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Humanin is a 21 or 24 amino acid peptide that is encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2^[1]. Humanin was independently discovered by three labs looking at Alzheimer’s disease, apoptosis, and IGF-1 signaling^[2]^[3]^[4]. Experiments using cultured cells have demonstrated that humanin has both neuroprotective as well as cytoprotective effects and experiments in rodents have found that it has protective effects in Alzheimer’s disease models, Huntington’s disease models and stroke models (reviewed in ^[5] ).

Discovery

Humanin was independently found by three different labs looking at different parameters. The first to publish was the Nishimoto lab in 2001 where they found humanin while looking for possible proteins that could protect cells from amyloid beta, a major component of Alzheimer’s disease^[6]. The Reed lab found humanin in a screen looking for proteins that could interact with Bcl-2-associated X protein (Bax), a major protein involved in apoptosis^[7]. The Cohen lab (Pinchas Cohen) independently discovered humanin when screening for proteins that interact with IGFBP3^[8].

Protective Effects

Humanin is proposed to have a myriad of neuroprotective and cytoprotective effects. Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in Alzheimer's disease models^[9]^[10] . In addition to Alzheimer’s disease, humanin has other neuroprotective effects against models of Huntington’s disease, prion disease, and stroke^[11]^[12]^[13]. Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack^[14]^[15]^[16]^[17]. Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with type 1 diabetes^[18], and increases insulin sensitivity, which may help with type 2 diabetes^[19].

Mechanism of Action

The beneficial effects of humanin have been proposed to have several different modes of action. Extracellular interaction with a tripartite receptor composed of gp130, WSX1, and CNTFR, as well as interaction with the formylpeptide-like-1 receptor have been published^[20]^[21]. Intracellular interaction with BAX, tBID, IGFBP3, and TRIM11 may also be required for the effects of humanin^[22]^[23]^[24]^[25].

References

^ Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Yen, K (2013 Feb). "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of molecular endocrinology. 50 (1): R11-9. PMID 23239898. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Tajima, H (2005 Mar 1). "A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice". Journal of neuroscience research. 79 (5): 714–23. PMID 15678515. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hashimoto, Y (2001 Dec 1). "Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults". The Journal of neuroscience : the official journal of the Society for Neuroscience. 21 (23): 9235–45. PMID 11717357. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Kariya, S (2005). "Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches". Journal of molecular neuroscience : MN. 25 (2): 165–9. PMID 15784964. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Sponne, I (2004 Jan). "Humanin rescues cortical neurons from prion-peptide-induced apoptosis". Molecular and cellular neurosciences. 25 (1): 95–102. PMID 14962743. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Xu, X (2006 Oct). "Humanin is a novel neuroprotective agent against stroke". Stroke; a journal of cerebral circulation. 37 (10): 2613–9. PMID 16960089. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Bachar, AR (2010 Nov 1). "Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress". Cardiovascular research. 88 (2): 360–6. PMID 20562421. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Oh, YK (2011 Nov). "Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice". Atherosclerosis. 219 (1): 65–73. PMID 21763658. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Zacharias, DG (2012). "Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans". PloS one. 7 (2): e31065. PMID 22328926. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Muzumdar, RH (2010 Oct). "Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice". Arteriosclerosis, thrombosis, and vascular biology. 30 (10): 1940–8. PMID 20651283. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hoang, PT (2010 Mar). "The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice". Metabolism: clinical and experimental. 59 (3): 343–9. PMID 19800083. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Muzumdar, RH (2009 Jul 22). "Humanin: a novel central regulator of peripheral insulin action". PloS one. 4 (7): e6334. PMID 19623253. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hashimoto, Y (2009 Jun). "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130". Molecular biology of the cell. 20 (12): 2864–73. PMID 19386761. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ying, G (2004 Jun 1). "Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor". Journal of immunology (Baltimore, Md. : 1950). 172 (11): 7078–85. PMID 15153530. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Zhai, D (2005 Apr 22). "Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak". The Journal of biological chemistry. 280 (16): 15815–24. PMID 15661737. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Niikura, T (2003 Mar). "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults". The European journal of neuroscience. 17 (6): 1150–8. PMID 12670303. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[1] Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[2] Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[3] Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[4] Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[5] Yen, K (2013 Feb). "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of molecular endocrinology. 50 (1): R11-9. PMID 23239898. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[6] Hashimoto, Y (2001 May 22). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41. PMID 11371646. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[7] Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[8] Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[9] Tajima, H (2005 Mar 1). "A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice". Journal of neuroscience research. 79 (5): 714–23. PMID 15678515. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[10] Hashimoto, Y (2001 Dec 1). "Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults". The Journal of neuroscience : the official journal of the Society for Neuroscience. 21 (23): 9235–45. PMID 11717357. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[11] Kariya, S (2005). "Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches". Journal of molecular neuroscience : MN. 25 (2): 165–9. PMID 15784964. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[12] Sponne, I (2004 Jan). "Humanin rescues cortical neurons from prion-peptide-induced apoptosis". Molecular and cellular neurosciences. 25 (1): 95–102. PMID 14962743. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[13] Xu, X (2006 Oct). "Humanin is a novel neuroprotective agent against stroke". Stroke; a journal of cerebral circulation. 37 (10): 2613–9. PMID 16960089. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[14] Bachar, AR (2010 Nov 1). "Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress". Cardiovascular research. 88 (2): 360–6. PMID 20562421. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[15] Oh, YK (2011 Nov). "Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice". Atherosclerosis. 219 (1): 65–73. PMID 21763658. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[16] Zacharias, DG (2012). "Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans". PloS one. 7 (2): e31065. PMID 22328926. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[17] Muzumdar, RH (2010 Oct). "Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice". Arteriosclerosis, thrombosis, and vascular biology. 30 (10): 1940–8. PMID 20651283. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[18] Hoang, PT (2010 Mar). "The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice". Metabolism: clinical and experimental. 59 (3): 343–9. PMID 19800083. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[19] Muzumdar, RH (2009 Jul 22). "Humanin: a novel central regulator of peripheral insulin action". PloS one. 4 (7): e6334. PMID 19623253. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[20] Hashimoto, Y (2009 Jun). "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130". Molecular biology of the cell. 20 (12): 2864–73. PMID 19386761. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[21] Ying, G (2004 Jun 1). "Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor". Journal of immunology (Baltimore, Md. : 1950). 172 (11): 7078–85. PMID 15153530. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[22] Zhai, D (2005 Apr 22). "Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak". The Journal of biological chemistry. 280 (16): 15815–24. PMID 15661737. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[23] Ikonen, M (2003 Oct 28). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7. PMID 14561895. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[24] Guo, B (2003 May 22). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61. PMID 12732850. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[25] Niikura, T (2003 Mar). "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults". The European journal of neuroscience. 17 (6): 1150–8. PMID 12670303. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

