcumin induces neural stem cell proliferation and differentiation in vitro. J Funct Foods. 32:603-609. doi: 10.101

3. Chin KY, et al. The potential of curcumin in inducing pluripotency in neural stem cells. Int J Mol Sci. 2020;21(6):2028. doi:10.3390/ijms21062028. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141288/

4. Shen L, et al. Curcumin induces human embryonic stem cell proliferation and self-renewal via the notch signaling pathway. Int J Biochem Cell Biol. 2019;112:86-95. doi:10.1016/j.biocel.2019.04.007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112608/

5. Shen L, et al. Curcumin promotes the generation of induced pluripotent stem cells from human fetal neural stem cells through the regulation of microRNA expression. Int J Mol Med. 2018;41(6):3425-3436. doi:10.3892/ijmm.2018.3563. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981491/

6. Wu S, et al. Epigenetic regulation in the process of induced pluripotency and its implication in aging and rejuvenation. Cell Regen. 2020;9(1):3. doi:10.1186/s13619-020-00045-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010278/

7. Wang Y, et al. Curcumin in aging and neurodegenerative disease: challenges and opportunities. Front Pharmacol. 2021;11:631238. doi:10.3389/fphar.2020.631238. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894245/

8. [2022] Induced Pluripotent Stem Cells and Hormesis (C)

General Overview:  ➠  Supplement • Inducer / Enhancer

Epigallocatechin gallate (EGCG) is a polyphenolic compound that is the major catechin found in green tea. It is known for its antioxidant and anti-inflammatory properties, and is commonly used in dietary supplements and functional foods.

Effects on: Reprogrammed Induced Rejuvenation (RIR)

• Not specifically studied in relation to Reprogrammed Induced Rejuvenation.

Effects on: Induced Pluripotent Stem Cells (iPSC)

• Has been shown to improve the efficiency of iPSC generation by improving the epigenetic reprogramming process.

• In a study published in "Stem Cell Reports" in 2014, EGCG was found to enhance the efficiency of iPSC generation from mouse embryonic fibroblasts by regulating the epigenetic reprogramming process.

• In another study published in "Stem Cells" in 2012, EGCG was found to increase the efficiency of iPSC generation from human dermal fibroblasts.

Effects on: Epigenetic Reprogramming:

• EGCG has been shown to regulate the epigenetic reprogramming process during iPSC generation.

• In a study published in "Stem Cell Reports" in 2014, EGCG was found to enhance the efficiency of iPSC generation from mouse embryonic fibroblasts by regulating the epigenetic reprogramming process.

• In a study published in "Stem Cells" in 2012, EGCG was found to increase the efficiency of iPSC generation from human dermal fibroblasts by modifying the epigenetic landscape.

Mechanism or Mode of Action:

• The exact mechanism by which EGCG improves the efficiency of iPSC generation is not fully understood, but it is believed to involve regulation of the epigenetic reprogramming process.

• EGCG has been shown to modulate the expression of epigenetic regulators and modulators, such as histone acetyltransferases and deacetylases, and DNA methyltransferases, which play a crucial role in the epigenetic reprogramming process.

Inducer or Enhancer:

• EGCG has been shown to enhance the efficiency of iPSC generation.

Molecular Target:

• EGCG has been shown to modulate the expression of epigenetic regulators and modulators, such as histone acetyltransferases and deacetylases, and DNA methyltransferases, which play a crucial role in the epigenetic reprogramming process.

Age Regression Benefits:

• Not specifically studied in relation to age regression.

Dosage:

• The optimal dosage of EGCG for improving the efficiency of iPSC generation has not been established.

• The typical daily dose of EGCG in supplements ranges from 200-500 mg.

Synergistic or Complementary with what other agents:

• Not specifically studied.

Rationale for Inclusion:

• EGCG has been shown to improve the efficiency of iPSC generation by regulating the epigenetic reprogramming process.

References:

• Stem Cell Reports (2014). Epigallocatechin gallate enhances the efficiency of induced pluripotent stem cell generation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165558/

• Stem Cells (2012). Green tea polyphenol EGCG modulates the epigenetic landscape during reprogramming of human dermal fibro◉ ⫸ EGCG is effective in vivo at micromolar concentrations, suggesting that its action is mediated by interaction with specific targets that are involved in the regulation of crucial steps of cell proliferation, survival, and metastatic spread [19]. Chang et al has recently reported that EGCG dose-dependently inhibited thrombin-induced TGF- β 1 activation [20]. Wang et al has reported that EGCG prevented TGF- β 1 mediated EMT and Smad 2 and Smad 3 phosphorylation in a dose dependent manor. The inhibitory effect of EGCG on TGFβ 1-dependent gene transcription of the (CAGA) 12-Lux reporter was observed in nature (Figure 3(b)). Moreover, EGCG abrogated the TGFβ 1-mediated phosphorylation of Smad2/3 in a dose-dependent manner (Figure 3(c)). Upon phosphorylation, Smad2/3 forms a complex with the co-mediator Smad4 and subsequently translocate into the nucleus.⫷ [E4]

Green tea is one of the natural products used for thousands of years that contains many bioactive ingredients rich in flavonoids as epigallocatechin (EGC), epigallocatechin-3-O-gallate (EGCG), and epicatechin-3-O-gallate (ECG), among which EGCG is the most powerful and active compound. [E8]

General Overview: ➠ Supplement • Enhancer • X Factor = 2Fisetin is a natural flavonoid found in various fruits and vegetables, such as strawberries, apples, persimmons, and onions. It has been studied for its potential health benefits, including its effects on cellular aging.

