Category Archives: Mitochondrial Biogenesis


The Proposed Nine Hallmarks of Aging

Scientist and researchers have attempted to identify and categorize the cellular and molecular hallmarks of aging in a published paper in the research journal Cell on 6th June 2013.  1 

In this paper, researchers proposed nine candidate hallmarks that are generally considered to contribute to the aging process and together determine the aging phenotype.

These nine hallmarks include:

  • altered intercellular communication
  • cellular senescence
  • deregulated nutrient-sensing
  • epigenetic alterations
  • genomic instability
  • loss of proteostasis
  • mitochondrial dysfunction
  • stem cell exhaustion
  • telomere attrition

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The 9 Hallmarks of Aging  (Source: The Hallmarks of Aging)

Researchers set three criteria for each ‘hallmark’:  2

  • it should manifest during normal aging;
  • its experimental aggravation should accelerate aging; and
  • its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan.

The challenge that the researchers encountered was to show the interconnectedness between the candidate hallmarks and their relative contribution to aging.  The ultimate goal of the research was to “identifying pharmaceutical targets to improve human health during aging with minimal side-effects.”  3

A clear and easy to understand article on the nine Hallmarks of Aging was published by on 23rd February 2017.  This article, written by Alexandra Bause, PhD, examines each of the nine hallmarks in plain English and provides a better understanding beyond the original publication in the journal Cell.   

Despite the fact that these hallmarks can be complex and complicated and the understanding of them are still limited, there is hope that new medical strategies will emerge that will ameliorate the the normal aging process. is the premier site for news, discussion, and scientific insight related to the basic biology of aging and the development of new medicines with the ability to cure or prevent the diseases of aging. is committed to bringing its readers the most interesting developments in the science of aging and will: 4

  • Feature a wide range of multimedia content including interviews with experts, looks behind the scenes of everyday lab life, and the latest trends from longevity conferences
  • Capture the perspectives of leading researchers, entrepreneurs, and other experts to act as a platform to share ideas about aging and longevity
  • Cover the emerging biotechnology business of geroscience, including investment coverage, clinical trial data, and insight into the regulatory world
  • Aid collaboration between cross-functional scientific communities, connecting researchers, investors, and industry heads from around the globe


Read the article at

The hallmarks of aging, in plain English, by Alexandra Bause, PhD at


Mitobolites (Mitochondrial metabolites): The Elixir of Life?

Mitochondrial metabolites, also known as Mitobolites, are mitochondrial tricarboxylic acid cycle (TCA) metabolites which are intermediate compounds that are found in the citric acid cycle and are necessary to generate cellular energy for tissue fuel.

The citric acid cycle – also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle – is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of guanosine triphosphate (GTP).

A study from July 2014 published in Cell Metabolism entitled, Mitobolites: The Elixir of Life, reviewed previously published studies that focused on how mitochondrial tricarboxylic acid cycle (TCA) metabolites work to increase lifespan.

The following mitochondrial tricarboxylic acid cycle (TCA) metabolites have been previously shown to extend lifespan upon feeding in C. elegans:

  • Alpha ketoglutarate  1 
  • Fumarate  2 
  • Malate  3 
  • Oxaloacetate  4 
  • Pyruvate  5  

The authors in the study entitled, The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR, reveal  how αlpha-ketoglutarate, a mitochondrial metabolite (mitobolite) inhibits mitochondrial ATPase and extends lifespan by mimicking dietary restriction in worms. 

The authors in the study showed that αlpha-ketoglutarate inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by αlpha-ketoglutarate leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells.  6

These small mitobolites may regulate cellular signaling pathways and result in a number of effects:  7

  • Inhibition of the TOR pathway
  • Increase in autophagy

Beyond the ability of mitobolites to increase lifespan, mitobolites also have shown to have a wide variety of other health benefits.  These additional health benefits are listed in the Table below:

