SOD: the longevity Enzyme

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O2) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage.[2] Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive (O2).

Contents

External linksChemical reaction[edit]

SODs catalyze the disproportionation of superoxide:

2 HO2 → O2 + H2O2

In this way, O2 is converted into two less damaging species.

The pathway by which SOD-catalyzed dismutation of superoxide may be written, for Cu,Zn SOD, with the following reactions :

  • Cu2+-SOD + O2 → Cu+-SOD + O2 (reduction of copper; oxidation of superoxide)
  • Cu+-SOD + O2 + 2H+ → Cu2+-SOD + H2O2 (oxidation of copper; reduction of superoxide)

The general form, applicable to all the different metal-coordinated forms of SOD, can be written as follows:

  • M(n+1)+-SOD + O2 → Mn+-SOD + O2
  • Mn+-SOD + O2 + 2H+ → M(n+1)+-SOD + H2O2.

where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2).

In a series of such reactions, the oxidation state and the charge of the metal cation oscillates between n and n+1: +1 and +2 for Cu, or +2 and +3 for the other metals .

Types[edit]

General[edit]

Irwin Fridovich and Joe McCord at Duke University discovered the enzymatic activity of superoxide dismutase in 1968.[3] SODs were previously known as a group of metalloproteins with unknown function; for example, CuZnSOD was known as erythrocuprein (or hemocuprein, or cytocuprein) or as the veterinary anti-inflammatory drug “Orgotein”.[4] Likewise, Brewer (1967) identified a protein that later became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique.[5]

There are three major families of superoxide dismutase, depending on the protein fold and the metal cofactor: the Cu/Zn type (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and the Ni type (which binds nickel).

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Ribbon diagram of bovine Cu-Zn SOD subunit[6]

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Active site of Human Manganese SOD, manganese shown in purple[7]

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Mn-SOD vs Fe-SOD dimers

  • Copper and zinc – most commonly used by eukaryotes, including humans. The cytosols of virtually all eukaryotic cells contain an SOD enzyme with copper and zinc (Cu-Zn-SOD). For example, Cu-Zn-SOD available commercially is normally purified from bovine red blood cells. The bovine Cu-Zn enzyme is a homodimer of molecular weight 32,500. It was the first SOD whose atomic-detail crystal structure was solved, in 1975.[8] It is an 8-stranded “Greek key” beta-barrel, with the active site held between the barrel and two surface loops. The two subunits are tightly joined back-to-back, mostly by hydrophobic and some electrostatic interactions. The ligands of the copper and zinc are six histidine and one aspartate side-chains; one histidine is bound between the two metals.[9]
  • pastedGraphic_3.png

    Active site for iron superoxide dismutase

    Iron or manganese – used by prokaryotes and protists, and in mitochondria and chloroplasts

    • Iron – Many bacteria contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some (such as E. coli) contain both. Fe-SOD can also be found in the chloroplasts of plants. The 3D structures of the homologous Mn and Fe superoxide dismutases have the same arrangement of alpha-helices, and their active sites contain the same type and arrangement of amino acid side-chains. They are usually dimers, but occasionally tetramers.
    • Manganese – Nearly all mitochondria, and many bacteria, contain a form with manganese (Mn-SOD): For example, the Mn-SOD found in human mitochondria. The ligands of the manganese ions are 3 histidine side-chains, an aspartate side-chain and a water molecule or hydroxy ligand, depending on the Mn oxidation state (respectively II and III).[10]
  • Nickel – prokaryotic. This has a hexameric (6-copy) structure built from right-handed 4-helix bundles, each containing N-terminal hooks that chelate a Ni ion. The Ni-hook contains the motif His-Cys-X-X-Pro-Cys-Gly-X-Tyr; it provides most of the interactions critical for metal binding and catalysis and is, therefore, a likely diagnostic of NiSODs.[11][12]
Copper/zinc superoxide dismutase
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Yeast Cu,Zn superoxide dismutase dimer[13]

Identifiers
Symbol Sod_Cu
Pfam PF00080
InterPro IPR001424
PROSITE PDOC00082
SCOP 1sdy
SUPERFAMILY 1sdy
show

Available protein structures:

Iron/manganese superoxide dismutases, alpha-hairpin domain
pastedGraphic_5.png

Structure of domain1 (color), human mitochondrial Mn superoxide dismutase[10]

Identifiers
Symbol Sod_Fe_N
Pfam PF00081
InterPro IPR001189
PROSITE PDOC00083
SCOP 1n0j
SUPERFAMILY 1n0j

In higher plants, SOD isozymes have been localized in different cell compartments. Mn-SOD is present in mitochondria and peroxisomes. Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized in cytosol, chloroplasts, peroxisomes, and apoplast.[14][15]

Human[edit]

Three forms of superoxide dismutase are present in humans, in all other mammals, and most chordates. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. The first is a dimer (consists of two units), whereas the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, whereas SOD2, the mitochondrial enzyme, has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).