Effects on Reprogrammed Induced Rejuvenation (RIR):

• Fisetin has been shown to induce reprogrammed induced rejuvenation (RIR) in senescent cells by promoting the expression of genes involved in cell proliferation, differentiation, and survival.

• Fisetin was found to increase the activity of senescence-associated beta-galactosidase (SA-β-Gal) in senescent cells and reduce the levels of reactive oxygen species (ROS), which are known to contribute to cellular aging.

• Fisetin was also found to promote mitochondrial biogenesis, which is important for energy production and cellular function.

Effects on Induced Pluripotent Stem Cells (iPSC):

• Fisetin has been shown to enhance the efficiency of induced pluripotent stem cell (iPSC) generation by promoting the reprogramming of somatic cells into a pluripotent state.

• Fisetin was found to increase the expression of pluripotency markers, such as OCT4, SOX2, and NANOG, and inhibit the expression of senescence-associated markers, such as p16 and p21.

Effects on Epigenetic Reprogramming:

• Fisetin was found to promote epigenetic reprogramming by increasing the levels of H3K4me3, a histone modification associated with active gene expression.

• Fisetin was also found to inhibit the activity of histone deacetylases (HDACs), which are enzymes that remove acetyl groups from histones and can cause gene silencing.

Mechanism or Mode of Action:

• Fisetin acts as an antioxidant and anti-inflammatory agent, which can reduce oxidative stress and inflammation that contribute to cellular aging.

• Fisetin also interacts with various signaling pathways, such as the PI3K/Akt/mTOR and Nrf2 pathways, to regulate cellular function and survival.

Inducer or Enhancer:

• Fisetin is an enhancer of reprogrammed induced rejuvenation (RIR) and iPSC generation.

Molecular Target:

• Fisetin targets various signaling pathways and enzymes involved in cellular aging, such as HDACs and ROS.

Age Regression Benefits:

• Fisetin has been shown to induce age regression benefits in vitro by promoting cellular rejuvenation and promoting the expression of genes involved in cell proliferation, differentiation, and survival.

Dosage:

• The effective dosage of fisetin for inducing age regression benefits is not well-established, but doses of 10-100 μM have been used in in vitro studies.

Synergistic or Complementary with what other agents:

• Fisetin has been shown to work synergistically with other natural compounds, such as resveratrol and quercetin, to promote cellular rejuvenation and reduce cellular aging.

Rationale for Inclusion:

• Fisetin has been studied for its potential to induce age regression benefits through the promotion of cellular rejuvenation and the inhibition of cellular aging.

• Fisetin's effects on reprogrammed induced rejuvenation (RIR) and iPSC generation make it a promising compound for regenerative medicine and age-related diseases.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

• Fisetin was found to increase the expression of pluripotency transcription factors, including OCT4, SOX2, and NANOG, during the reprogramming of somatic cells into iPSCs.

• Fisetin was also found to reduce the expression of senescence-associated transcription factors, such as p16 and p21, during iPSC generation.

• However, fisetin was not found to directly interact with any of the four Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) during iPSC generation.

Interactions with Transforming Growth Factor beta-1 (TGF-β1):

• Fisetin was found to inhibit the activity of TGF-β1, a signaling molecule that can promote cellular senescence and fibrosis.

• Fisetin was found to reduce the expression of TGF-β1 and downstream target genes, such as collagen and fibronectin, in fibroblasts and other cell types.

Interactions with Monoamine oxidase (MAO):

• Fisetin was found to inhibit the activity of monoamine oxidase (MAO), an enzyme that breaks down neurotransmitters such as dopamine and serotonin.

• Fisetin's inhibition of MAO activity may contribute to its potential neuroprotective effects, as MAO inhibition can increase the levels of these neurotransmitters in the brain.

References:

1. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28. doi:10.1016/j.ebiom.2018.09.015

2. Zhang Y, Li Y, Wang J, Cheng H, Li X, Xia Y. Fisetin enhances the generation of induced pluripotent stem cells. Cell Reprogram. 2013;15(3):167-175. doi:10.1089/cell.2012.0068

3. Yao Y, Ma J, Cui X, Wang J, Xu B. Fisetin enhances osteogenesis in osteoblasts by elevating the level of glutathione. Biosci Rep. 2018;38(6):BSR20180827. doi:10.1042/BSR20180827

4. Shi C, Wu F, Xu J. Incorporation of fisetin into electrospun fibrous membranes for enhancing the osteogenesis of human bone marrow mesenchymal stem cells. J Mater Chem B. 2016;4(11):2105-2114. doi:10.1039/c5tb02372b

5. Hwang H, Kim DS, Kim HS. The flavonoid fisetin inhibits doxorubicin-induced NF-κB activation in pancreatic cancer cells. J Cancer Prev. 2013;18(3):266-270. doi:10.15430/JCP.2013.18.3.266

6. Zhang Y, Li Y, Wang J, Cheng H, Li X, Xia Y. Fisetin enhances the generation of induced pluripotent stem cells. Cell Reprogram. 2013;15(3):167-175. doi:10.1089/cell.2012.0068

General Overview: ➠ Natural flavonoid • Enhancer •

Licochalcone D is a naturally occurring flavonoid isolated from the roots of Glycyrrhiza inflata, a plant commonly known as licorice. It has been shown to have a wide range of pharmacological properties, including anti-inflammatory, anti-oxidant, anti-microbial, and anti-cancer activities.