Health Benefits of Mitobolites

Alpha-Ketoglutarate may protect the Brain and Liver from Cyanide toxicity1
Alpha-Ketoglutarate may help to remove Ammonia from the body2
Alpha-Ketoglutarate may inhibit the ability of Nitrosamines to cause Liver Cancer3
Alpha-Ketoglutarate may increase Muscle Strength4
Alpha-Ketoglutarate (Pyridoxine Alpha-Ketoglutarate (PAK) form - 1,800 mg per day) may enhance the effectiveness of Insulin and Phenformin in Diabetes Mellitus patients (both Diabetes Mellitus Type 1 and Diabetes Mellitus Type 2)5
The changes in muscle metabolism produced by citrulline/malate (CM) treatment indicate that CM may promote aerobic energy production.6
Malic Acid may increase Stamina and may minimize Muscle damage during Exercise7
Malic Acid may facilitate the excretion (chelation) of Aluminium from the body8
Super Malic, a proprietary tablet containing malic acid (200 mg) and magnesium (50 mg), in treatment of primary fibromyalgia syndrome (FM).9
Oxaloacetate increases energy production. These studies highlight the importance of optimal substrate concentrations in the CO2 release isotopic PDHC method. Higher PDHC activity is found with intact mitochondria and thus activity values should be interpreted in the light of the presence or absence of intact mitochondria in individual preparations.10
Brain neuroprotection by scavenging blood glutamate. We observed highly significant improvements of the neurological status of rats submitted to closed head injury (CHI) following an intravenous treatment with 1 mmol oxaloacetate/100 g rat weight which decreases blood glutamate levels by 40%.11
Oxaloacetate reduces brain trauma. Oxaloacetate restores the long-term potentiation impaired in rat hippocampus CA1 region by 2-vessel occlusion. Our results suggest that oxaloacetate-mediated blood and brain glutamate scavenging contributes to the restoration of the LTP after its impairment by brain ischaemia. 12
Oxaloacetate Feeds and Grows Brain Cells13
Oxaloacetate is known to be a glutamate scavenger The results of this study demonstrate that the primary mechanism by which oxaloacetate provides neuroprotective activity after CHI is related to its blood glutamate scavenging activity.14
Oxaloacetate induces at least a partial mitochondrial biogenesis, reduces inflammation, and may enhance neurogenesis activity and glucose utilization15
Oxaloacetic Acid Supplementation as a Mimic of Calorie Restriction 16
Acute Oxaloacetate Exposure Enhances Resistance to Fatigue in in vitro Mouse Soleus Muscle. These results demonstrate that acute exposure to oxaloacetate increases resistance to fatigue in mouse slow-twitch muscle, and potential sources of this improvement may be due to increased substrate-level phosphorylation within the mitochondria or some other enhancement of the TCA cycle function. 17
Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway18
Acetyl-L-carnitine and oxaloacetate in post-treatment against LTP impairment in a rat ischemia model19
Pyruvate and oxaloacetate limit zinc-induced oxidative HT-22 neuronal cell injury20
The Effect of Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome in a Rat Model of Subarachnoid Hemorrhage21
The study reviews the recent experimental and clinical results where it is demonstrated the potential applicability of oxaloacetate as a novel and powerful neuroprotective treatment against ischemic stroke.22
Neuroprotective effect of pyruvate and oxaloacetate during pilocarpine induced status epilepticus in rats23
The permeability of mitochondria to oxaloacetate and malate24
Neuroprotective effect of oxaloacetate in a focal brain ischemic model in the rat. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients. 25
Oxaloacetate decreases the infarct size and attenuates the reduction in evoked responses after photothrombotic focal ischemia in the rat cortex. We suggest that the neuroprotective effects of OxAc are due to its blood Glu-scavenging activity, which, by increasing the brain-to-blood Glu efflux, reduces the excess Glu responsible for the anatomical and functional correlates of the ischemia, as evaluated by electrophysiological evoked potential (EP) measurements.26
Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. 27
Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. These results demonstrate that supplementation of the citric acid cycle metabolite, oxaloacetate, influences a longevity pathway, and suggest a tractable means of introducing the health-related benefits of dietary restriction.28
Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. These results suggest that alpha-keto acids such as alpha-ketoglutarate and oxaloacetate play a role in the inhibition of seizures and subsequent mtDNA damage induced by the excitotoxic/neurotoxic agent, kainic acid.29
Studies on the anti-diabetic effect of sodium oxaloacetate.30
Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. The authors demonstrate that the blood glutamate scavengers oxaloacetate and pyruvate provide neuroprotection after traumatic brain injury, expressed both by reduced neuronal loss in the hippocampus and improved neurologic outcomes.31
Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment. In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. 32
Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. 33
MRS of Brain Metabolite Levels Demonstrates the Ability of Scavenging of Excess Brain Glutamate to Protect against Nerve Agent Induced Seizures. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate.34
Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. 35
Pyruvate may improve Insulin Sensitivity and may reduce Blood Sugar in Diabetes Mellitus Type 236
Pyruvate appeared to reduce the insulin resistance that develops spontaneously in obese rats. 37
ingestion of 6 g of pyruvate for 6 wk, in conjunction with mild physical activity, resulted in a significant decrease in body weight and fat mass.38
Pyruvate (6,000 mg per day) may improve Stamina39