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 ==Discovery==
-Humanin was independently found by three different labs looking at different parameters.  The first to publish was the Nishimoto lab in 2001 where they found humanin while looking for possible proteins that could protect cells from [[amyloid beta]], a major component of [[Alzheimer’s disease]]<ref>{{cite journal|last=Hashimoto|first=Y|coauthors=Niikura, T; Tajima, H; Yasukawa, T; Sudo, H; Ito, Y; Kita, Y; Kawasumi, M; Kouyama, K; Doyu, M; Sobue, G; Koide, T; Tsuji, S; Lang, J; Kurokawa, K; Nishimoto, I|title=A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2001 May 22|volume=98|issue=11|pages=6336-41|pmid=11371646}}</ref>.  The Reed lab found humanin in a screen looking for proteins that could interact with [[Bcl-2-associated X protein]] (Bax), a major protein involved in [[apoptosis]]<ref>{{cite journal|last=Guo|first=B|coauthors=Zhai, D; Cabezas, E; Welsh, K; Nouraini, S; Satterthwait, AC; Reed, JC|title=Humanin peptide suppresses apoptosis by interfering with Bax activation.|journal=Nature|date=2003 May 22|volume=423|issue=6938|pages=456-61|pmid=12732850}}</ref>.  The Cohen lab independently discovered humanin when screening for proteins that interact with [[IGFBP3]]<ref>{{cite journal|last=Ikonen|first=M|coauthors=Liu, B; Hashimoto, Y; Ma, L; Lee, KW; Niikura, T; Nishimoto, I; Cohen, P|title=Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2003 Oct 28|volume=100|issue=22|pages=13042-7|pmid=14561895}}</ref>.
+Humanin was independently found by three different labs looking at different parameters.  The first to publish was the Nishimoto lab in 2001 where they found humanin while looking for possible proteins that could protect cells from [[amyloid beta]], a major component of [[Alzheimer’s disease]]<ref>{{cite journal|last=Hashimoto|first=Y|coauthors=Niikura, T; Tajima, H; Yasukawa, T; Sudo, H; Ito, Y; Kita, Y; Kawasumi, M; Kouyama, K; Doyu, M; Sobue, G; Koide, T; Tsuji, S; Lang, J; Kurokawa, K; Nishimoto, I|title=A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2001 May 22|volume=98|issue=11|pages=6336-41|pmid=11371646}}</ref>.  The Reed lab found humanin in a screen looking for proteins that could interact with [[Bcl-2-associated X protein]] (Bax), a major protein involved in [[apoptosis]]<ref>{{cite journal|last=Guo|first=B|coauthors=Zhai, D; Cabezas, E; Welsh, K; Nouraini, S; Satterthwait, AC; Reed, JC|title=Humanin peptide suppresses apoptosis by interfering with Bax activation.|journal=Nature|date=2003 May 22|volume=423|issue=6938|pages=456-61|pmid=12732850}}</ref>.  The Cohen lab ([[Pinchas Cohen]]) independently discovered humanin when screening for proteins that interact with [[IGFBP3]]<ref>{{cite journal|last=Ikonen|first=M|coauthors=Liu, B; Hashimoto, Y; Ma, L; Lee, KW; Niikura, T; Nishimoto, I; Cohen, P|title=Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2003 Oct 28|volume=100|issue=22|pages=13042-7|pmid=14561895}}</ref>.
 ==Protective Effects==
 Humanin is proposed to have a myriad of neuroprotective and cytoprotective effects.  Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in [[Alzheimer's disease]] models<ref>{{cite journal|last=Tajima|first=H|coauthors=Kawasumi, M; Chiba, T; Yamada, M; Yamashita, K; Nawa, M; Kita, Y; Kouyama, K; Aiso, S; Matsuoka, M; Niikura, T; Nishimoto, I|title=A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice.|journal=Journal of neuroscience research|date=2005 Mar 1|volume=79|issue=5|pages=714-23|pmid=15678515}}</ref><ref>{{cite journal|last=Hashimoto|first=Y|coauthors=Niikura, T; Ito, Y; Sudo, H; Hata, M; Arakawa, E; Abe, Y; Kita, Y; Nishimoto, I|title=Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults.|journal=The Journal of neuroscience : the official journal of the Society for Neuroscience|date=2001 Dec 1|volume=21|issue=23|pages=9235-45|pmid=11717357}}</ref> .  In addition to [[Alzheimer’s disease]], humanin has other neuroprotective effects against models of [[Huntington’s disease]], [[prion disease]], and [[stroke]]<ref>{{cite journal|last=Kariya|first=S|coauthors=Hirano, M; Nagai, Y; Furiya, Y; Fujikake, N; Toda, T; Ueno, S|title=Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches.|journal=Journal of molecular neuroscience : MN|date=2005|volume=25|issue=2|pages=165-9|pmid=15784964}}</ref><ref>{{cite journal|last=Sponne|first=I|coauthors=Fifre, A; Koziel, V; Kriem, B; Oster, T; Pillot, T|title=Humanin rescues cortical neurons from prion-peptide-induced apoptosis.