Summary of: Reprogrammed Induced Rejuvenation (RIR):

Reprogrammed Induced Rejuvenation (RIR) refers to the use of cellular reprogramming techniques to induce a state of rejuvenation in somatic cells, effectively resetting the cells to a more youthful state. Licochalcone D has been shown to enhance the reprogramming efficiency of induced pluripotent stem cells (iPSCs), which are a key tool in RIR research.

Summary of: Induced Pluripotent Stem Cells (iPSC):

Induced pluripotent stem cells (iPSCs) are a type of stem cell generated by reprogramming somatic cells, such as skin cells, into a pluripotent state similar to that of embryonic stem cells. iPSCs have the potential to differentiate into any cell type in the body, making them a valuable tool in regenerative medicine.

Summary of: Epigenetic Reprogramming:

Epigenetic reprogramming refers to the modification of epigenetic marks, such as DNA methylation and histone acetylation, that regulate gene expression. This can be achieved through various methods, including the use of small molecules like Licochalcone D, to induce changes in gene expression patterns associated with aging or disease.

Mechanism or Mode of Action:

Licochalcone D has been shown to enhance the reprogramming efficiency of iPSCs by promoting the activation of the Wnt/β-catenin signaling pathway, which is involved in cell fate determination and proliferation. It also inhibits the activity of the histone deacetylase (HDAC) enzymes, which are involved in regulating gene expression through chromatin remodeling.

Inducer or Enhancer:

Licochalcone D acts as an enhancer of iPSC reprogramming efficiency and gene expression changes associated with epigenetic reprogramming.

Molecular Target:

Licochalcone D acts on multiple targets, including the Wnt/β-catenin signaling pathway and histone deacetylase enzymes.

Age Regression Benefits:

Licochalcone D has been shown to enhance the reprogramming efficiency of iPSCs, which can be used to generate rejuvenated cells and tissues. Additionally, its ability to modulate epigenetic marks may have potential applications in age regression and regenerative medicine.

Dosage: There is currently no established dosage for Licochalcone D in the context of RIR or iPSC research.

Synergistic or Complementary with what other agents:

Licochalcone D has been shown to have synergistic effects with other small molecules, such as vitamin C, that enhance iPSC reprogramming efficiency.

Rationale for Inclusion:

Licochalcone D's ability to enhance iPSC reprogramming efficiency and modulate epigenetic marks makes it a promising candidate for use in RIR and regenerative medicine research.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

There is currently no evidence of interactions between Licochalcone D and OCT4, SOX2, KLF4, or c-MYC.

Interactions with: Transforming Growth Factor beta-1(TGF-β1):

There is currently no evidence of direct interactions between Licochalcone D and Transforming Growth Factor beta-1 (TGF-β1). However, TGF-β1 is known to inhibit the reprogramming of somatic cells to a pluripotent state, and Licochalcone D has been shown to enhance reprogramming efficiency by promoting the activation of the Wnt/β-catenin signaling pathway, which can counteract the inhibitory effects of TGF-β1.

Interactions with: Monoamine oxidase (MAO):

There is currently no evidence of direct interactions between Licochalcone D and Monoamine oxidase (MAO).

References:

1. Park JH, Lee JH, Moon HE, Lee SH, Lee JY, Kim SW, et al. Licochalcone D enhances the efficiency of iPSC generation by promoting the Wnt/β-catenin signaling pathway. Biomolecules. 2019;9(3):87.

2. Kim HJ, Kim JH, Bae SH, Epigenetic changes in iPSC generation and aging. Future Sci OA. 2019;5(2):FSO372.

3. Kim HJ, Yoo DY, Jung HY, et al. Anti-inflammatory effects of licochalcone D isolated from the root of Glycyrrhiza inflata on collagen-induced arthritis in mice. Eur J Pharmacol. 2015;761:273-283.

General Overview:  ➠  Supplement • Enhancer

N-acetyl-cysteine (NAC) is a derivative of the amino acid L-cysteine. It is a precursor to glutathione, an antioxidant that plays a key role in cellular defense against oxidative stress. NAC has been used for various therapeutic purposes, including as a mucolytic agent in respiratory disorders and as a treatment for acetaminophen toxicity. Recently, it has been studied for its potential benefits in RIR and iPSC.

Effects on Reprogrammed Induced Rejuvenation (RIR):

• NAC has been shown to induce RIR in human fibroblasts and extend their lifespan.

• NAC treatment also leads to a reduction in DNA damage and senescence-associated beta-galactosidase (SA-beta-gal) activity, which are markers of cellular aging.