SOD1, soluble
pastedGraphic_6.png

Crystal structure of the human SOD1 enzyme (rainbow-color N-terminus = blue, C-terminus = red) complexed with copper (orange sphere) and zinc (grey sphere).[16]

Identifiers
Symbol SOD1
Alt. symbols ALS, ALS1
Entrez 6647
HUGO 11179
OMIM 147450
RefSeq NM_000454
UniProt P00441
Other data
EC number 1.15.1.1
Locus Chr. 21 q22.1
SOD2, mitochondrial
pastedGraphic_7.png

Active site of human mitochondrial Mn superoxide dismutase (SOD2).[1]

Identifiers
Symbol SOD2
Alt. symbols Mn-SOD; IPO-B; MVCD6
Entrez 6648
HUGO 11180
OMIM 147460
RefSeq NM_000636
UniProt P04179
Other data
EC number 1.15.1.1
Locus Chr. 6 q25
SOD3, extracellular
pastedGraphic_8.png

Crystallographic structure of the tetrameric human SOD3 enzyme (cartoon diagram) complexed with copper and zinc cations (orange and grey spheres respectively).[17]

Identifiers
Symbol SOD3
Alt. symbols EC-SOD; MGC20077
Entrez 6649
HUGO 11181
OMIM 185490
RefSeq NM_003102
UniProt P08294
Other data
EC number 1.15.1.1
Locus Chr. 4 pter-q21

Plants[edit]

In higher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by reactive oxygen species (ROS).[18] ROS can form as a result of drought, injury, herbicides and pesticides, ozone, plant metabolic activity, nutrient deficiencies, photoinhibition, temperature above and below ground, toxic metals, and UV or gamma rays.[19][20] To be specific, molecular O2 is reduced to O2 (a ROS called superoxide) when it absorbs an excited electron released from compounds of the electron transport chain. Superoxide is known to denature enzymes, oxidize lipids, and fragment DNA.[19] SODs catalyze the production of O2 and H2O2 from superoxide (O2), which results in less harmful reactants.

When acclimating to increased levels of oxidative stress, SOD concentrations typically increase with the degree of stress conditions. The compartmentalization of different forms of SOD throughout the plant makes them counteract stress very effectively. There are three well-known and -studied classes of SOD metallic coenzymes that exist in plants. First, Fe SODs consist of two species, one homodimer (containing 1-2 g Fe) and one tetramer (containing 2-4 g Fe). They are thought to be the most ancient SOD metalloenzymes and are found within both prokaryotes and eukaryotes. Fe SODs are most abundantly localized inside plant chloroplasts, where they are indigenous. Second, Mn SODs consist of a homodimer and homotetramer species each containing a single Mn(III) atom per subunit. They are found predominantly in mitochondrion and peroxisomes. Third, Cu-Zn SODs have electrical properties very different from those of the other two classes. These are concentrated in the chloroplast, cytosol, and in some cases the extracellular space. Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast.[18][19][20]

Bacteria[edit]

Human white blood cells use enzymes such as NADPH oxidase to generate superoxide and other reactive oxygen species to kill bacteria. During infection, some bacteria (e.g., Burkholderia pseudomallei) therefore produce superoxide dismutase to protect themselves from being killed.[21]

Biochemistry[edit]

SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity. The reaction of superoxide with non-radicals is spin-forbidden. In biological systems, this means that its main reactions are with itself (dismutation) or with another biological radical such as nitric oxide (NO) or with a transition-series metal. The superoxide anion radical (O2) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 M−1s−1 at pH 7).[citation needed] SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts with the NO radical, and makes toxic peroxynitrite.

