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Pinchas Cohen - One of the best experts on this subject based on the ideXlab platform.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment
Metabolomics, 2019Co-Authors: Hemal H. Mehta, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Pinchas CohenAbstract:Introduction The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. Objectives By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Methods Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. Results HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. Conclusions The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment.
Metabolomics : Official journal of the Metabolomic Society, 2019Co-Authors: Hemal H. Mehta, Su-jeong Kim, Pinchas Cohen, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Kelvin YenAbstract:The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Chronic treatment with the mitochondrial peptide Humanin prevents age-related myocardial fibrosis in mice.
American journal of physiology. Heart and circulatory physiology, 2018Co-Authors: Qing Qin, Kelvin Yen, Hemal H. Mehta, Gerardo Navarrete, Sebastian Brandhorst, Junxiang Wan, Lilach O. Lerman, Silvia Delrio, Xin Zhang, Pinchas CohenAbstract:Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and...
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the mitochondrial derived peptide Humanin activates the erk1 2 akt and stat3 signaling pathways and has age dependent signaling differences in the hippocampus
Oncotarget, 2016Co-Authors: Su-jeong Kim, Hemal H. Mehta, Noel Guerrero, Pinchas Cohen, Gabriella Wassef, Jialin Xiao, Kelvin YenAbstract:// Su-Jeong Kim 1 , Noel Guerrero 1 , Gabriella Wassef 1 , Jialin Xiao 1 , Hemal H. Mehta 1 , Pinchas Cohen 1 and Kelvin Yen 1 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA Correspondence to: Kelvin Yen, email: // Keywords : Humanin, ERK1/2, AKT, STAT3, signaling pathway, Gerotarget Received : April 22, 2016 Accepted : June 20, 2016 Published : July 01, 2016 Abstract Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer’s disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the Humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that Humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with Humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of Humanin that is important for Humanin’s function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.
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the mitochondrial derived peptide Humanin activates the erk1 2 akt and stat3 signaling pathways and has age dependent signaling differences in the hippocampus
Oncotarget, 2016Co-Authors: Su-jeong Kim, Hemal H. Mehta, Noel Guerrero, Pinchas Cohen, Gabriella Wassef, Jialin Xiao, Kelvin YenAbstract:Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the Humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that Humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with Humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of Humanin that is important for Humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.
Kelvin Yen - One of the best experts on this subject based on the ideXlab platform.
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The mitochondrial derived peptide Humanin is a regulator of lifespan and healthspan.
Aging, 2020Co-Authors: Kelvin Yen, Hemal H. Mehta, Su-jeong Kim, Yanhe Lue, James Hoang, Noel Guerrero, Jenna Port, Gerardo Navarrete, Sebastian BrandhorstAbstract:Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of Humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous Humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent Humanin analogue HNG, Humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, Humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating Humanin levels are much greater than age-matched control subjects. Further linking Humanin to healthspan, we observe that Humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that Humanin is linked to improved healthspan and increased lifespan.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment.
Metabolomics : Official journal of the Metabolomic Society, 2019Co-Authors: Hemal H. Mehta, Su-jeong Kim, Pinchas Cohen, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Kelvin YenAbstract:The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.
Scientific reports, 2018Co-Authors: Kelvin Yen, Hemal H. Mehta, Sebastian Brandhorst, Junxiang Wan, Jialin Xiao, Brendan Miller, Amy Christensen, Morgan E. Levine, Matthew P. Salomon, Su-jeong KimAbstract:Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that Humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that Humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the Humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating Humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that Humanin is an important factor in cognitive aging.
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Chronic treatment with the mitochondrial peptide Humanin prevents age-related myocardial fibrosis in mice.
American journal of physiology. Heart and circulatory physiology, 2018Co-Authors: Qing Qin, Kelvin Yen, Hemal H. Mehta, Gerardo Navarrete, Sebastian Brandhorst, Junxiang Wan, Lilach O. Lerman, Silvia Delrio, Xin Zhang, Pinchas CohenAbstract:Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and...
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the mitochondrial derived peptide Humanin activates the erk1 2 akt and stat3 signaling pathways and has age dependent signaling differences in the hippocampus
Oncotarget, 2016Co-Authors: Su-jeong Kim, Hemal H. Mehta, Noel Guerrero, Pinchas Cohen, Gabriella Wassef, Jialin Xiao, Kelvin YenAbstract:Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the Humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that Humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with Humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of Humanin that is important for Humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.
Masaaki Matsuoka - One of the best experts on this subject based on the ideXlab platform.
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Apollon/Bruce is upregulated by Humanin.