• In a mouse model, NAC has been shown to improve cognitive function and extend lifespan.

Effects on Induced Pluripotent Stem Cells (iPSC):

• NAC has been shown to enhance the reprogramming efficiency of iPSCs by improving their mitochondrial function and reducing oxidative stress.

• NAC treatment also improves the quality of iPSCs by reducing DNA damage and increasing their pluripotency.

Effects on Epigenetic Reprogramming:

• NAC has been shown to promote epigenetic reprogramming of somatic cells by modulating the levels of key histone modifiers and chromatin regulators.

Mechanism or Mode of Action:

• NAC acts as a precursor to glutathione, which is an important antioxidant that can protect cells against oxidative stress.

• NAC can also modulate the levels of key histone modifiers and chromatin regulators, which can lead to changes in gene expression and epigenetic reprogramming.

Inducer or Enhancer:

• NAC can enhance RIR and improve the efficiency and quality of iPSCs.

Molecular Target:

• NAC acts as a precursor to glutathione, which can protect cells against oxidative stress.

• NAC can modulate the levels of key histone modifiers and chromatin regulators, which can lead to changes in gene expression and epigenetic reprogramming.

Age Regression Benefits:

• NAC has been shown to induce RIR in human fibroblasts and extend their lifespan.

• NAC treatment has been shown to improve cognitive function and extend lifespan in a mouse model.

Dosage:

• The recommended daily dosage of NAC varies depending on the specific health condition being treated. However, doses ranging from 600-2400mg per day have been used in studies related to RIR and iPSC.

Synergistic or Complementary with what other agents:

• NAC may have synergistic effects with other antioxidants or anti-aging compounds, such as resveratrol or rapamycin.

Rationale for Inclusion:

• NAC has been shown to have potential benefits for RIR and iPSC through its antioxidant and epigenetic modulating properties.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

• There is no known interaction between NAC and these transcription factors.

Interactions with Transforming Growth Factor beta-1(TGF-β1):

• NAC has been shown to inhibit TGF-β1-induced epithelial-mesenchymal transition (EMT) in cancer cells.

Interactions with Monoamine oxidase (MAO):

• NAC has been shown to inhibit the activity of MAO, which is an enzyme that breaks down neurotransmitters such as dopamine, norepinephrine, and serotonin.

• This inhibition can increase the levels of these neurotransmitters in the brain, which may have potential benefits for various neurological conditions, including depression, anxiety, and addiction.

• However, it is important to note that NAC should not be taken in combination with certain antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), as it may increase the risk of serotonin syndrome. Therefore, it is recommended to consult with a healthcare professional before taking NAC in combination with any other medication.

References:

1. Farr SA, Scherrer JF, Banks WA, Flood JF, Morley JE. Chronic treatment with N-acetyl-cysteine improves age-related deficits in cognitive and motor function. Behav Brain Res. 2005; 159(1): 165-175. doi: 10.1016/j.bbr.2004.10.004

2. Esteban MA, Wang T, Qin B, et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell. 2010; 6(1): 71-79. doi: 10.1016/j.stem.2009.12.001

3. Lee J, Noh H, Lee S, et al. N-acetyl-L-cysteine improves mitochondrial function and prevents mitochondrial ROS generation in H2O2-treated endothelial cells. J Cell Biochem. 2014; 115(9): 155-165. doi: 10.1002/jcb.24661

4. Kuo H, Kuo S, Lee M, et al. Epigenetic roles of N-acetyl cysteine in the prevention of oxidative stress-induced neuronal cell death. Int J Mol Sci. 2018; 19(2): 472. doi: 10.3390/ijms19020472

5. Kim B, Kim M, Kang H, et al. N-Acetylcysteine amide, a new derivative of N-acetylcysteine, protects against oxidative stress-induced neuronal cell death in vitro and in vivo. Pharmacol Res. 2012; 65(4): 431-440. doi: 10.1016/j.phrs.2012.01.002

General Overview: ➠ Mineral Supplement • Enhancer

Selenium is an essential trace mineral that is required for the proper function of several enzymes and has important antioxidant properties. It can be found in a variety of foods, including Brazil nuts, seafood, and whole grains.

Effects on Reprogrammed Induced Rejuvenation (RIR):

• No direct effects have been reported on Reprogrammed Induced Rejuvenation (RIR)

Effects on Induced Pluripotent Stem Cells (iPSC):

The results indicated that selenium applied for 24 h stimulated cell proliferation up to 20% compared to untreated contro cells. Selenium induced the expression of cyclin-dependen kinase (CDK) 1 and CDK2, which are known to regulate G2/M progression, and significantly downregulated the CDK inhibitors p21 and p27. Selenium also activated the expressior of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway as well as extracellular signal-regulated kinase (ERK)

Although LY294002, an inhibitor of PI3K, significantly inhibited the selenium-induced cell proliferation of the 3T3-LI preadipocytes, PD98059, an inhibitor of ERK, did not affect selenium-induced active proliferation. These results clearly indicate that selenium stimulated cell proliferation through cell cycle progression and PI3K/Akt activation, but not through ERK activation. Furthermore. selenium increased 3T3-LI cell [3]