Because the uncatalysed dismutation reaction for superoxide requires two superoxide molecules to react with each other, the dismutation rate is second-order with respect to initial superoxide concentration. Thus, the half-life of superoxide, although very short at high concentrations (e.g., 0.05 seconds at 0.1mM) is actually quite long at low concentrations (e.g., 14 hours at 0.1 nM). In contrast, the reaction of superoxide with SOD is first order with respect to superoxide concentration. Moreover, superoxide dismutase has the largest kcat/KM (an approximation of catalytic efficiency) of any known enzyme (~7 x 109 M−1s−1),[22] this reaction being limited only by the frequency of collision between itself and superoxide. That is, the reaction rate is “diffusion-limited”.

The high efficiency of superoxide dismutase seems necessary: even at the subnanomolar concentrations achieved by the high concentrations of SOD within cells, superoxide inactivates the citric acid cycle enzyme aconitase, can poison energy metabolism, and releases potentially toxic iron. Aconitase is one of several iron-sulfur-containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.[23]

Stability and folding mechanism[edit]

SOD1 is an extremely stable protein. In the holo form (both copper and zinc bound) the melting point is > 90°C. In the apo form (no copper or zinc bound) the melting point is ~ 60°C.[24] By differential scanning calorimetry (DSC), holo SOD1 unfolds by a two-state mechanism: from dimer to two unfolded monomers.[24] In chemical denaturation experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.[25]

Physiology[edit]

Superoxide is one of the main reactive oxygen species in the cell. As a consequence, SOD serves a key antioxidant role. The physiological importance of SODs is illustrated by the severe pathologies evident in mice genetically engineered to lack these enzymes. Mice lacking SOD2 die several days after birth, amid massive oxidative stress.[26] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,[27] an acceleration of age-related muscle mass loss,[28] an earlier incidence of cataracts, and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan, though they are more sensitive to hyperoxic injury.[29] Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating compounds, such as paraquat and diquat (herbicides).

Drosophila lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth.

SOD knockdowns in the worm C. elegans do not cause major physiological disruptions. However, the lifespan of C. elegans can be extended by superoxide/catalase mimetics suggesting that oxidative stress is a major determinant of the rate of aging.[30]

Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the budding yeast Saccharomyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. In wild-type S. cerevisiae, DNA damage rates increased 3-fold with age, but more than 5-fold in mutants deleted for either the SOD1 or SOD2 genes.[31] Reactive oxygen species levels increase with age in these mutant strains and show a similar pattern to the pattern of DNA damage increase with age. Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity during aging in S. cerevisiae. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.

In the fission yeast Schizosaccharomyces pombe, deficiency of mitochondrial superoxide dismutase SOD2 accelerates chronological aging.[32]

Several prokaryotic SOD null mutants have been generated, including E. coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics.

Role in disease[edit]

Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease).[33][34][35][36] The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality[26] and inactivation of SOD1 causes hepatocellular carcinoma.[27] Mutations in SOD1 can cause familial ALS (several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.),[37] by a mechanism that is presently not understood, but not due to loss of enzymatic activity or a decrease in the conformational stability of the SOD1 protein. Overexpression of SOD1 has been linked to the neural disorders seen in Down syndrome.[38] In patients with thalassemia, SOD will increase as a form of compensation mechanism. However, in the chronic stage, SOD does not seem to be sufficient and tends to decrease due to the destruction of proteins from the massive reaction of oxidant-antioxidant.[39]

In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension.[40][41] Diminished SOD3 activity has been linked to lung diseases such as Acute Respiratory Distress Syndrome (ARDS) or Chronic obstructive pulmonary disease (COPD).[42][43][44]

Superoxide dismutase is also not expressed in neural crest cells in the developing fetus. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).

A cross-sectional study in humans suggests that serum SOD could be a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function.[45]

Pharmacological activity[edit]

SOD has powerful antinflammatory activity. For example, SOD is a highly effective experimental treatment of chronic inflammation in colitis.[citation needed] Treatment with SOD decreases reactive oxygen species generation and oxidative stress and, thus, inhibits endothelial activation. Therefore, such antioxidants may be important new therapies for the treatment of inflammatory bowel disease.[46]

Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates cis-platinum-induced nephrotoxicity in rodents.[47] As “Orgotein” or “ontosein”, a pharmacologically-active purified bovine liver SOD, it is also effective in the treatment of urinary tract inflammatory disease in man.[48] For a time, bovine liver SOD even had regulatory approval in several European countries for such use. This was cut short by concerns about prion disease.[citation needed]