|journal=Molecular and cellular neurosciences|date=2004 Jan|volume=25|issue=1|pages=95-102|pmid=14962743}}</ref><ref>{{cite journal|last=Xu|first=X|coauthors=Chua, CC; Gao, J; Hamdy, RC; Chua, BH|title=Humanin is a novel neuroprotective agent against stroke.|journal=Stroke; a journal of cerebral circulation|date=2006 Oct|volume=37|issue=10|pages=2613-9|pmid=16960089}}</ref>.  Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack<ref>{{cite journal|last=Bachar|first=AR|coauthors=Scheffer, L; Schroeder, AS; Nakamura, HK; Cobb, LJ; Oh, YK; Lerman, LO; Pagano, RE; Cohen, P; Lerman, A|title=Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress.|journal=Cardiovascular research|date=2010 Nov 1|volume=88|issue=2|pages=360-6|pmid=20562421}}</ref><ref>{{cite journal|last=Oh|first=YK|coauthors=Bachar, AR; Zacharias, DG; Kim, SG; Wan, J; Cobb, LJ; Lerman, LO; Cohen, P; Lerman, A|title=Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice.|journal=Atherosclerosis|date=2011 Nov|volume=219|issue=1|pages=65-73|pmid=21763658}}</ref><ref>{{cite journal|last=Zacharias|first=DG|coauthors=Kim, SG; Massat, AE; Bachar, AR; Oh, YK; Herrmann, J; Rodriguez-Porcel, M; Cohen, P; Lerman, LO; Lerman, A|title=Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans.|journal=PloS one|date=2012|volume=7|issue=2|pages=e31065|pmid=22328926}}</ref><ref>{{cite journal|last=Muzumdar|first=RH|coauthors=Huffman, DM; Calvert, JW; Jha, S; Weinberg, Y; Cui, L; Nemkal, A; Atzmon, G; Klein, L; Gundewar, S; Ji, SY; Lavu, M; Predmore, BL; Lefer, DJ|title=Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.|journal=Arteriosclerosis, thrombosis, and vascular biology|date=2010 Oct|volume=30|issue=10|pages=1940-8|pmid=20651283}}</ref>.
+Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with [[type 1 diabetes]]<ref>{{cite journal|last=Hoang|first=PT|coauthors=Park, P; Cobb, LJ; Paharkova-Vatchkova, V; Hakimi, M; Cohen, P; Lee, KW|title=The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice.|journal=Metabolism: clinical and experimental|date=2010 Mar|volume=59|issue=3|pages=343-9|pmid=19800083}}</ref>, and increases insulin sensitivity, which may help with [[type 2 diabetes]]<ref>{{cite journal|last=Muzumdar|first=RH|coauthors=Huffman, DM; Atzmon, G; Buettner, C; Cobb, LJ; Fishman, S; Budagov, T; Cui, L; Einstein, FH; Poduval, A; Hwang, D; Barzilai, N; Cohen, P|title=Humanin: a novel central regulator of peripheral insulin action.|journal=PloS one|date=2009 Jul 22|volume=4|issue=7|pages=e6334|pmid=19623253}}</ref>.
 ==Mechanism of Action==
 The beneficial effects of humanin have been proposed to have several different modes of action.   Extracellular interaction with a tripartite receptor composed of gp130, WSX1, and CNTFR, as well as interaction with the formylpeptide-like-1 receptor have been published<ref>{{cite journal|last=Hashimoto|first=Y|coauthors=Kurita, M; Aiso, S; Nishimoto, I; Matsuoka, M|title=Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130.|journal=Molecular biology of the cell|date=2009 Jun|volume=20|issue=12|pages=2864-73|pmid=19386761}}</ref><ref>{{cite journal|last=Ying|first=G|coauthors=Iribarren, P; Zhou, Y; Gong, W; Zhang, N; Yu, ZX; Le, Y; Cui, Y; Wang, JM|title=Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor.|journal=Journal of immunology (Baltimore, Md. : 1950)|date=2004 Jun 1|volume=172|issue=11|pages=7078-85|pmid=15153530}}</ref>.  Intracellular interaction with BAX, tBID, IGFBP3, and TRIM11 may also be required for the effects of humanin<ref>{{cite journal|last=Zhai|first=D|coauthors=Luciano, F; Zhu, X; Guo, B; Satterthwait, AC; Reed, JC|title=Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak.|journal=The Journal of biological chemistry|date=2005 Apr 22|volume=280|issue=16|pages=15815-24|pmid=15661737}}</ref><ref>{{cite journal|last=Ikonen|first=M|coauthors=Liu, B; Hashimoto, Y; Ma, L; Lee, KW; Niikura, T; Nishimoto, I; Cohen, P|title=Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=2003 Oct 28|volume=100|issue=22|pages=13042-7|pmid=14561895}}</ref><ref>{{cite journal|last=Guo|first=B|coauthors=Zhai, D; Cabezas, E; Welsh, K; Nouraini, S; Satterthwait, AC; Reed, JC|title=Humanin peptide suppresses apoptosis by interfering with Bax activation.|journal=Nature|date=2003 May 22|volume=423|issue=6938|pages=456-61|pmid=12732850}}</ref><ref>{{cite journal|last=Niikura|first=T|coauthors=Hashimoto, Y; Tajima, H; Ishizaka, M; Yamagishi, Y; Kawasumi, M; Nawa, M; Terashita, K; Aiso, S; Nishimoto, I|title=A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults.|journal=The European journal of neuroscience|date=2003 Mar|volume=17|issue=6|pages=1150-8|pmid=12670303}}</ref>.