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Mitochondria-based therapeutics: perspectives and first CohBar clinical trials
The preliminary results on the safety and efficacy of MDPs give hope for further development of anti-aging science.
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Highlights:
- Functions of mitochondria reach far beyond producing energy for a cell
- Mitochondrial DNA encodes a range of proteins and peptides with important biological functions
- Among eight identified mitochondrial peptides, MOTS-c attracted particular attention due to its ability to reduce obesity and insulin resistance
- CohBar company created a synthetic analog for MOTS-c for the treatment of obesity and nonalcoholic steatohepatitis (NASH), which is now in stage 2a of clinical trials
Introduction
Multiple interventions have been shown to increase lifespan in short-lived model organisms, such as yeast, worms, flies, mice, and others. More importantly, such interventions also increase a healthspan by delaying the onset of age-related diseases. These pharmacological, dietary, and genetic breakthroughs boosted the development of geroscience and gave rise to hope that these findings could be used to delay or slow human aging.
Many potential strategies have been identified on this quest, including modulation of common pathways and processes like insulin and TOR signaling. One of the recently emerged promising strategies is improving mitochondrial functions via mitochondrial peptides to fight aging.
The hidden life of mitochondria
One of the most repeated lines in biology is that “mitochondria is a powerhouse of a cell”. Though they are indeed heavily involved in cell energy production, mitochondria’s functions are not limited to that. Mitochondria have been shown to participate in signaling within and between cells, metabolism and immune system regulation, cell cycle control, cell growth, and death (apoptosis). Recent research shows that mitochondria, among other things, participate in several known signaling pathways interacting with various molecules such as reactive oxygen species (ROS), calcium ions (Ca2+), and cytochrome C (1,2). Further evidence consistently emerges of the importance of mitochondrial signaling in critical processes, such as stress resistance, inflammation, and aging (3–5). Even self-produced mitochondrial ROS, initially thought to be carrying only damaging function, were rediscovered as a key communication method between cell and mitochondria that regulates homeostasis and normal cellular function (6). Currently, mitochondria are considered as playing a major role in aging and age-related diseases (7,8). For example, in aged mice, an improvement of mitochondrial function has been shown to ameliorate age-related memory loss (9).
The ability of mitochondria to convey all these functions is reached through a range of peptides and proteins. Though some proteins participating in signaling are coded in nuclear DNA, most of the mitochondrial proteins are encoded by the separate mitochondrial DNA (mtDNA). For a range of reasons, mtDNA is inherited by the maternal line and is relatively well conserved. The mitochondrial genome (DNA present in mitochondria) is much smaller than one in the cell’s nucleus – only about 16,000 base pairs and is described as a compact circular genetic system, which encodes 13 energy production-related proteins. Initially mitochondrial transcriptome (a product of genome expression, all RNA molecules derived from genes) was perceived as relatively simple. But in reality, it is a highly complex system involving many elements, such as small RNAs and a range of small open reading frames (sORFs), that only recently were described (10). The open reading frame (ORF) is a part of DNA between a start-codon (codon is a nucleotide triplet), where the translation of a protein starts, and a stop-codon, where it ends. sORFs are the particular subtype of ORFs having 100 codons or less. They are frequently overlooked or misannotated during the gene description and were initially dismissed as non-functional or junk DNA (11). However, the latest research shows that in multiple organisms, sORFs are important sources of multiple peptides that are involved, among other processes, in muscle performance regulation (12), organ growth and development (13,14), and cardiac calcium uptake (15).
What are mitochondrial peptides?
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by the abovementioned sORF in mtDNA. Interestingly, each of the corresponding sORFs was discovered using in silico bioinformatics methods. At the moment, only eight MDPs have been discovered, but each of them has demonstrated some cyto- or metaboloprotective properties. Seven of these MDPs – humanin and small humanin-like peptides (SHLP) 1 to 6 – are encoded by the 16S ribosomal RNA gene. The eighth peptide – mitochondrial ORF of the 12S rRNA type-c (MOTS-c) – as follows from its name is encoded by the 12S RNA gene (16).