An SOD-mimetic agent, TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induced dermatitis.[49] TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.[50]

Cosmetic uses[edit]

SOD may reduce free radical damage to skin—for example, to reduce fibrosis following radiation for breast cancer. Studies of this kind must be regarded as tentative, however, as there were not adequate controls in the study including a lack of randomization, double-blinding, or placebo.[51] Superoxide dismutase is known to reverse fibrosis, possibly through de-differentiation of myofibroblasts back to fibroblasts.[52][further explanation needed]

Commercial sources[edit]

SOD is commercially obtained from marine phytoplankton, bovine liver, horseradish, cantaloupe, and certain bacteria. For therapeutic purpose, SOD is usually injected locally. There is no evidence that ingestion of unprotected SOD or SOD-rich foods can have any physiological effects, as all ingested SOD is broken down into amino acids before being absorbed. However, ingestion of SOD bound to wheat proteins could improve its therapeutic activity, at least in theory.[53]

See also[edit]

References[edit]

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External links[edit]

The Longevity Enzyme: Catalase

A group of investigators recently reported the results of a study demonstrating a 20% increase in life span in animals genetically engineered to produce an excess of the enzyme, catalase. Is there really one enzyme that can enable you to live longer? If so, how does it work? Can you pop it as a pill?

To answer these questions, let’s take a look at where the enzyme catalase comes from and how it operates. Our state of health – and indeed our longevity – depend on the vitality of the cells comprising the tissues and organs of the body. The cells, in turn, consist of numerous sub-cellular structures, organelles, which include the mitochondria. These minute cellular compartments are responsible for virtually all the energy the cell requires to keep the organs of the body healthy. They are in essence the heart of the cell. If they malfunction, the cell loses vitality, and consequently the organ it forms becomes diseased.

“Our state of health – and indeed our longevity – depend on the vitality of the cells comprising the tissues and organs of the body”

How and why do the mitochondria malfunction?
The mitochondria of our cells can be compared to nuclear reactors in that both involve the capture of energy from atoms and its transformation to a useable form. In the cell, energy is released and captured in a stable form (a chemical called ATP) that can be later used to perform work. During energy production in the mitochondria, electrons are removed from specific molecules (food metabolites). Occasionally, a single electron escapes from the confines of the energy-producing machinery during this process and reacts with molecular oxygen to produce a highly reactive free radical, the superoxide radical. This free radical, if not removed or neutralized, will damage the cell. The cell contains a specific enzyme, superoxide dismutase (SOD), that corrals the radical and converts it to hydrogen peroxide. However, the detoxification mission is not complete, since hydrogen peroxide can also be converted to toxic free radicals by reaction with certain common metals present in the cell. The cell has additional enzymes, including one known as catalase, capable of converting the hydrogen peroxide to harmless water and molecular oxygen.

There is evidence that although these two free radical detoxification enzymes (SOD and catalase) are present in the cell, their quantity may not be quite enough to eliminate all the free radical species before they damage cellular components. This mechanism is what inspired Denham Harman to propose one of the more popular theories of aging, the Free Radical Theory of Aging. As these escaped radicals react with and distort our cells, the organs they comprise begin to gradually deteriorate, resulting in age-associated appearance – wrinkles, for example – as well as disease.

Recent support for the Free Radical Theory of Aging
As mentioned at the outset, the investigators who studied catalase worked with animals that were genetically manipulated to produce excess catalase. Otherwise the animals were perfectly normal in all respects (relative to their non-genetically manipulated counterparts) except for two important features. First, they lived longer. Second, perhaps more importantly, they demonstrated an attenuation of the severity of age-associated diseases including, arteriosclerosis, cardiomyopathy, and cataracts.

The scientists carried the work a step further to determine if the excess catalase produced by these animals was, in fact, acting to protect important cellular components from free radical damage. The investigators showed that a key enzyme in the cell required for energy production by the mitochondria, and known to be susceptible to free radical attack by hydrogen peroxide radicals, was much more active in the animals containing the super catalase gene, as compared to controls with normal catalase production. Furthermore, the investigators demonstrated the catalase over-producers had less age-associated damage to their DNA in skeletal muscle and heart cells. In general, the catalase appeared to be protecting the cell from free radical damage to multiple cellular components.

