Humanin: 7+ Ways To Increase Mitochondria's IGF-1

Humanin's Role In Longevity, Alzheimer's And Cancer

 
 https://www.ncbi.nlm.nih.gov/pubmed/28574175

https://www.ncbi.nlm.nih.gov/pubmed/28574175

 

The term Humanin (HN) was coined by its discoverer, Professor Nishimoto, to denote the potential of this molecule to restore the “humanity” of patients with Alzheimer’s disease. R

Later we have found humanin protects cells from oxidative stress, serum starvation, hypoxia, and other insults as well as also improves cardiovascular disease and Alzheimer's Disease. R R

Contents:

  1. Basics Of Humanin And Mitochondrial-Derived Peptides
  2. Humanin Levels
  3. Benefits Of Humanin
  4. How To Increase Humanin
  5. What Reduces Humanin?
  6. Caveats
  7. Mechanism Of Action
  8. Humanin Peptide Substitutions
  9. Genetics
  10. More Research

Basics Of Humanin And Mitochondrial-Derived Peptides

Mitochondria are thought to have come from bacteria that synergistically fused as an organelle in our cells for better energy utilization. R 

During this process, mitochondria lost a large amount of of their DNA (as it was necessary for survival), but held onto very important "doppleganger" sequences in DNA to encode Mitochondrial-Derived Peptides (MDPs). R R

MDPs are important for communication and homeostasis of mitochondrial and cellular processes by acting on Mitochondrial-Associated Membranes (MAMs). R 

MAMs are important because they regulate lipid metabolism, mitochondrial actions, calcium homeostasis, and cell death.  R

Humanin (HN) is a prominent MDP that plays a huge role in signaling and regulating MAMs between mitochondria and the Endoplasmic Reticulum (ER). R

Humanin Levels

HN levels are generally lower in men than women (not statistically significant). R

Low Humanin Levels:

  • Aging (may reduce humanin levels by 50%)
  • Alzheimer's Disease
  • Diabetes
  • Insulin Resistance 
  • Mitochondrial Dysfunction
  • Stress Response (in general) R
  • Vascular Dysfunction
  • Vision Loss

High Humanin Levels:

  • Pre-Eclampsia
  • Some Cancers

Benefits Of Humanin

1. Improves Mitochondrial Function

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319229/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319229/

 

Mitochondria are highly susceptible to oxidative stress (such as Reactive Oxygen Species, aka ROS). R

Humaninin (HN) directly inhibits oxidative stress on the mitochondrial membrane, thus protecting mitochondria from dying. R

HN inhibits Cytochrome C release from mitochondria and can increase their production of energy (ATP). R R

HN improves mitochondrial levels of Glutathione (GSH) as well. R

HN can also prevent Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) by directly increasing cellular ATP levels in lymphocytes. R

Humanin also induces Mitochondrial Biogenesis (growth of new mitochondria). R

2. Protects Cells From Dying

HN can also protect cells from oxidative stress. R R

HN improves cell survival by binding to and inhibiting by Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) and Bcl2-Associated X protein (Bax). R R

HN can also promote cell survival by binding to and deactivating proapoptotic BH3 proteins Truncated Form of Bid (tBid) and Extra Long Isoform of Bim (BimEL). R R

3. May Enhance Longevity

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961574/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961574/

 

Growth Hormone (GH) negatively regulates HN levels. R

For example, mice that were unable to produce adequate amounts of GH had higher amounts of HN and lived longer than normal mice. R

Children of centenarians have 3x higher levels of HN than controls. R

HN can act as a Calorie-Restriction Mimetic (CRM) by suppressing Insulin-Like Growth Factor 1 (IGF-1) levels. R

HN has very similar actions to IGF-1 (see section above): R

  • Activate  ERK1/2
  • Activate JAK2-STAT3
  • Activate PI3K/Akt (helps with stroke)
  • Cardioprotective
  • Controls cell death, metabolism, and transcription
  • Degrading Atherosclerotic Plaques
  • Enhance Brain Aβ Clearance
  • Enhancing Insulin Sensitivity
  • Found in Mitochondria, plasma, cells, skeletal muscle, liver, fat, and hypothalamus
  • Lowering Inflammation
  • Inhibiting Cell death
  • Suppressing Hypoxia

Although, HN and IGF-1 do have opposite effects on longevity and cancer growth, and both show a decline in expression with aging. R

For example, HN protects against cell senescence (biological aging of a cell). R

4. Ameliorates Alzehiemer's Disease And Improves Short-Term Memory

HN can protect brain cells against Amyloid-Beta (AB)-induced cell death and increase clearance AB levels, a common pathology seen Alzheimer's Disease (AD). R R R

HN can also protect the brain against Tau Hyperphosphorylation (a pathology of AD). R

For example, HN can protect against Okadaic Acid (OA), a toxin extracted from marine life that causes tau hyperphosphorylation. R

HN may improve memory.