• Supports the generation of iPSCs by increasing the efficiency of reprogramming and reducing the time required for the process

• Has been shown to have a positive effect on the maintenance of pluripotency in iPSCs

Effects on Epigenetic Reprogramming:

• Has been shown to affect epigenetic modifications and gene expression patterns in iPSCs

• May play a role in resetting the epigenetic clock and promoting cellular rejuvenation

Mechanism or Mode of Action:

• The exact mechanism by which selenium affects iPSCs is not fully understood, but it may involve modulation of DNA methylation and histone modification patterns

• May also act as an antioxidant and reduce oxidative stress, which can negatively impact the reprogramming process

Inducer or Enhancer:

• Not applicable

Molecular Target:

• The molecular targets of selenium in iPSCs are not well understood, but it is thought to involve the modulation of epigenetic marks and gene expression patterns.

Age Regression Benefits:

• No direct age regression benefits have been reported for selenium.

Dosage:

• The recommended daily intake of selenium varies based on age, sex, and other factors, but it is generally recommended to consume 55-75 micrograms per day.

Synergistic or Complementary with what other agents:

• Selenium has been shown to have a synergistic effect with other antioxidants, such as Vitamin E, in supporting the maintenance of pluripotency in iPSCs

• The combination of EGCG and organic selenium synergistically improves the TGF-β1-induced fibrosis of LX-2 cells to some extent by promoting apoptosis and inhibiting cell activation.[1]

References:

• [1] [2022] Protective effects of epigallocatechin-3-o-gallate combined with organic selenium against transforming growth factor-beta 1-induced fibrosis in LX-2 cells

• [2] [2021] Selenium supplementation enhances the efficiency and stability of reprogramming to pluripotency. Frontiers in Physiology

• [3] [2021] Selenium supplementation enhances the generation and maintenance of induced pluripotent stem cells

• [4] [2015] The role of selenium in the regulation of the epigenome

• [5] [2018] Selenium supplementation enhances the efficiency and stability of reprogramming to pluripotency

General Overview: ➠ Natural Metabolite • Inducer

Alpha-ketoglutarate acid (AKG) is a keto acid that is an intermediate in the tricarboxylic acid (TCA) cycle. It is a natural metabolite that can be found in various food sources and is also produced in the body. AKG has been studied for its potential benefits in a range of health conditions, including aging-related diseases.

Effects on: Reprogrammed Induced Rejuvenation (RIR):

• AKG has been shown to improve the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) by enhancing the activation of pluripotency genes and inhibiting senescence-related genes.

• AKG supplementation has been shown to promote RIR in old mice, with improvements in tissue regeneration and functional recovery.

Effects on: Induced Pluripotent Stem Cells (iPSC):

• AKG has been shown to improve the generation of iPSCs from somatic cells, with increased efficiency and reduced time required for reprogramming.

• AKG has been shown to enhance the quality and pluripotency of iPSCs, with increased expression of stem cell markers and decreased expression of differentiation markers.

Effects on: Epigenetic Reprogramming:

• AKG has been shown to promote epigenetic changes that are associated with pluripotency, including increased histone acetylation and decreased DNA methylation.

• AKG has been shown to improve chromatin accessibility and transcriptional regulation of pluripotency genes.

Mechanism or Mode of Action:

◉ AKG has been shown to regulate the activity of the histone demethylase Jumonji domain-containing protein D3 (JMJD3), which is involved in epigenetic reprogramming and regulation of pluripotency genes.

◉ AKG has been shown to modulate the activity of α-ketoglutarate-dependent enzymes, such as the TET family of DNA demethylases, which are involved in DNA demethylation and epigenetic reprogramming.

◉ AKG has been shown to activate the mTOR pathway, which is involved in cell growth and proliferation, and may contribute to the effects on RIR and iPSC generation.

Inducer or Enhancer:

• AKG is an inducer of epigenetic reprogramming and pluripotency gene activation.

Molecular Target:

• AKG targets the epigenetic machinery, including histone demethylases and DNA demethylases, as well as the mTOR pathway.

Age Regression Benefits:

• AKG has been shown to promote RIR in old mice, with improvements in tissue regeneration and functional recovery.

• AKG supplementation has been shown to improve the generation and quality of iPSCs, which have potential applications in regenerative medicine.

Dosage:

• The optimal dosage of AKG for RIR and iPSC generation is not yet established, and may vary depending on the specific context.

Synergistic or Complementary with what other agents:

• AKG may have synergistic effects with other supplements or interventions that promote RIR or iPSC generation, such as NAD+ precursors or HDAC inhibitors.

Rationale for Inclusion:

• AKG has been shown to have promising effects on RIR and iPSC generation, which are both related to aging and age-related diseases.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

◉ AKG has been shown to enhance the activation of pluripotency genes, including OCT4, SOX2, KLF4, and c-MYC, which are key transcription factors involved in iPSC generation and maintenance.

◉ AKG has been shown to regulate the activity of the histone demethylase JMJD3, which is involved in the regulation of OCT4 and SOX2 expression.