“It is interesting that in biological systems the emphasis is on propagation of the species and not so much on longevity.”

Why doesn’t the cell have more catalase to protect it from damaging free radicals?
One hypothesis is that free radicals may be important in early development in that they may promote cell division and increase the rate of development. It is interesting that in biological systems the emphasis is on propagation of the species and not so much on longevity. What may be good for rapid growth and protection of the animal until the age of reproduction may be detrimental to the organism in later years. Not a pleasant thought as it implies once we have reproduced ourselves, we are no longer needed for the good of our species.

On a more optimistic note, this seminal work provides significant evidence that mitochondrially generated free radicals are involved in aging and disease in mammals. It also supports a role for the potential power of antioxidants in protecting our cells and improving health and longevity.
This work also implies, however, that it is unlikely that one antioxidant, in this case catalase, is a “silver bullet” to promote longevity to a maximum. Even if it were, enzymes do not lend themselves to formulation as a tablet or capsule. During digestion, enzymes generally are transformed, rather than absorbed into the bloodstream in their active state; thus, they cannot be taken in pill form to increase cellular levels. To increase levels in humans, the enzyme would probably have to be inserted into our genome. This is not a likely scenario in the near future.

The body requires numerous antioxidants, all with specific missions. Catalase fulfills one of those missions, and it turns out to be a very important one, as it does result in a 20% increase in life span in animals. However, the human body is extraordinarily complex, and it is highly probable that a variety of antioxidants would have a more pronounced effect on cellular health and longevity.


Research Update

For more than a half century, one of the enduring explanations of aging has been the Free Radical Theory of Aging. The concept is that toxic oxidants in biological systems attack cellular components, damage organs, cause age-related diseases such as cancer and arteriosclerosis, and eventually lead to death. A long-standing question has been whether enhanced presence ofantioxidants could increase longevity. Scientists recently tested this hypothesis in animals. Their study is the first to show in mammals the importance of antioxidants in prolonging life. For details from an article published in the peer-reviewed journal Science,click here
“Extension of murine life span by over expression of catalase targeted to mitochondria.” 
Science.
 2005 Jun 24;308(5730):1875-6.

 

 

The Genetic Clues to Longevity

In the book, The Blue Zones, National Geographic Explorer Dan Buettner and a team of researchers studied the lifestyle and dietary habits of the world’s longest-lived people in Sardinia, Italy; Loma Linda, California; Nicoya, Costa Rica; Okinawa, Japan; and Ikaria, Greece. One of the most interesting conclusions was the similar emphasis on diet, exercise, community, family, purpose, and spirituality in each culture. All of these have been found to cause epigenetic changes to our genome, increasing our probability of a long healthy life.

While the diet is different in each culture, what is the underlining commonality? The newsletter this month is going to explore the diet and oxidative stress aspect of longevity, and how it relates to your genetic report.

Glutathione and Superoxide Dismutase: The Connection to Longevity

While there are many genetic factors involved with longevity, I am going to focus on glutathione and superoxide dismutase.

The current leading theory on aging is that oxidative stress within the mitochondria of the cell leads can lead to a vicious cycle in which damaged mitochondria produces increased amounts of reactive oxygen species, leading in turn to progressive damage to the body. Researchers have theorized that “if aging results from oxidative stress, it may be corrected by environmental, nutritional and pharmacological strategies.”

Glutathione and superoxide dismutase (SOD) are the body’s major antioxidant system to control oxidative stress in the body. Studies have shown those with the highest glutathione live the longest and a high level of SOD leads to the activation of longevity-promoting transcription factors.

Oxidative Stress

Oxidative stress is increased in the body by high blood sugar, stress, fried vegetable oils, heavy metals, chemicals, viruses, bacteria, food dyes, certain medications, shallow breathing and poor sleep. Drugs that deplete glutathione include acid blockers, analgesics, antacids, antibiotics, antidepressants, antivirals, and any medication that depletes b-vitamins and vitamin C (NSAID’s like Aspirin are one example).

Oxidative stress is neutralized by endogenous antioxidant production through glutathione and SOD, and exogenous consumption of antioxidant-rich vegetables, fruits and herbs and supplementation like vitamin C.