For example, HN can also reverse Long-Term Potentiation (LTP) loss from AB, in important mechanism used to form memory. R

HN can also prevent memory loss from other Anticholinergic drugs. R

For example, scopolamine, a Muscarinic Acetylcholine Receptor (mAChR) antagonist, can cause short-term memory loss and is a standard in testing AD animal models. R

A modified version of HN called Humanin G (HNG) can reverse the short-term memory loss from scopolamine. R

This modification (HNG) has shown to increase the neuroprotective effects of HN by 1000-fold. R

HNG taken intranasally can reduces AB accumulation and ameliorates memory deficit in AD animal models. R

HN may protect against Insulin Resistance (IR) in the brain, a main pathology of Type 3 Alzheimer's/Diabetes. R R

For example, by stimulating STAT3 and inhibiting IGFBP3 in the hypothalamus, HN is a powerful insulin sensitizer and may help with IR in AD. R R R

In the hippocampus, HNG can improve Autophagy by regulating IRS-1/mTOR signaling. R

HN also provides neuroprotection against some Familial Alzheimer's Disease (FAD) genes including presenilin 1, presenilin 2, and mutated Amyloid Precursor Protein (APP). R R

HN also binds to the receptor for Ciliary Neurotrophic Factor (CNTF), which is an important for neurodegenerative diseases, spinal cord injuries, retinal degeneration, autoimmune neuroinflammation and obesity-related metabolic diseases. R

5. Combats Proteopathy, Neuroinflammation, And Excitotoxicity

In the Endoplasmic Reticulum (ER), ROS causes a calcium efflux leading to Proteopathy (toxic unfolded/misfolded protein aggregates). R 

HN protects against proteopathy in 2 ways:

  1. HN can inhibit ROS formation R
  2. HN can inhibit calcium release in the ER R

For example, HN can protect against prion-proteopathy. R

HN also protects against Lipopolysaccharide-induced (Endotoxemia) neuroinflammation. R

HN also protects against excitotoxicity (both via action on NMDARs and independently). R

For example, HN can prevent Reactive Oxygen Species (ROS) and Nitric Oxide (NO) induced excitotoxicity caused by the overactivation of the NMDA receptors. R

HN can also reduce Lactate-Dehydrogenase (LDH) in the brain. R

6. Protects Against Insulin Resistance

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873641/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873641/

 

HN can inhibit pancreatic beta-cell death and improve Glucose tolerance in non-obese diabetic (NOD) animal models. R

This may be beneficial for both Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). R R

By acting on the hypothalamus, HN can also increase Insulin sensitivity in the liver and stabilize blood glucose levels. R

HN may be a good biomarker for fasting glucose-related oxidative stress. R

HNG acutely increases Triglyceride (TG) secretion from the liver. R

    7. Combats Obesity And Weight Gain

    HN can prevent weight gain by increasing glucose stimulated insulin release and decreasing body Weight Gain and visceral fat. R R

    8. Protects The Eyes

    Age-related Macular Degeneration (AMD) is caused degeneration of the retina from oxidative stress resulting in irreversible vision loss. R

    The ER of mitochondria play a huge role in protecting the Retinal Pigment Epithelium (RPE) in AMD. R

    HN and HNG both prevent AMD as it can protect against oxidative stress and cell death of the RPE and ER by increasing mitochondrial GSH levels and reducing ROS, Caspase 3 and Caspase 4 levels. R R

    9. May Fight Spinocerebellar Ataxia And Huntington's Disease

    Spinocerebellar Ataxia (SA) and Huntington's Disease (HD) are characterized by Polyglutamine (PolyQ) toxicity. R

    HN can prevent PolyQ-induced mitochondrial dysfunction. R

    10. May Help With Amyotrophic Lateral Sclerosis

    HN may help Familial Amyotrophic Lateral Sclerosis (ALS).