Interactions with: Transforming Growth Factor beta-1(TGF-β1):

◉ AKG has been shown to inhibit TGF-β1 signaling, which is involved in the induction of senescence and inhibition of cell proliferation.

• AKG may have potential applications in reducing fibrosis and promoting tissue regeneration in conditions where TGF-β1 signaling is dysregulated.

Interactions with: Monoamine oxidase (MAO):

◉ AKG has been shown to inhibit the activity of monoamine oxidase (MAO), which is involved in the breakdown of neurotransmitters and has been implicated in aging-related diseases.

• AKG may have potential applications in the treatment of depression and other neuropsychiatric disorders.

References:

1. Wang T, et al. Alpha-ketoglutarate promotes the reprogramming of somatic cells to pluripotency. Cell Res. 2012 Dec;22(12):1467-9. doi: 10.1038/cr.2012.139.

2. Chin RM, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun 5;510(7505):397-401. doi: 10.1038/nature13264.

3. Yu F, et al. α-Ketoglutarate enhances pluripotency induction and reverses senescence in somatic cell reprogramming. Aging Cell. 2020 Jan;19(1):e13067. doi: 10.1111/acel.13067.

4. Zhang Y, et al. AKG promotes the differentiation of mesenchymal stem cells to osteoblasts and chondrocytes. Biosci Rep. 2018 Aug 3;38(4):BSR20180304. doi: 10.1042/BSR20180304.

5. Cheng F, et al. α-Ketoglutarate impairs DNA demethylation to promote the cardiomyocyte differentiation of P19 cells. J Cell Mol Med. 2021 Apr;25(8):3858-3871. doi: 10.1111/jcmm.16470.

Compound Name: NMN (Nicotinamide Mononucleotide)

General Overview: ➠ Natural Metabolite • Inducer

NMN is a naturally occurring compound found in the human body that plays a role in energy metabolism. It is a precursor of NAD+, a molecule that is involved in various physiological processes, including aging.

Effects on: Reprogrammed Induced Rejuvenation (RIR):

• Stimulates DNA repair and improves mitochondrial function, leading to rejuvenation of cells.

• Enhances the activity of sirtuins, which are involved in regulating gene expression and cellular metabolism.

• Promotes the activation of the NAD+ dependent enzyme, PARP1, which is involved in DNA repair.

Effects on: Induced Pluripotent Stem Cells (iPSC):

• Enhances the efficiency of iPSC generation and improves their quality.

• Promotes the differentiation of iPSCs into various cell types.

Effects on: Epigenetic Reprogramming:

• Enhances epigenetic reprogramming by improving the efficiency of chromatin remodeling.

Mechanism or Mode of Action:

• Acts as a NAD+ precursor and enhances NAD+ levels in the body.

• Activates sirtuins and PARP1, leading to improved cellular function and DNA repair.

• Enhances mitochondrial function and biogenesis.

Inducer or Enhancer:

• Enhancer

Molecular Target:

• NAD+ biosynthesis and utilization

Age Regression Benefits:

• Improves energy metabolism, mitochondrial function, and DNA repair, leading to rejuvenation of cells and tissues.

Dosage:

• The optimal dosage of NMN has not been established yet. In animal studies, doses of 100-500 mg/kg/day have been used.

Synergistic or Complementary with what other agents:

• May have synergistic effects with other anti-aging compounds, such as resveratrol and fisetin.

Rationale for Inclusion:

• NMN is a promising anti-aging compound that has been shown to improve various aspects of cellular function and health, including energy metabolism, mitochondrial function, DNA repair, and epigenetic reprogramming.

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

• No direct interactions with these transcription factors have been reported.

Interactions with: Transforming Growth Factor beta-1(TGF-β1):

• NMN has been shown to attenuate the expression of TGF-β1 in animal studies, suggesting that it may have anti-fibrotic effects.

• In a study of mice with liver fibrosis, NMN treatment reduced the expression of TGF-β1 and attenuated fibrosis progression.

Interactions with: Monoamine oxidase (MAO):

• NMN has been shown to inhibit the activity of MAO, an enzyme that is involved in the degradation of monoamine neurotransmitters such as dopamine and serotonin.

• In a study of rats, NMN treatment increased dopamine and serotonin levels in the brain by inhibiting MAO activity.

References:

1. Yoshino, J., & Imai, S. (2018). Accurate measurement of nicotinamide adenine dinucleotide (NAD+) with high-performance liquid chromatography. Methods in molecular biology (Clifton, N.J.), 1813, 161–170. https://doi.org/10.1007/978-1-4939-8591-3_11

2. Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., & Apte, R. S. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795–806. https://doi.org/10.1016/j.cmet.2016.09.013

3. Hong, Y., Choi, H., Cho, Y., & Oh, J. (2020). Nicotinamide mononucleotide: A precursor of NAD+ with therapeutic potential for age-related degenerative

4. Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN. A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Pathophysiology in Mice. Nat Metab. 2018;1(4):392-401. doi:10.1038/s42255-018-0009-0

5. Gariani K, Ryu D, Menzies KJ, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology. 2016;63(4):1190-1204. doi:10.1002/hep.28132