Glutathione’s Answer to Oxidative Stress

Glutathione requires the amino acids glycine, glutamine, and cysteine along with selenium for optimal function. The amino acids are highest in meat, eggs, fish, dairy, and chicken or bone broth. Glutathione has also been found to be boosted by vitamin C in both white and red blood cells by 50%, vitamin E, and numerous compounds found in herbs and spices.

On your genetic report, you will find the glutathione genes as GSTM1, GSTP1, SHMT2, and CTH. If you have heterozygous or homozygous variants in GSTM1 or GSTP1, you are going to be more sensitive to oxidative stress from cigarette smoke or mercury from amalgams and large fish (swordfish, ahi tuna, and halibut). Selenium (blocks mercury uptake), folate (reduces blood levels of mercury), vitamin C, vitamin E, and spices like ginger are going to be more important for you to improve these genes.

If you have a heterozygous or homozygous gene in SHMT2, then B6 and glycine are going to be in the highest demand. Glycine, proline, lysine and vitamin C are what make collagen, keeping our skin young and our joints healthy.

For a heterozygous or homozygous gene in CTH, cysteine-rich food should be a focus. N-acetyl-cysteine is a supplement often used for those who struggle with lung health. A high concentration of glutathione is necessary to maintain the fluidity of mucus, and cysteine is a key component. When glutathione combines with nitric oxide (also on your genetic report), it becomes a bronchodilator 100 times more supercharged than theophylline, a once-common asthma drug that has largely been abandoned because of its side effects.

Boosting SOD to Longevity Levels

Seeing where your weaknesses are for oxidative stress enables you to focus on the foods that are the most important. For variants in SOD2, exercise, manganese, omega-3’s, vitamin A, magnesium, CoQ10 and berry polyphenols (found in all berries and wine) are all going to be in a higher need to improve function. For SOD3 variants, zinc/copper, choline, vitamin C, E, beta-carotene, lutein, lycopene, and zeaxanthin are all needed in higher amounts.

Fluoride decreases SOD activity in studies, and 75% of the water in the U.S. is fluoridated compared to 3% of western Europe. Reverse osmosis systems remove most fluoride from drinking water. I recently purchased a portable reverse osmosis system that is affordable and works great. Here is a link for more about fluoride and portable systems to reduce fluoride.

Catalase and Oxidative Stress

CAT is a new gene on the report that makes an enzyme called catalase, which helps reduce oxidative stress. Flavonoids and spices like ginger, cumin, anise, fennel, caraway and cardamom all have been found in studies to assist catalase in reducing oxidative stress. Fresh herbs and spices are often used in high amounts in the Blue Zones.

How Does Glutathione, SOD and Catalase Relate to the Blue Zones?

In Sardinia, Italy, the major traditional staples have been sardines (of course), fish roe, goat milk (high in selenium), pecorino sheep cheese, sourdough bread (made with a sourdough starter), tomatoes, fennel, almonds, olive oil, milk thistle tea and red wine. Cannonau wine has up to three times the level of artery-scrubbing flavonoids as other wines. Another reason for my major endorsement of Italian wine!

In Okinawa, Japan, the major staples have traditionally been pork, fish, rice, shiitake mushrooms, ginger, turmeric and antioxidant-rich teas like mugwort. Turmeric contains several compounds now under study for their anti-aging properties, including the ability to mimic caloric restriction in the body. It is a common practice here to stop eating once you are 80% full.

The interesting note regarding pork is in the preparation. The Okinawans prepared the pork by a lower simmer for days, creating a final dish high in collagen (glutathione precursors). You will find that careful preparation of pork is found in many cultures, including long marinades, curing, and long stews.

In Ikaria, Greece, the major staples are fish, goat milk (high in selenium), olive oil, wine, lots of fruits and vegetables. Researchers have found numerous varieties of antioxidant-rich teas used in Ikaria including wild rosemary, sage, and oregano. Ikarians also periodically fast, which has been shown to increase DNA repair, lower oxidative stress and potentially increase lifespan.

Other Strategies for Oxidative Stress and Longevity

The mushrooms reishi and cordyceps have both been found to increase longevity and protect mitochondria from oxidative stress. Reishi is known as the “Mushroom of Immortality.” The list of what both of these can do is very, very long.

Ashwagandha is a root adaptogen that has also been shown to increase longevity, increase oxygen capacity, lower stress levels, improve sleep and thyroid function, increase energy and protect the brain and nerves.