Humanin was found to enhance cellular protection (17,18) and improve patients’ condition after Alzheimer’s disease-related cellular insults (19). SHLPs regulate mitochondrial and cellular health and functions and have cytoprotective properties (20). The specific biological functions of all other SHLPs are still being studied (21).
However, the MDP that attracted the most attention due to its effect on age-related conditions is MOTS-c. Discovered and described by Lee et al. (22), MOTS-c was found to participate in multiple age-related pathways. It targets skeletal muscle metabolism via the AMPK (adenosine monophosphate-activated protein kinase) pathway and mediates the mitochondrial regulation of insulin and metabolic homeostasis. In healthy organisms, secretion of MOTS-c is induced by exercise, and its levels (as other MDPs’) lower with age (23). In the initial experiments on mice, Lee et al. discovered that MOTS-c protects against age- and diet-dependent insulin resistance and obesity.
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CohBar clinical trials
MOTS-c discovery and its promising properties in 2009 inspired the creation of CohBar – a clinical-stage biotechnology company with a US$9.2 million budget (24), whose research is focused on mitochondria-based therapies. Through their proprietary in-silico Mito+ platform, CohBar identifies and develops peptides that can be used as potential human therapeutics (25).
Based on the previous research, CohBar developed an analog of MOTS-c peptide, called CB4211. CB4211 aims to treat obesity and nonalcoholic steatohepatitis (NASH, an age-related pathological condition of liver fat accumulation). As the company states, compared to MOTS-c, CB4211 has an improved activity, safety, and producibility. Testing CB4211 in preclinical mice models (26) demonstrated that its administration reduces free fatty acids in adipocytes. In mice NASH model, CB4211 led to reducing signs of steatohepatitis, and in obese mice, it produced significant and sustained weight loss. No body weight loss occurred in healthy mice. Further studies of CB4211 mechanism of action (27) showed that it participates in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. CB4211 activity is insulin-dependent and observed only at intermediate concentrations. It was shown that CB4211 participates in insulin receptor signaling, and its acute administration of CB4211 enhances insulin sensitivity in vivo.
In 2018 CohBar announced Phase 1 trials for an analog of MOTS-c peptide, called CB4211. In August 2021, CohBar announced positive results from their Phase 1a/1b study of CB4211 (28). Phase 1b of the trial was a randomized, placebo-controlled, multi-center clinical study conducted for four weeks in 20 obese subjects with fatty liver disease. Initial CB4211 dose selection was performed in single and 7-day multiple ascending dose cohorts in 65 healthy adults (29). The study showed that CB4211 was well-tolerated and appeared safe with no serious adverse effects. Generally mild to moderate injections site reactions were the only treatment related adverse effect. Notably, phase 1b demonstrated a significant reduction in key biomarkers of liver damage, a significant decrease in glucose levels, and a trend towards lower body weight after the course of treatment compared to placebo. The absolute reduction in liver fat content was, however, comparable between CB4211 and placebo groups. This follows the previosly suggested mechanism of action that CB4211 selectively extends the duration of insulin receptor activation, thus regulating fatty acids metabolisms, glucose homeostasis, and insulin sensitivity.
Currently, CohBar works on moving CB4211 to phase 2 clinical study and develops several more drug candidates, such as CB5138-3 peptide that showed promising results against pulmonary fibrosis and other fibrotic conditions in a preclinical experiment. Clinical trials for CB5138-3 are planned for 2022. Other drug candidates include CB5064 for acute respiratory distress syndrome and CB5046 for cancer treatment.
Conclusions
MDPs are a powerful intervention able to improve many age-related pathological conditions significantly. Though discovered relatively recently, these compounds greatly enhanced our understanding of mitochondria’s functions and intervention possibilities. As the clinical trials are still in their early stages, probably these interventions will take some more time before they enter the routine clinical practice. However, the preliminary results on the safety and efficacy of MDPs give hope for further auspicious development of anti-aging science.
References
1. Houtkooper RH, Argmann C, Houten SM, Cantó C, Jeninga EH, Andreux PA, et al. The metabolic footprint of aging in mice. Sci Rep. 2011 Dec;1(1):134.
2. Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006 Feb;5(1):91–116.
3. Durieux J, Wolff S, Dillin A. The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity. Cell. 2011 Jan;144(1):79–91.
4. Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011 Mar;12(3):222–30.
5. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014 May;19(5):757–66.
6. Sena LA, Chandel NS. Physiological Roles of Mitochondrial Reactive Oxygen Species. Mol Cell. 2012 Oct;48(2):158–67.
7. Hur JH, Cho J, Walker DW. Aging: Dial M for Mitochondria. Aging. 2010 Jan 26;2(1):69–73.
8. Jang JY, Blum A, Liu J, Finkel T. The role of mitochondria in aging. J Clin Invest. 2018 Aug 31;128(9):3662–70.
9. Thomas RR, Khan SM, Smigrodzki RM, Onyango IG, Dennis J, Khan OM, et al. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging. 2012 Sep 30;4(9):620–35.
10. Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood A-MJ, et al. The Human Mitochondrial Transcriptome. Cell. 2011 Aug;146(4):645–58.
11. Guerra-Almeida D, Nunes-da-Fonseca R. Small Open Reading Frames: How Important Are They for Molecular Evolution? Front Genet. 2020 Oct 20;11:574737.
12. Anderson DM, Anderson KM, Chang C-L, Makarewich CA, Nelson BR, McAnally JR, et al. A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance. Cell. 2015 Feb;160(4):595–606.
13. Vassallo A, Palazzotto E, Renzone G, Botta L, Faddetta T, Scaloni A, et al. The Streptomyces coelicolor Small ORF trpM Stimulates Growth and Morphological Development and Exerts Opposite Effects on Actinorhodin and Calcium-Dependent Antibiotic Production. Front Microbiol. 2020 Feb 19;11:224.
14. Pueyo JI, Couso JP. The 11-aminoacid long Tarsal-less peptides trigger a cell signal in Drosophila leg development. Dev Biol. 2008 Dec;324(2):192–201.
15. Magny EG, Pueyo JI, Pearl FMG, Cespedes MA, Niven JE, Bishop SA, et al. Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames. Science. 2013 Sep 6;341(6150):1116–20.
16. Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumagai H, Kim S-J, et al. Mitochondrial-derived peptides in energy metabolism. Am J Physiol-Endocrinol Metab. 2020 Oct 1;319(4):E659–66.
17. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May;423(6938):456–61.
18. Ikonen M, Liu B, Hashimoto Y, Ma L, Lee K-W, Niikura T, et al. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci. 2003 Oct 28;100(22):13042–7.
19. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and A. Proc Natl Acad Sci. 2001 May 22;98(11):6336–41.
20. Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging. 2016 Apr 10;8(4):796–809.
21. Nashine S, Kenney MC. Effects of Mitochondrial-Derived Peptides (MDPs) on Mitochondrial and Cellular Health in AMD. Cells. 2020 Apr 29;9(5):1102.
22. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metab. 2015 Mar;21(3):443–54.
23. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021 Dec;12(1):470.
24. de Magalhães JP, Stevens M, Thornton D. The Business of Anti-Aging Science. Trends Biotechnol. 2017 Nov;35(11):1062–73.
25. CohBar: About [Internet]. 2022 [cited 2022 Nov 2]. Available from: https://www.cohbar.com/about
26. Cundy K. et al. CB4209 and CB4211 Reduce the NAFLD Activity Score in the STAM Model of NASH, Reduce Triglyceride Levels, and Induce Selective Fat Mass Loss in DIO Mice. AASLD The Liver Meeting. 2017.
27. Grindstaff K. et al. CB4211 is a Potential Treatment for Metabolic Diseases with a Novel Mechanism of Action: Sensitization of the Insulin Receptor. ADA Conference. 2018.
26. CohBar: CB4211 [Internet]. 2022 [cited 2022 Nov 2]. Available from: https://www.cohbar.com/programs-pipelines/cb4211
29. Loomba R. CB4211, a Novel Analog of MOTS-c, Improves Markers of Liver Injury and Metabolism in Obese Subjects with Nonalcoholic Fatty Liver Disease: a Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. AASLD The Liver Meeting. 2021.