Different forms of supplemental Mitobolites

Each mitobolite has different forms as supplements which are distinguished by their differing function and bioavailability. 

The Table below lists the various forms of each mitobolite:

Forms of Mitobolites

Forms of Mitobolites 
Alpha-ketoglutarate (AKG)
Arginine AKG (also known as AAKG) is a form of AKG that consists of AKG bound to Arginine
Calcium AKG is a form of AKG that consists of AKG bound to Calcium
Creatine AKG is a newly-developed supplemental form of AKG consisting of Creatine bound to Alpha-Ketoglutarate
Magnesium Alpha-Ketoglutarate (also known as Magnesium AKG or Mag-AKG) is a supplemental form of AKG that consists of 87.5% AKG bound to 12.5% Magnesium
Ornithine AKG (OKG) is a supplemental form of AKG that consists of 64% Ornithine bound to 36% Alpha-Ketoglutarate
Potassium Alpha-Ketoglutarate (also known as Potassium AKG or Pot-AKG) is a supplemental form of AKG that consists of 70% AKG bound to 30% Potassium
Pyridoxine AKG (also known as PAK) is a supplemental form of AKG that consists of AKG bound to the Pyridoxine form of Vitamin B6
L-Carnitine Fumarate is fumurate bound to L-carnitine
Calcium Malate consists of Calcium bound to Malic Acid
DiCalcium Malate consists of 30% Calcium bound to 70% Malic Acid
Citrulline Malate consists of Citrulline bound to Malic Acid
Creatine Malate consists of Creatine bound to Malic Acid
Magnesium Malate consists of 82.5% to 87% Malic Acid bound to Magnesium
DiMagnesium Malate consists of 81% Malic Acid bound to 19% Magnesium
BENAGENE(TM) brand Thermally Stabilized Oxaloacetate
The US Patent and Trademark Office has issued Patent 9,050,306 for the thermal stabilization of oxaloacetate compounds. This thermal stabilization has allowed Benagene(TM) to provide room-temperature oxaloacetate with a shelf-life of over two years
The National Institute on Aging (part of NIH) has selected oxaloacetic acid (benaGeneTM) for long-term testing under the Interventions Testing Program (ITP). NIA's ITP is a multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction. Oxaloacetic acid is in Cohort 4
Calcium Pyruvate is comprised of 60 - 80% Pyruvic Acid combined with 20 - 40% Calcium
Creatine Pyruvate consists of 60% Creatine bound to 40% Pyruvic Acid
Magnesium Pyruvate consists of Magnesium bound to Pyruvic Acid
Potassium Pyruvate consists of Potassium bound to Pyruvic Acid
Pyruvylglycine consists of Pyruvic Acid bound to Glycine
Sodium Pyruvate consists of Pyruvic Acid bound to Sodium







*  BioFoundations does not endorse any mitobolite supplement, supplement company or retailer, but simply provides a resource to purchase them.

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Mitophagy: Maintaining the integrity of the Cell by Elimination of Dysfunctional Mitochondria

A human cell may contain from 2 to 2,500 mitochondria, depending on tissue type, antioxidant status, and other factors.   The functional mitochondria in the cell are the active mitochondria and the more functional mitochondria, the stronger is the health of the cell.