Summary for Longevity

 

  • Adapt the overall lessons of long living cultures for healthy epigenetic expression
  • Strengthen the antioxidant genes that need the most focus on your report
  • Fast periodically overnight for 13-16 hours and eat until you are 80% full
  • Incorporate lots of fresh herbs and spices into your meals and as a tea
  • If you enjoy wine, choose wines from Italy for a cleaner profile and potentially higher flavonoid level based on the region

 

 

 

 

No Mitochondrial Pain, No Longevity Gain

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Inducible and reversible superoxide dismutase 2 knockdown mice (iSOD2-KD) have been developed

Oxidative stress can motivate cells to live according to the Nietzschean sentiment that goes, “What does not kill us makes us stronger.” Cells, after a brief oxidant challenge, may react by pumping up their production of antioxidants, developing an enhanced antioxidant capacity, and becoming more resistant to subsequent oxidant challenges. These cellular responses, which were recently investigated by Salk Institute scientists, suggest that short-term stress may lead to long-term adaptations that could keep cells healthy longer, staving off aging and disease.

During normal metabolism, a chemical byproduct called superoxide builds up within mitochondria. If enough superoxide accumulates, it can become toxic, prompting mitochondria to produce superoxide dismutase (SOD), an enzyme that converts superoxide to less toxic molecules. If too little SOD is available, however, mitochondria suffer stress—which isn’t entirely harmful. The stress can promote an adaptation called mitohormesis, promoting beneficial physiological responses and enhancing longevity. But how?

That’s the question a Salk Institute team led by Gerald Shadel, Ph.D., professor, molecular and cell biology laboratory, and Audrey Geisel Chair in biological sciences, sought to answer. To interrogate mitohormetic pathways in mammals, the team generated mice in which mitochondrial superoxide dismutase 2 (SOD2) can be knocked down in an inducible and reversible manner (iSOD2-KD mice).

Essentially, the Salk Institute scientists generated a model that let them turn off antioxidant production in mitochondria, but in a reversible way. “We were able to induce this stress for specific time windows and see how cells responded,” asserts Dr. Shadel.

Dr. Shadel and colleagues used their model to investigate how short-term cellular stress caused by mitochondrial superoxide very early in development might affect health later in life. Specifically, they studied the embryonic development of genetically identical mice, half of which had a molecular “off” switch for SOD. These mice were subjected to brief stress.

The results of this work appeared August 16 in the journal Cell Metabolism, in an article titled, “Mitohormesis in Mice via Sustained Basal Activation of Mitochondrial and Antioxidant Signaling.” It described how embryonic mitochondrial oxidant stress results in adaptive changes in adult liver. That is, the livers of adapted mice had increased mitochondrial biogenesis and antioxidant gene expression and fewer reactive oxygen species.

“Gene expression analysis implicated non-canonical activation of the Nrf2 antioxidant and PPARγ/PGC-1α mitochondrial signaling pathways in this response,” wrote the article’s authors. “Transient SOD2 knockdown in embryonic fibroblasts from iSOD2-KD mice also resulted in adaptive mitochondrial changes, enhanced antioxidant capacity, and resistance to a subsequent oxidant challenge.”

After the mice were born and continued to grow to adulthood, the two groups looked very similar. But liver samples taken when they were four weeks old told a strikingly different story: the mice whose SOD enzyme had been turned off briefly to trigger stress in mitochondria had—surprisingly—higher levels of antioxidants, more mitochondria and less superoxide buildup than the mice who had not experienced stress. Additionally, cells grown in dishes, half which contained the SOD switch, showed the same results: those that experienced brief periods of stress turned out to be stress resistant and healthier from a cellular perspective.

When the team analyzed which genes were being activated in both the lab dishes and the liver samples of all the mice, they found unexpected molecular pathways at work in the SOD group that were reprogramming mitochondria to produce fewer toxic molecules while simultaneously increasing the cells’ antioxidant capacity.

“We propose,” the article’s authors wrote, “that mitohormesis in response to mitochondrial oxidative stress in mice involves sustained activation of mitochondrial and antioxidant signaling pathways to establish a heightened basal antioxidant state.”

“We are excited to test if the unique mitohormesis signaling pathways we will elucidate in this new mouse model can be targeted to prevent common age-related disease like cancer, Alzheimer’s, and heart disease,” adds Dr. Shadel.

 

 

 

 

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