Molecular and cellular biochemistry, 2014Co-Authors: Yuichi Hashimoto, Yuji Takeshita, Hiroyuki Uchino, Mikihiko Naito, Masaaki MatsuokaAbstract:Humanin, a short bioactive peptide, inhibits a variety of cell deaths. Humanin-mediated inhibition of neuronal cell death, caused by an Alzheimer's disease (AD)-linked mutant gene occurs via binding of Humanin to its heterotrimeric Humanin receptor (htHNR), which results in the activation of the Janus-associated kinases (JAKs) and signal transducer and activator and transcription 3 (STAT3) signaling pathway. A previous study demonstrated that the Humanin-induced activation of the htHNR/JAK2/STAT3 signaling pathway leads to increased expression of SH3 domain-binding protein 5 (SH3BP5), which is an essential effector of Humanin's anti-cell death activity in some cultured neuronal cells. However, it remains unknown whether SH3BP5 is the sole effector of the Humanin signaling pathway via htHNR/JAKs/STAT3. Here we show that the Humanin signaling pathway via htHNR/JAKs/STAT3 increased the expression levels of mRNA and protein of Apollon/Bruce, an unusual member of the inhibitors of apoptosis proteins, and that overexpression of Apollon/Bruce inhibits neuronal death, caused by a London-type familial AD-linked mutant (V642I) of amyloid β precursor protein. Overall, the results indicate that expression of Apollon/Bruce is upregulated by Humanin, and Apollon/Bruce could be an effector of Humanin in a context-dependent manner.
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Protective Effects of Humanin and Calmodulin-Like Skin Protein in Alzheimer’s Disease and Broad Range of Abnormalities
Molecular neurobiology, 2014Co-Authors: Masaaki MatsuokaAbstract:Humanin is a 24-amino acid, secreted bioactive peptide that prevents various types of cell death and improves some types of cell dysfunction. Humanin inhibits neuronal cell death that is caused by a familial Alzheimer’s disease (AD)-linked gene via binding to the heterotrimeric Humanin receptor (htHNR). This suggests that Humanin may play a protective role in AD-related pathogenesis. Calmodulin-like skin protein (CLSP) has recently been identified as a physiological agonist of htHNR with 105-fold more potent anti-cell death activity than Humanin. Humanin has also shown to have protective effects against some metabolic disorders. In this review, the broad range of functions of Humanin and the functions of CLSP that have been characterized thus far are summarized.
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sh3 binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide Humanin by inhibiting c jun nh2 terminal kinase
Journal of Biological Chemistry, 2013Co-Authors: Yuji Takeshita, Mikiro Nawa, Yuichi Hashimoto, Hiroyuki Uchino, Masaaki MatsuokaAbstract:Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined. In the present study, Humanin increased the mRNA and protein expression of SH3 domain-binding protein 5 (SH3BP5), which has been known to be a JNK interactor, in neuronal cells. Similar to Humanin treatment, overexpression of SH3BP5 inhibited AD-related neuronal death, while siRNA-mediated knockdown of endogenous SH3BP5 expression attenuated the neuroprotective effect of Humanin. These results indicate that SH3BP5 is a downstream effector of Humanin. Furthermore, biochemical analysis has revealed that SH3BP5 binds to JNK and directly inhibits JNK through its two putative mitogen-activated protein kinase interaction motifs (KIMs).
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Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor.
Cell death & disease, 2013Co-Authors: Yuichi Hashimoto, Mikiro Nawa, M Kurita, M Tokizawa, A Iwamatsu, Masaaki MatsuokaAbstract:Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer’s disease models via the heterotrimeric Humanin receptor
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Humanin signal for Alzheimer's disease.
Journal of Alzheimer's Disease, 2011Co-Authors: Masaaki MatsuokaAbstract:Despite a bulk of evidence supporting the idea that increased neurotoxic insults lead to Alzheimer's disease (AD), the possibility still remains that insufficiency of an endogenous defense system contributes to the disease progression. Humanin is a bioactive peptide that is likely to inhibit both neuronal death and dysfunction only related to AD by binding to a Humanin receptor on the cell-surface and by activating a STAT3-mediated signal, preventing the onset of dementia. A couple of recent studies presented evidence suggesting that the Humanin signal is decreased in neurons of AD patients. If this is the case, the restoration or activation of the Humanin signal in neurons may change the course of AD.
Hemal H. Mehta - One of the best experts on this subject based on the ideXlab platform.
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The mitochondrial derived peptide Humanin is a regulator of lifespan and healthspan.