A biological theory states that mitochondrial number and function determine human longevity.   It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.  1  2

The dysfunction of the mitochondria occurs more rapidly than any other components of the cell.  Mitochondrial degradation and dysfunction occurs as a result of the aging process.   A healthy population of mitochondria is critical for the well-being of cells.

These dysfunctional mitochondria have to be removed from the cell. Because of the danger of having damaged mitochondria in the cell, the timely elimination of damaged and aged mitochondria is essential for maintaining the integrity of the cell. This turnover process consists of the sequestration and hydrolytic degradation by the lysosome, a process also known as mitophagy.  3


Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress.  The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.  4

The dysfunctional mitochondria release hazardous materials, particularly when they have been compromised by damage or age. Accordingly, ensuring proper elimination of dysfunctional mitochondria is imperative to cellular survival, and mitochondrial damage has been implicated in aging, 5 diabetes, and neurodegenerative diseases.  6

Mutations in mitochondrial DNA, due to the aging process, can cause mitophagy to become less efficient.  Eventually, damaged mitochondria build up, leading to cell death.  7 

There are certain identified substances that enhance autophagy and thus probably apply to mitophagy:

  • Nicotinamide treatment decreases mitochondrial content and helps cells maintain high mitochondrial quality.  8
  • Wogonin and luteolin, have been shown cancer cell death through inhibition of autophagy.  9  10  11
  • Ginsenosides such as F2 have also been shown to exhibit anti-cancer effects through the modulation of autophagy.  12
  • Naphthazarin, a naphthoquinone compound, is a microtubule depolymerising agent that induces cell death by activating apoptosis and autophagy.  13
  • Plumbagin induces G2-M arrest and autophagic cell death by inhibiting the AKT/mTOR (mammalian target of rapamycin) pathway in breast cancer cells.  14
  • Berberine exhibits its anti-cancer effects by inducing autophagic cell death and mitochondrial apoptosis in liver cancers.  15
  • Tetrandrine acts as an enhancer of autophagy that induces early G1 arrest in colon carcinoma cells.  16

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Control Certain Factors of Aging by Combining acetyl-L-carnitine and lipoic acid

Aging in characterized by a number of conditions and factors.  Some of these conditions and factors include:

  • Decline of mitochondrial membrane function
  • Ambulatory activity
  • Lethargy
  • Infirmity
  • Weakness
  • Decline in memory
  • Age-associated mitochondrial structural decay
  • Free radical-induced lipid peroxidation

The National Academy of Sciences (NAS) is a private non-profit organization in the United States. It was founded in 1863 as a result of an Act of Congress that was approved by Abraham Lincoln.

The National Academy of Sciences studied the effects of acetyl-L-carnitine and lipoic acid on aging and found that the factors listed above could be partially reversed with their combined consumption.  They published three separate studies confirming the benefit of combining acetyl-L-carnitine and lipoic acid in controlling some of the conditions and factors of aging.

Study 1

This animal study demonstrated that the combination of acetyl-L-carnitine and lipoic acid improved ambulatory activity and a partial reversal of the decline of mitochondrial membrane function while consumption of oxygen significantly increased.  1

Study 2

This animal study showed that supplementation with acetyl-L-carnitine and lipoic acid resulted in improved memory in old rats. Acetyl-L-carnitine and lipoic acid reversed age-associated mitochondrial structural decay in the hippocampus region of the brain.  2

Study 3

In the third study, the authors tested whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA).  Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity.

Supplementation also inhibited free radical-induced lipid peroxidation, which enhanced the activity of the energy-producing enzyme in the mitochondria.

Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction.  3


To purchase acetyl-l-carnitine and R-lipoic acid visit:  Geronova Research

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Flip Your AMPK switch to the “ON” position

Introduction to AMPK

AMPK (adenosine monophosphate-activated protein kinase) is an enzyme contained in every cell of the human body that serves as the body’s master regulating switch.