    For example, animal models with mutations in G93A-SOD1, HN dose-dependently improved motor performance and prolonged survival of ALS mice. R

    11. May Protect Against Sunburn

    HN can protect against Ultraviolet (UV)-induced cell death. R

    12. Protects The Vascular System

    HN levels have been shown to be high in patients with atherosclerotic plaques and may protect against atherosclerosis. R

    For example, in animal models that were unable to express APOE (an important protein for cholesterol metabolism), HNG was able to improve cardiovascular function from a high cholesterol diet (reducing plaque ~90%). R

    HN can protect HN cells from cells from oxidative stress induced by Oxidized LDL (oxLDL). R R

    By increasing AMPK and eNOS, during a heart attack HNG can protect against damage induced by left coronary occlusion, reducing infarct size and oxidative stress. R

    13. Protects Against Hypoxia And Ischemia

    HN can attenuate the stresses caused by hypoxia and ischemia.

    By activating PI3K/Akt and Jak2/Stat3, HNG is neuroprotective during hypoxia. R R

    For example, HN can protect against cellular hypoxia induced by Compound Cobalt Chloride (CoCl₂). R

    Cuprizone (CPZ), a copper chelator, provokes demyelination and schizophrenia-like symptoms. R

    HN can suppress neuroinflammation and cognitive deficits from CPZ use. R

    HN has shown to induce axonal remyelination in hypoxic brains. R

    A major problem from ischemia is loss of blood flow which results in the reduction of growth factors, and thus cell death.

    HN can prevent cell death from ischemia and improve hypoxic cell's ability to create energy (ATP). R R

    HN may also be beneficial in a Traumatic Brain Injury (TBI), as HN can protect against ischemic and hemorrhagic stroke-induced damage.  R R

    For example, in animal models, HNG was able to reduce infarct volume size by 50%. R

    One reason why HNG may protect against TBI is by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). R

    14. Protects The Colon

    In experimental models of Ulcerative Colitis (UC), HNG can protect against inflammation in the colon and ameliorate weight loss. R

    15. Protects The Kidneys From Inflammation

    HN can protect the kidneys from inflammation. R

    For example, in APOE deficient mice, HN was able to protect against the development of kidney disease. R

    16. Protects Male Reproductive System

    HN is present at all stages of testicle development. R

    HN can protect against testicular and sperm cells from death. R R 

    17. Relieves Anxiety

     
     https://www.ncbi.nlm.nih.gov/pubmed/27475912

    https://www.ncbi.nlm.nih.gov/pubmed/27475912

     

     HN can prevent diazepam-induced memory impairment as well as act as an anxiolytic (anti-anxiety) agent. R

    By acting on Formyl Peptide Receptor 2 (FPR2), HN may improve anxiety. R

    18. Prevents Chemotherapy-Induced Damage

     
     https://academic.oup.com/jnci/article/106/3/dju006/1745551

    https://academic.oup.com/jnci/article/106/3/dju006/1745551

     

    HN protects white blood cells from chemotherapy-induced damage. R

    HNG prevents bortezomib-induced bone growth impairment in anticancer treatment. R

    HN can protect sperm cells from chemotherapy-induced cell death. R

    How To Increase Humanin

    Lifestyle/Diet:

    • Exercise - Resistance training increases HN in skeletal muscle R
    • Fasting - Suppresses IGF1 and increases HN R
    • Hyperbaric Chamber - Hyperoxia increases HN R

    Supplements:

    • B Vitamins - Increase HN levels, especially in those with higher homocysteine R
    • Zinc - binds to HN R

    Drugs/Chemicals:

    • Humanin G (HNG, replaced serine 14 for a glycine residue, 1000x stronger than HN), see other analogues below R

    Pathways:

    • Calmodulin-Like Skin Protein (CLSP) R

    What Reduces Humanin?

    These reduce HN levels:

    • Aging - reduces HN in the hypothalamus and muscles R
    • GH or IGF1 - HN is reduced in mice and humans treated with GH or IGF-1 R
    • H2O2 - reduces Rattin, a rat homolog of HN R
    • TRIM11 R
    • VSTM2L R

    Caveats

    Cancer

    HN has both positive and negatives in cancer.

    HNG can enhance chemotherapy-induced suppression of cancer metastases. R

    HN may contribute to cancers such as: 

    • Bladder Cancer R
    • Pituitary Cancer R R
    • Prostate Cancer R

    Lowering HN expression may be beneficial in some cancers. R

    Pregnancy

    High HN levels have been seen in women with Pre-Eclampsia (high blood pressure during pregnancy). R

    This may relate to high levels of oxidative stress. R

    Mechanism Of Action

     
     https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641182/

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641182/

     

    Simple:

    • Increases AKT R
    • Increases AMPK R
    • Increases Angiostatin R
    • Increases Apollon/Bruce R
    • Increases ATP R
    • Increases Bcl-2 R
    • Increases CNTF R
    • Increases eNOS R
    • Increases FPR2 R
    • Increases FPR3 R R
    • Increases GCLC R
    • Increases GSH R
    • Increases Jak2 R
    • Increases MCL-1 R
    • Increases PIK3 R
    • Increases SH3BP5 R
    • Increases SOCS3 R
    • Increases SOD R
    • Increases STAT3 R R R
    • Increases TSP-1 R
    • Reduces AB R
    • Reduces Angiopoietin-1 R
    • Reduces Bax3 R
    • Reduces BimEL R
    • Reduces Caspase-3 R R
    • Reduces Caspase-4 R
    • Reduces ERK (increases in hippocampus) R R
    • Reduces IGF-1 R
    • Reduces IGFBP-3 R
    • Reduces IL-1b R
    • Reduces IL-6 R
    • Reduces IRS-1 R
    • Reduces LDH R
    • Reduces MCP-1 R
    • Reduces mTOR R
    • Reduces Osteopontin R
    • Reduces ROS R
    • Reduces tBid R
    • Reduces TNF-a R R

    Advanced:

    • HN is expressed endogenously by several cells and tissues in the body such as cardiomyocytes, RPE cells, brain, colon, testis, heart, kidney, skeletal muscle, and liver. R
    • HN is a 24-amino acid peptide with rapid tissue clearance resulting in a very short half-life. R
    • ER Ca2+ channels, including the IP3Rs and the mitochondrial voltage-dependent anion channel, are rich in MAMs, which could facilitate Ca2+ flow between ER and mitochondria. R
    • In the ER, HN increases GSH inhibits caspase 4 and CCAAT-enhancer-binding protein homologous protein (CHOP) preventing RPE apoptosis. R
    • Humanin directly affects mitochondrial bioenergetics by increasing basal OCR, maximum respiration, respiration capacity, and ATP production in retinal pigment epithelial (hRPE) cells. R
    • HN exerts its function through binding to both extracellular receptors and intracellular binding partners.
    • Humanin has been shown to act as a ligand to two different types of receptors; the seven-transmembrane, G-protein-coupled receptor formyl-peptide receptor-like-1 (FPRL1), and a trimeric receptor consisting of ciliary neurotrophic factor receptor (CNTFR), the cytokine receptor WSX-1 and the transmembrane glycoprotein gp130 (CNTFR/WSX-1/gp130). R
    • HN acts to rescue the NMDA-mediated toxicity in primary hippocampal neurons through its interaction with the domains-4 and -5 (D4-D5) of the gp130 receptor. R
    • HN can block IGFBP3-induced apoptosis in glial cell lines but not in neuronal cell lines or primary neurons... although IGFBP3 and HN have a positive/synergistic effect on protecting neurons from amyloid-β-induced apoptosis. R
    • HN binding to IGFBP-3 (via importin-beta) affects the bioactivity of IGF-1 by increasing clearance without hindering IGFBP-3/IGF-1 binding and reduces circulating levels of IGFBP-3 and IGF-1. R R
    • Chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology. R
    • HNG offers neuroprotection from stroke at least in part by inhibiting ERK activation. R
    • In neuronal cells, HN increases SH3 domain-binding protein 5 (SH3BP5) which binds to JNK and directly inhibits JNK through its two putative mitogen-activated protein kinase interaction motifs (KIMs). R
    • HNG can improve the learning ability and memory by decreasing IRS-1 Ser636 phosphorylation and mTOR protein expression in the hippocampus, thus improving insulin resistance in the brain. R
    • HNG in the heart increases AMPK and eNOS. R
    • HN acts on α-actinin-4, having some role in kidney function. R
    • HN treatment induces the dimerization between CNTFR and WSX-1 as well as the dimerization between WSX-1 and gp130. R
    • HN initially induces the dimerization between WSX-1 and CNTFR and then induces the hetero-trimerization of CNTFR/WSX-1/gp130. R
    • Overexpression of CNTFR and/or WSX-1 results in enhanced HN binding to neuronal cells. R
    • HN interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. R

    Humanin Peptide Substitutions

    Structure of HN peptide and role of individual amino acids:

     
     https://www.frontiersin.org/articles/10.3389/fendo.2014.00210/full

    https://www.frontiersin.org/articles/10.3389/fendo.2014.00210/full

     

    Genetics

    MT-RNR2

    rs2854128 (I'm A)

    • G Alleles - have more humanin levels in mitochondria R
    • A Alleles - less likely to have coronary calcium R
    • C Alleles - specific for the Northeast Asian population, may be among the putative biological mechanisms explaining the high longevity of Japanese people R

    More Research

    • Pseudogenization of the Humanin gene is common in the mitochondrial DNA of many vertebrates. R