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Highlights:
- Functions of mitochondria reach far beyond producing energy for a cell
- Mitochondrial DNA encodes a range of proteins and peptides with important biological functions
- Among eight identified mitochondrial peptides, MOTS-c attracted particular attention due to its ability to reduce obesity and insulin resistance
- CohBar company created a synthetic analog for MOTS-c for the treatment of obesity and nonalcoholic steatohepatitis (NASH), which is now in stage 2a of clinical trials
Introduction
Multiple interventions have been shown to increase lifespan in short-lived model organisms, such as yeast, worms, flies, mice, and others. More importantly, such interventions also increase a healthspan by delaying the onset of age-related diseases. These pharmacological, dietary, and genetic breakthroughs boosted the development of geroscience and gave rise to hope that these findings could be used to delay or slow human aging.
Many potential strategies have been identified on this quest, including modulation of common pathways and processes like insulin and TOR signaling. One of the recently emerged promising strategies is improving mitochondrial functions via mitochondrial peptides to fight aging.
The hidden life of mitochondria
One of the most repeated lines in biology is that “mitochondria is a powerhouse of a cell”. Though they are indeed heavily involved in cell energy production, mitochondria’s functions are not limited to that. Mitochondria have been shown to participate in signaling within and between cells, metabolism and immune system regulation, cell cycle control, cell growth, and death (apoptosis). Recent research shows that mitochondria, among other things, participate in several known signaling pathways interacting with various molecules such as reactive oxygen species (ROS), calcium ions (Ca2+), and cytochrome C (1,2). Further evidence consistently emerges of the importance of mitochondrial signaling in critical processes, such as stress resistance, inflammation, and aging (3–5). Even self-produced mitochondrial ROS, initially thought to be carrying only damaging function, were rediscovered as a key communication method between cell and mitochondria that regulates homeostasis and normal cellular function (6). Currently, mitochondria are considered as playing a major role in aging and age-related diseases (7,8). For example, in aged mice, an improvement of mitochondrial function has been shown to ameliorate age-related memory loss (9).
The ability of mitochondria to convey all these functions is reached through a range of peptides and proteins. Though some proteins participating in signaling are coded in nuclear DNA, most of the mitochondrial proteins are encoded by the separate mitochondrial DNA (mtDNA). For a range of reasons, mtDNA is inherited by the maternal line and is relatively well conserved. The mitochondrial genome (DNA present in mitochondria) is much smaller than one in the cell’s nucleus – only about 16,000 base pairs and is described as a compact circular genetic system, which encodes 13 energy production-related proteins. Initially mitochondrial transcriptome (a product of genome expression, all RNA molecules derived from genes) was perceived as relatively simple. But in reality, it is a highly complex system involving many elements, such as small RNAs and a range of small open reading frames (sORFs), that only recently were described (10). The open reading frame (ORF) is a part of DNA between a start-codon (codon is a nucleotide triplet), where the translation of a protein starts, and a stop-codon, where it ends. sORFs are the particular subtype of ORFs having 100 codons or less. They are frequently overlooked or misannotated during the gene description and were initially dismissed as non-functional or junk DNA (11). However, the latest research shows that in multiple organisms, sORFs are important sources of multiple peptides that are involved, among other processes, in muscle performance regulation (12), organ growth and development (13,14), and cardiac calcium uptake (15).
What are mitochondrial peptides?
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by the abovementioned sORF in mtDNA. Interestingly, each of the corresponding sORFs was discovered using in silico bioinformatics methods. At the moment, only eight MDPs have been discovered, but each of them has demonstrated some cyto- or metaboloprotective properties. Seven of these MDPs – humanin and small humanin-like peptides (SHLP) 1 to 6 – are encoded by the 16S ribosomal RNA gene. The eighth peptide – mitochondrial ORF of the 12S rRNA type-c (MOTS-c) – as follows from its name is encoded by the 12S RNA gene (16).