When the AMPK master switch is turned “ON” (by activating AMPK), it inhibits multiple damaging factors of aging and enables cells to become revitalized.  Scientists have found that activated AMPK promotes longevity factors that have been shown to extend life span in numerous organisms.  1  2 

There are various studies that show an increase in AMPK supports:

  • Reduced fat storage 3 
  • New mitochondria production  4 
  • Promotion of healthy blood glucose and lipids already within normal range  5 


Roles of AMPK in the control of whole-body energy metabolism. Notes: Activation of AMPK (green lines) stimulates the energy-generating pathways in several tissues while inhibiting the energy-consuming pathways (red lines). In skeletal muscle and heart, activation of AMPK increases glucose uptake and fatty acid oxidation. In the liver, AMPK activity inhibits fatty acid and cholesterol synthesis. Lipolysis and lipogenesis in adipose tissue are also reduced by AMPK activation. Activation of AMPK in pancreatic β-cells is associated with decreased insulin secretion. In the hypothalamus, activation of AMPK increases food intake.  Source: AMPK activation: a therapeutic target for type 2 diabetes? Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, and Asish K Saha, Diabetes Metab Syndr Obes. 2014; 7: 241–253. Published online 2014 Jun 24. doi: 10.2147/DMSO.S43731

Activating AMPK:  Turning the Switch “ON”

The two major methods of activating AMPK is through:

  • exercise and
  • calorie restriction

When you exercise, you use up more ATP which generates higher AMP levels, which then activates AMPK.  6

The other method of activating AMPK is through calorie restriction by at least 30%.  This means cutting daily calorie consumption by 30%.  By reducing calorie consumption, the lower levels of available energy leads to rising AMP levels, which then activates AMPK.  7

In addition to exercise and calorie restriction, there are many other ways to activate AMPK, particularly through certain foods, herbs and nutraceuticals.  The Table below lists the many researched methods of activating AMPK:

AMPK Activators

Fasting and Intermittant Fasting2
Cold water exposure (raise AMPK in the hypothalamus)3
Calorie Restriction4
Extra Virgin Olive Oil 5
Royal Jelly (10-Hydroxy-2-decenoic acid (10H2DA)6
Dashi kombu (Laminaria japonica Areschon)7
Bitter Orange (Citrus aurantum Linn)8
Garlic and Olives (Oleanolic acid)9
Apple Cider Vinegar10
Rose Hips (Trans-Tiliroside)11
Mulberry leaves extracts12
Fish Oil – EPA , DHA 13 14
Anthocyanins 15
Bitter melon16
Herbs and Spices
Cinnamon 18
Astragalus 19 20
Marijuana (Cannabinoids)21
Green Tea/EGCG22
Danshen (Chinese Red Sage)24
Gynostemma pentaphyllum (Jiagulon)25
Baicalin26 27
Adiponectin 28 29
Thyroid hormones, especiallly T3 30
Nitric Oxide32 33
Immune System
Interleukin-6 (IL-6)34
Butyrate (Calcium/Magnesium ) or Sodium Butyrate (Short Chain Fatty-Acid)37
Co-enzyme Q1039
Glucosamine44 45
Quercetin48 49
Red yeast rice50
R-Lipoic Acid52 53
Vitamin E - gamma tocotrienol54

Informational References:

Life Extension – AMPK and Aging “A Technical Review”  (November 2015)

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Nitric oxide (NO) triggers mitochondrial biogenesis

In the November 23, 2004 (vol. 101 no. 47 16507-16512) issue of the Proceedings of the National Academy of Sciences of the United States of America, an article entitled “Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals”, stated that “long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues”.

Excerpt from the article:

“We recently found that long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues by activation of guanylate cyclase and generation of cGMP. Here, we report that the NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration and content of ATP in U937, L6, and PC12 cells.

The observed increase in ATP content depended entirely on oxidative phosphorylation, because ATP formation by glycolysis was unchanged. Brain, kidney, liver, heart, and gastrocnemius muscle from endothelial NO synthase null mutant mice displayed markedly reduced mitochondrial content associated with significantly lower oxygen consumption and ATP content.