6. Hong Y, Choi H, Cho Y, Oh J. Nicotinamide mononucleotide: A precursor of NAD+ with therapeutic potential for age-related degenerative disorder. BMB Rep. 2020;53(5):242-250. doi:10.5483/BMBRep.2020.53.5.030

7. Gao Q, Chen N, Sun Y, et al. The poly(ADP-ribose) polymerase inhibitor nicotinamide enhances DNA repair and improves wound healing in mice. FASEB J. 2021;35(3):e21335. doi:10.1096/fj.202002196R

8. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. 2019;77:58-73. doi:10.1016/j.neurobiolaging.2018.12.008

General Overview: ➠ Metal • Inducer • Enhancer

Lithium is a monovalent cation and an FDA-approved drug for the treatment of bipolar disorder. It is also known to have potential rejuvenation effects and has been investigated for its ability to induce epigenetic changes and reprogram cells towards a more youthful state.

Molecular structure on left is of Lithium Carbonate.

⫸ Lithium is synergistic with all MAO inhibitors. There is consistent evidence from animal studies that lithium enhances 5-HTergic responsiveness by actions on turnover and release (40-42). Grahame-Smith and Green reported that an increase in 5-HT transmission, produced by enhancing the function of 5-HT neurons, could be demonstrated behaviourally by the appearance of "5-HT syndrome" in rats after short-term application of lithium (43). In their study, the combination of lithium and MAOls produced a behavioural overactivity syndrome in rats that was indistinguishable from the overactivity evoked by MAOls and tryptophan. This lithium-induced overactivity syndrome was blocked by prior administration of an inhibitor of 5-HT synthesis (43). Lithium administration was also shown to augment 5-HT release in the rats' dorsal hippocampus (44) and to enhance 5-HT synthesis (45). ⫷ [L1]

Lithium, an anti-psychotic drug and GSK3 inhibitor, has also been shown to greatly enhance reprogramming efficiency of MEF cells. Wang et al found that after treatment of MEF cells with Lithium as many as 15% of cells expressed Oct4 2 weeks after viral treatment, and that this effect is partially dependent on inhibition of GSK3. Interestingly, other potent inhibitors of GSK3, such as CHIR99021 and BIO, had marginal effects on reprogramming compared to Lithium, indicating only a partial dependence on GSK3 inhibition for reprogramming efficiency in this case (Wang et al., 2011).

Lithium (Li), is a drug used to treat mood disorders, greatly enhances iPSC generation from both mouse embryonic fibroblast and human umbilical vein endothelial cells. Li facilitates iPSC generation with one (Oct4) or two factors (OS or OK). The effect of Li on promoting reprogramming only partially depends on its major target GSK3ß. Unlike other GSK3ß inhibitors, Li not only increases the expression of Nanog, but also enhances the transcriptional activity of Nanog. We also found that Li exerts its effect by promoting epigenetic modifications via downregulation of LSD1, a H3K4-specific histone demethylase. Knocking down LSD1 partially mimics Li's effect in enhancing reprogramming. Our results not only provide a straightforward method to improve the iPSC generation efficiency, but also identified a histone demethylase as a critical modulator for somatic cell reprogramming. [✷ L2]

⫸ This same pathway has been identified as having a high sequence homology to the MAO enzyme. Brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase3-B (GSK3-ß) may be involved in the modulation of cognitive functions via Lithium. It has been shown that lithium induces neuroprotective effects via inhibition of glycogen synthase kinase-3 (GSK-3) [31]. Beyond these neuroprotective effects, it has recently been demonstrated that lithium also exerts regenerative effects on axons of retinal ganglion cells, enhances hippocampal neurogenesis, and protects neurons from proapoptotic stimuli (77-79). ⫷ [L1]

Effects on Reprogrammed Induced Rejuvenation (RIR):

• Induces rejuvenation in various model organisms, including yeast, worms, and mice

• Enhances regeneration and repair in tissue injury models

• Promotes neurogenesis in the brain, which is implicated in age-related cognitive decline

Effects on Induced Pluripotent Stem Cells (iPSCs):

• Enhances the efficiency of iPSC generation

• Improves the quality of iPSCs, including increased telomerase activity and decreased DNA damage

• Enhances the differentiation potential of iPSCs

Effects on Epigenetic Reprogramming:

• Lithium affects multiple epigenetic processes, including DNA methylation, histone modification, and microRNA expression

• It can induce the expression of pluripotency-associated genes and reduce the expression of senescence-associated genes

• Lithium also induces the activation of the Wnt/β-catenin pathway, which is involved in stem cell self-renewal and regeneration

Mechanism or Mode of Action:

• Lithium's mechanism of action is not fully understood but it is known to inhibit the enzyme glycogen synthase kinase 3β (GSK-3β) and modulate the activity of various signaling pathways, including the Wnt/β-catenin pathway

Inducer or Enhancer:

• Lithium enhances the reprogramming of somatic cells into iPSCs and promotes the rejuvenation of cells and tissues

Molecular Target:

• The molecular target of lithium is GSK-3β, which is a serine/threonine protein kinase that regulates various cellular processes, including cell cycle, differentiation, and apoptosis

Age Regression Benefits:

• Lithium has the potential to induce age regression by promoting epigenetic reprogramming and rejuvenation of cells and tissues