Humanin was found to enhance cellular protection (17,18) and improve patients’ condition after Alzheimer’s disease-related cellular insults (19). SHLPs regulate mitochondrial and cellular health and functions and have cytoprotective properties (20). The specific biological functions of all other SHLPs are still being studied (21).
However, the MDP that attracted the most attention due to its effect on age-related conditions is MOTS-c. Discovered and described by Lee et al. (22), MOTS-c was found to participate in multiple age-related pathways. It targets skeletal muscle metabolism via the AMPK (adenosine monophosphate-activated protein kinase) pathway and mediates the mitochondrial regulation of insulin and metabolic homeostasis. In healthy organisms, secretion of MOTS-c is induced by exercise, and its levels (as other MDPs’) lower with age (23). In the initial experiments on mice, Lee et al. discovered that MOTS-c protects against age- and diet-dependent insulin resistance and obesity.
CohBar clinical trials
MOTS-c discovery and its promising properties in 2009 inspired the creation of CohBar – a clinical-stage biotechnology company with a US$9.2 million budget (24), whose research is focused on mitochondria-based therapies. Through their proprietary in-silico Mito+ platform, CohBar identifies and develops peptides that can be used as potential human therapeutics (25).
Based on the previous research, CohBar developed an analog of MOTS-c peptide, called CB4211. CB4211 aims to treat obesity and nonalcoholic steatohepatitis (NASH, an age-related pathological condition of liver fat accumulation). As the company states, compared to MOTS-c, CB4211 has an improved activity, safety, and producibility. Testing CB4211 in preclinical mice models (26) demonstrated that its administration reduces free fatty acids in adipocytes. In mice NASH model, CB4211 led to reducing signs of steatohepatitis, and in obese mice, it produced significant and sustained weight loss. No body weight loss occurred in healthy mice. Further studies of CB4211 mechanism of action (27) showed that it participates in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. CB4211 activity is insulin-dependent and observed only at intermediate concentrations. It was shown that CB4211 participates in insulin receptor signaling, and its acute administration of CB4211 enhances insulin sensitivity in vivo.
In 2018 CohBar announced Phase 1 trials for an analog of MOTS-c peptide, called CB4211. In August 2021, CohBar announced positive results from their Phase 1a/1b study of CB4211 (28). Phase 1b of the trial was a randomized, placebo-controlled, multi-center clinical study conducted for four weeks in 20 obese subjects with fatty liver disease. Initial CB4211 dose selection was performed in single and 7-day multiple ascending dose cohorts in 65 healthy adults (29). The study showed that CB4211 was well-tolerated and appeared safe with no serious adverse effects. Generally mild to moderate injections site reactions were the only treatment related adverse effect. Notably, phase 1b demonstrated a significant reduction in key biomarkers of liver damage, a significant decrease in glucose levels, and a trend towards lower body weight after the course of treatment compared to placebo. The absolute reduction in liver fat content was, however, comparable between CB4211 and placebo groups. This follows the previosly suggested mechanism of action that CB4211 selectively extends the duration of insulin receptor activation, thus regulating fatty acids metabolisms, glucose homeostasis, and insulin sensitivity.
Currently, CohBar works on moving CB4211 to phase 2 clinical study and develops several more drug candidates, such as CB5138-3 peptide that showed promising results against pulmonary fibrosis and other fibrotic conditions in a preclinical experiment. Clinical trials for CB5138-3 are planned for 2022. Other drug candidates include CB5064 for acute respiratory distress syndrome and CB5046 for cancer treatment.
Conclusions
MDPs are a powerful intervention able to improve many age-related pathological conditions significantly. Though discovered relatively recently, these compounds greatly enhanced our understanding of mitochondria’s functions and intervention possibilities. As the clinical trials are still in their early stages, probably these interventions will take some more time before they enter the routine clinical practice. However, the preliminary results on the safety and efficacy of MDPs give hope for further auspicious development of anti-aging science.
References
1. Houtkooper RH, Argmann C, Houten SM, Cantó C, Jeninga EH, Andreux PA, et al. The metabolic footprint of aging in mice. Sci Rep. 2011 Dec;1(1):134.
2. Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006 Feb;5(1):91–116.