In these tissues, ultrastructural analyses revealed significantly smaller mitochondria. Furthermore, a significant reduction in the number of mitochondria was observed in the subsarcolemmal region of the gastrocnemius muscle. We conclude that NO/cGMP stimulates mitochondrial biogenesis, both in vitro and in vivo, and that this stimulation is associated with increased mitochondrial function, resulting in enhanced formation of ATP.”

So how does one increase Nitric Oxide (NO) in the body.  One way to is to consume L-Citrulline DL-Malate.

L-citrulline is converted to the amino acid L-arginine, which goes on to make another important substance nitric oxide. In contrast to L-arginine, L-citrulline is not metabolized in the areas of the body where arginase, the enzyme that breaks down L-arginine, is present, like the the intestines and liver. Instead, L-citrulline goes into the kidneys where it is rapidly converted into L-arginine.


Effect of citrulline and glutamine on nitric oxide production in RAW 264.7 cells in an arginine-depleted environment.


L-Citrulline DL-Malate 2:1 (Powder City)

L-Citrulline DL-Malate 2:1 (Pure Bulk)

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Nutrients that are shown to activate mitochondrial biogenesis

Mitochondria are the only cell components (other than the nucleus) to possess their own DNA. This means mitochondria have the ability to replicate and increase their number within a single human cell. Human cells may house anywhere from 2 to 2,500 mitochondria, depending on tissue type, antioxidant status, and other factors.

It is claimed in scientific circles that mitochondrial number and function determine human longevity. Thus the more functional mitochondria you have in your cells, the greater your overall health and durability.

As we age and grow older, the problem is that our mitochondria degrade and become dysfunctional. Age-related destruction of the mitochondria occurs more rapidly than in other cell components, meaning that for most people it is loss of functional mitochondria that ultimately leads to personal extinction.

Up until recently, mitochondrial biogenesis, the creating of new mitochondria within cells, has been problematic and the only recognized natural ways to stimulate mitochondrial biogenesis were:

  • calorie restriction or
  • aerobic exercise

Fortunately, the scientific substantiation and research on mitochondrial biogenesis has indicated that there are certain nutrients to enhance mitochondrial performance and biogenesis. These nutrients have been identified in the scientific literature to activate mitochondrial biogenesis, and are as follows:

  • Acetyl-L-Carnitine
  • Alpha Lipoic Acid
  • Branched Chain Amino Acids
  • Nicotinamide
  • Pyrroloquinoline quinone (PQQ)
  • Pterostilbene (doubly methylated resveratrol)
  • Quercetin
  • Resveratrol
  • Se-Methyl L-Selenocysteine (Selenium)


Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89.

Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion, and life span. Curr Aging Sci. 2009 Mar;2(1):12-27.

Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci. 2004;107:355-364.

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Mitochondrial Biogenesis

Mitochondria are the organelles inside cells that produce energy. Representing approximately 10% of total body weight, mitochondria have a number of roles in the body. Primarily, they are cellular “energy process factories” responsible for supplying greater than 95% of the body’s energy needs. Mitochondria are found in all of our cells, but are especially abundant the brain, skeletal muscle, heart, liver, and kidney.

As biochemical processing units, the mitochondria within each of our cells utilize carbohydrates and fat which are then converted into adenosine triphosphate (ATP). ATP transports chemical energy within cells for metabolism. The primary function of mitochondria is to produce ATP. The more ATP we have available, the more efficient our cellular metabolism will be, and consequently the aging process slows.

Mitochondrial biogenesis is the process by which new mitochondria are formed in the cell. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli. It is critical that new mitochondria are generated if we are to protect against age-related decline, since it is believed to delay the effects of aging and the onset of age-associated diseases.

The master regulators of mitochondrial biogenesis appear to be the peroxisome proliferator-activated receptor gamma (PGC) family of transcriptional coactivators, including PGC-1α, PGC-1β, and the PGC-related coactivator, PRC. PGC-1α, in particular, is thought to be a master regulator.

Aerobic exercise and caloric restriction are the primary activators of the “master regulator” of mitochondrial biogenesis, PGC-1α.