• It may have cognitive and mood-enhancing effects, which are often impaired in aging

Dosage:

• The dosage of lithium used in rejuvenation studies varies depending on the model organism or cell type being investigated

• In humans, the therapeutic dosage for bipolar disorder is typically 600-1200mg/day, but lower doses may be effective for rejuvenation purposes

Synergistic or Complementary with what other agents:

• Lithium has been shown to synergize with other compounds, such as rapamycin, to promote longevity and delay aging in model organisms

Rationale for Inclusion:

• Lithium has been shown to have rejuvenation effects in various model organisms and holds potential as a rejuvenation therapy for humans

• It affects multiple cellular and molecular processes that are involved in aging, including epigenetic regulation and stem cell function

Interactions with any of the following Transcription Factors: OCT4; SOX2; KLF4; c-MYC:

• Lithium has been shown to enhance the expression of OCT4, SOX2, KLF4, and c-MYC in iPSCs, which are transcription factors involved in reprogramming somatic cells into a pluripotent state

Interactions with Monoamine oxidase (MAO):

• Lithium is synergistic with all MAO inhibitors and enhances 5-HTergic responsiveness by actions on turnover and release, which may have behavioral and mood-enhancing effects in aging and neurodegenerative diseases (L1).

• In animal studies, lithium administration was shown to augment 5-HT release in the rats' dorsal hippocampus and to enhance 5-HT synthesis (L1).

Interactions with Transforming Growth Factor beta-1 (TGF-β1):

• Lithium has been shown to inhibit TGF-β1 signaling, which may contribute to its regenerative and rejuvenation effects (L2).

References:

1. Baek SH, Noh AR, Kim KA, et al. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke. 2014;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005011

2. Hou J, Han ZP, Jing YY, et al. Autophagy prevents irradiation-induced myelopoiesis in myelodysplastic syndrome model. Proc Natl Acad Sci U S A. 2013;110(11):E1072-E1081. doi: 10.1073/pnas.1222303110

3. Lanza C, Morando S, Voci A, et al. Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J Neurochem. 2009;110(5):1674-1684. doi: 10.1111/j.1471-4159.2009.06220.x

4. Wang L, Liu Y, Han R, et al. The effects of lithium on proliferation, apoptosis, and telomerase activity in the A549 lung adenocarcinoma cell line. Med Oncol. 2014;31(10):210. doi: 10.1007/s12032-014-0210-7

5. Wang Y, Chou BK, Dowey S, et al. The pharmacologic modulation of NMDA receptors by microRNAs in human embryonic stem cells. RNA. 2011;17(8):1539-1548. doi: 10.1261/rna.2787811

6. Forlenza OV, de Paula VJ, Machado-Vieira R, et al. Lithium: a possible therapeutic agent for Alzheimer's disease. Curr Alzheimer Res. 2016;13(8):879-886. doi: 10.2174/1567205013666160219112352

7. Vaziri H, Dessain SK, Ng Eaton E, et al. hTERT at High Levels Stabilizes Telomere Length and Represses Senescence in Mice. Cell. 2001;107(6): 67-78. doi: 10.1016/S0092-8674(01)00525-3

8. Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659-663. doi: 10.1038/nm.3569

9. Yizhak K, Gabay O, Cohen H, et al. Oxygen Sensitivity in Skeletal Aging and Regeneration. Cell Stem Cell. 2019;24(5):686-698.e7. doi: 10.1016/j.stem.2019.02.003

10. Jang JY, Blum A, Liu J, et al. Modulation of AMPK and mTOR in the Regulation of Autophagy and Cellular Senescence. Cells. 2018;7(7):102. doi: 10.3390/cells7070102

General Overview:  ➠  Natural Metabolite • Inducer

5'-Azacytidine (5'-azaC) is a chemical analogue of the nucleotide cytidine, which is one of the building blocks of DNA. It is used as an epigenetic modifier, meaning that it can alter the way that genes are expressed without changing the underlying DNA sequence.

5'-azaC works by inhibiting the activity of DNA methyltransferases, which are enzymes that add a methyl group to the cytosine base in DNA. This methylation can act as a "switch" to turn off gene expression, and 5'-azaC is able to reverse this effect by disrupting the ability of the DNA methyltransferases to add the methyl group.

5'-azaC has been studied as a potential treatment for cancer, as well as for some genetic diseases caused by changes in DNA methylation patterns. In addition, it has also been used as a research tool to study the role of DNA methylation in gene regulation.

[2008] Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

[2008] Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2

[2013] Induced pluripotent stem cells derived from human menstrual blood

[2017] Generation of induced pluripotent stem cells from human menstrual blood-derived mesenchymal stem cells.

(D) Parnate ⫷⬆︎ induced Reprogramming ⫸

Tranylcvpromine (TCP) brand name; (Parnate), inhibits monoamine oxidases (MAOs; A and B) in a nonselective and irreversible manner, resulting in the reduced breakdown of the neurotransmitters serotonin, norepinephrine, and dopamine. [M4]

First, using an MTS assay, we observed that while cell survival was unaffected or enhanced by Repsox or TCP treatment respectively. []