3. Durieux J, Wolff S, Dillin A. The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity. Cell. 2011 Jan;144(1):79–91.
4. Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011 Mar;12(3):222–30.
5. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014 May;19(5):757–66.
6. Sena LA, Chandel NS. Physiological Roles of Mitochondrial Reactive Oxygen Species. Mol Cell. 2012 Oct;48(2):158–67.
7. Hur JH, Cho J, Walker DW. Aging: Dial M for Mitochondria. Aging. 2010 Jan 26;2(1):69–73.
8. Jang JY, Blum A, Liu J, Finkel T. The role of mitochondria in aging. J Clin Invest. 2018 Aug 31;128(9):3662–70.
9. Thomas RR, Khan SM, Smigrodzki RM, Onyango IG, Dennis J, Khan OM, et al. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging. 2012 Sep 30;4(9):620–35.
10. Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood A-MJ, et al. The Human Mitochondrial Transcriptome. Cell. 2011 Aug;146(4):645–58.
11. Guerra-Almeida D, Nunes-da-Fonseca R. Small Open Reading Frames: How Important Are They for Molecular Evolution? Front Genet. 2020 Oct 20;11:574737.
12. Anderson DM, Anderson KM, Chang C-L, Makarewich CA, Nelson BR, McAnally JR, et al. A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance. Cell. 2015 Feb;160(4):595–606.
13. Vassallo A, Palazzotto E, Renzone G, Botta L, Faddetta T, Scaloni A, et al. The Streptomyces coelicolor Small ORF trpM Stimulates Growth and Morphological Development and Exerts Opposite Effects on Actinorhodin and Calcium-Dependent Antibiotic Production. Front Microbiol. 2020 Feb 19;11:224.
14. Pueyo JI, Couso JP. The 11-aminoacid long Tarsal-less peptides trigger a cell signal in Drosophila leg development. Dev Biol. 2008 Dec;324(2):192–201.
15. Magny EG, Pueyo JI, Pearl FMG, Cespedes MA, Niven JE, Bishop SA, et al. Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames. Science. 2013 Sep 6;341(6150):1116–20.
16. Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumagai H, Kim S-J, et al. Mitochondrial-derived peptides in energy metabolism. Am J Physiol-Endocrinol Metab. 2020 Oct 1;319(4):E659–66.
17. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May;423(6938):456–61.
18. Ikonen M, Liu B, Hashimoto Y, Ma L, Lee K-W, Niikura T, et al. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci. 2003 Oct 28;100(22):13042–7.
19. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and A. Proc Natl Acad Sci. 2001 May 22;98(11):6336–41.
20. Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging. 2016 Apr 10;8(4):796–809.
21. Nashine S, Kenney MC. Effects of Mitochondrial-Derived Peptides (MDPs) on Mitochondrial and Cellular Health in AMD. Cells. 2020 Apr 29;9(5):1102.
22. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metab. 2015 Mar;21(3):443–54.
23. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021 Dec;12(1):470.
24. de Magalhães JP, Stevens M, Thornton D. The Business of Anti-Aging Science. Trends Biotechnol. 2017 Nov;35(11):1062–73.
25. CohBar: About [Internet]. 2022 [cited 2022 Nov 2]. Available from: https://www.cohbar.com/about
26. Cundy K. et al. CB4209 and CB4211 Reduce the NAFLD Activity Score in the STAM Model of NASH, Reduce Triglyceride Levels, and Induce Selective Fat Mass Loss in DIO Mice. AASLD The Liver Meeting. 2017.
27. Grindstaff K. et al. CB4211 is a Potential Treatment for Metabolic Diseases with a Novel Mechanism of Action: Sensitization of the Insulin Receptor. ADA Conference. 2018.
26. CohBar: CB4211 [Internet]. 2022 [cited 2022 Nov 2]. Available from: https://www.cohbar.com/programs-pipelines/cb4211
29. Loomba R. CB4211, a Novel Analog of MOTS-c, Improves Markers of Liver Injury and Metabolism in Obese Subjects with Nonalcoholic Fatty Liver Disease: a Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. AASLD The Liver Meeting. 2021.
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
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Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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