Other biochemical substances that have been studied and research to be activators of the master regulator, PGC-1α to convey their signals to induce mitochondrial biogenesis include:

  • 5′ adenosine monophosphate-activated protein kinase (AMPK)
  • Ca2+/calmodulin-dependent protein kinase (CaMK)
  • Calcium-activated enzyme calcineurin
  • Nitric Oxide (NO)
  • Silent Information Regulator of Transcription 1 (SIRT1)

There exists natural and nutritional compounds that may stimulate the pathways that lead to mitochondrial biogenesis. These compounds are directed towards the primary biochemical targets required for mitochondrial biogenesis.


Nisoli E, Carruba MO. Nitric oxide and mitochondrial biogenesis. J Cell Sci 2006; 119:2855-2862.

Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the
insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350:664-671.

Zhou G, Myers R, Li Y et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108:1167-1174.

Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacol Rev 2002; 54:101-127.

Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge
provides clues to modern understanding of metabolism. Cell Metab 2005; 1:15-25.

Winder WW, Taylor EB, Thomson DM. Role of AMP-activated protein kinase in the molecular
adaptation to endurance exercise. Med Sci Sports Exerc 2006; 38:1945-1949.

Witters LA. The blooming of the French lilac. J Clin Invest 2001; 108:1105-1107.

Musi N, Hirshman MF, Nygren J et al. Metformin increases AMP-activated protein kinase activity in
skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51:2074-2081.

Conley KE, Marcinek DJ, Villarin J. Mitochondrial dysfunction and age. Curr Opin Clin Nutr Metab
Care 2007; 10:688-692.

Boss O, Hagen T, Lowell BB. Uncoupling proteins 2 and 3: potential regulators of mitochondrial
energy metabolism. Diabetes 2000; 49:143-156.

Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer:
a dawn for evolutionary medicine. Annu Rev Genet 2005; 39:359-407.

Reznick RM, Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J
Physiol 2006; 574:33-39.

Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and
their potential links with mitochondrial dysfunction. Diabetes 2006; 55 (Suppl 2):S9-S15.

Zong H, Ren JM, Young LH et al. AMP kinase is required for mitochondrial biogenesis in skeletal
muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 2002; 99:15983-15987.

Scheffler IE. Evolutionary Origin of Mitochondria. Mitochondria. 2nd ed. Hoboken: John Wiley & Sons; 2008 p. 7-17.

Hardie DG. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease.
FEBS Lett 2008; 582:81-89.

Ruderman NB, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic
syndrome. Nat Rev Drug Discov 2004; 3:340-351.

Misra P. AMP activated protein kinase: a next generation target for total metabolic control. Expert
Opin Ther Targets 2008; 12:91-100.

Colman E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul Toxicol
Pharmacol 2007; 48:115-117.

Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120:483-495.

Conley KE, Jubrias SA, Esselman PC. Oxidative capacity and ageing in human muscle. J Physiol 2000; 526 (Pt 1):203-210.

Wallace DC, Singh G, Lott MT et al. Mitochondrial DNA mutation associated with Leber’s hereditary
optic neuropathy. Science 1988; 242:1427-1430.

Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283:1482-1488.

Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic
disease. Nature 2008; 454:463-469.

Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972; 20:145-147.

Bua E, Johnson J, Herbst A et al. Mitochondrial DNA-deletion mutations accumulate intracellularly
to detrimental levels in aged human skeletal muscle fibers. Am J Hum Genet 2006; 79:469-480.

Arany Z, He H, Lin J et al. Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005; 1:259-271.

Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function.
Physiol Rev 2008; 88:611-638

Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer’s disease. Prog
Neuropsychopharmacol Biol Psychiatry 2005; 29:407-410.

Gu M, Cooper JM, Taanman JW, Schapira AH. Mitochondrial DNA transmission of the mitochondrial

Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion, and life span. Curr Aging Sci. 2009 Mar;2(1):12-27.

Befroy DE, Petersen KF, Dufour S et al. Impaired mitochondrial substrate oxidation in muscle of
insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007; 56:1376-1381.

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