Aging, 2020Co-Authors: Kelvin Yen, Hemal H. Mehta, Su-jeong Kim, Yanhe Lue, James Hoang, Noel Guerrero, Jenna Port, Gerardo Navarrete, Sebastian BrandhorstAbstract:Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of Humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous Humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent Humanin analogue HNG, Humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, Humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating Humanin levels are much greater than age-matched control subjects. Further linking Humanin to healthspan, we observe that Humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that Humanin is linked to improved healthspan and increased lifespan.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment
Metabolomics, 2019Co-Authors: Hemal H. Mehta, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Pinchas CohenAbstract:Introduction The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. Objectives By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Methods Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. Results HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. Conclusions The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment.
Metabolomics : Official journal of the Metabolomic Society, 2019Co-Authors: Hemal H. Mehta, Su-jeong Kim, Pinchas Cohen, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Kelvin YenAbstract:The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.
Scientific reports, 2018Co-Authors: Kelvin Yen, Hemal H. Mehta, Sebastian Brandhorst, Junxiang Wan, Jialin Xiao, Brendan Miller, Amy Christensen, Morgan E. Levine, Matthew P. Salomon, Su-jeong KimAbstract:Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that Humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that Humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the Humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating Humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that Humanin is an important factor in cognitive aging.
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Chronic treatment with the mitochondrial peptide Humanin prevents age-related myocardial fibrosis in mice.
American journal of physiology. Heart and circulatory physiology, 2018Co-Authors: Qing Qin, Kelvin Yen, Hemal H. Mehta, Gerardo Navarrete, Sebastian Brandhorst, Junxiang Wan, Lilach O. Lerman, Silvia Delrio, Xin Zhang, Pinchas CohenAbstract:Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and...
Su-jeong Kim - One of the best experts on this subject based on the ideXlab platform.
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The mitochondrial derived peptide Humanin is a regulator of lifespan and healthspan.
Aging, 2020Co-Authors: Kelvin Yen, Hemal H. Mehta, Su-jeong Kim, Yanhe Lue, James Hoang, Noel Guerrero, Jenna Port, Gerardo Navarrete, Sebastian BrandhorstAbstract:Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of Humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous Humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent Humanin analogue HNG, Humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, Humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating Humanin levels are much greater than age-matched control subjects. Further linking Humanin to healthspan, we observe that Humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that Humanin is linked to improved healthspan and increased lifespan.
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Metabolomic profile of diet-induced obesity mice in response to Humanin and small Humanin-like peptide 2 treatment.
Metabolomics : Official journal of the Metabolomic Society, 2019Co-Authors: Hemal H. Mehta, Su-jeong Kim, Pinchas Cohen, Jialin Xiao, Brendan Miller, Ricardo Ramirez, Kelvin YenAbstract:The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both Humanin and small-Humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to Humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either Humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. The present study indicates that Humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of Humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for Humanin and SHLP2 treatment.
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Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.
Scientific reports, 2018Co-Authors: Kelvin Yen, Hemal H. Mehta, Sebastian Brandhorst, Junxiang Wan, Jialin Xiao, Brendan Miller, Amy Christensen, Morgan E. Levine, Matthew P. Salomon, Su-jeong KimAbstract:Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that Humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that Humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the Humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating Humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that Humanin is an important factor in cognitive aging.
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the mitochondrial derived peptide Humanin activates the erk1 2 akt and stat3 signaling pathways and has age dependent signaling differences in the hippocampus
Oncotarget, 2016Co-Authors: Su-jeong Kim, Hemal H. Mehta, Noel Guerrero, Pinchas Cohen, Gabriella Wassef, Jialin Xiao, Kelvin YenAbstract:Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the Humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that Humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with Humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of Humanin that is important for Humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.
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the mitochondrial derived peptide Humanin activates the erk1 2 akt and stat3 signaling pathways and has age dependent signaling differences in the hippocampus
Oncotarget, 2016Co-Authors: Su-jeong Kim, Hemal H. Mehta, Noel Guerrero, Pinchas Cohen, Gabriella Wassef, Jialin Xiao, Kelvin YenAbstract:// Su-Jeong Kim 1 , Noel Guerrero 1 , Gabriella Wassef 1 , Jialin Xiao 1 , Hemal H. Mehta 1 , Pinchas Cohen 1 and Kelvin Yen 1 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA Correspondence to: Kelvin Yen, email: // Keywords : Humanin, ERK1/2, AKT, STAT3, signaling pathway, Gerotarget Received : April 22, 2016 Accepted : June 20, 2016 Published : July 01, 2016 Abstract Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer’s disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the Humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that Humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with Humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of Humanin that is important for Humanin’s function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.