Antioxidants and free radicals

Reactive oxygen species known as free radicals

image1Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen (SUPEROXIDE). However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. Cumulatively, this is known as OXIDATIVE STRESS. ROS are also generated by exogenous sources such as ionizing radiation. Oxidative stress can be exogenous (induced by outside world stimuli) and Endogenous (produced inside cells)

image2Oxidative stress

Oxidative stress generally results from an imbalance between free radicals generated during normal cellular metabolism and the free radical or oxidant scavenging capacity of the endogenous antioxidant enzymes.

Joe McCord et al, synergistic induction of heme oxygenase-1 by the components of the antioxidant supplement Protandim., 2008

Reactive oxygen species known as free radicalsimage3

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically.This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress. ROS are also generated by exogenous sources such as ionizing radiation.

Oxidative stress and what is does to our bodies. Oxidative stress has been implicated in many chronic diseases including Alzheimer’s, diabetes and coronary artery disease (CAD). Increased production of reactive oxygen species (ROS) and oxidative damage in the vascular endothelium contribute to CAD initiation and progression. Specifically, increased vascular superoxide causes oxidation of lipids, decreased nitric oxide availability, increased expression of adhesion molecules and inflammatory mediators, and recruitment of monocytes to the endothelium aka leads to PLAQUE FORMATIONHEART ATTACKSSTROKES. Endothelium-bound superoxide dismutase is also decreased in CAD patients compared to healthy controls, impairing the cellular response to excessive ROS production

ROS/FREE RADICALS

In general, harmful effects of reactive oxygen species on the cell are most often:

  • damage of DNA
  • oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)
  • oxidations of amino acids in proteins
  • oxidatively inactivate specific enzymes by oxidation of co-factors

ROS/FREE RADICALS and aging

Regardless of how or where ROS are generated, a rise in intracellular oxidant levels has two potentially important effects:
Damage to various cell components and triggering of the activation of specific signalling pathways.  Both of these effects can influence numerous cellular processes linked to ageing and the development of age-related diseases. After a finite number of divisions, primary cell cultures enter a state of replicative senescence in which they are growth-arrested and refractory to further mitogenic stimulation. Although the relevance of in vitro senescence to organismal ageing remains controversial, several studies indicate that oxidants are important in the development of the senescent phenotype

In general, harmful effects of reactive oxygen species on the cell are most often:
damage of DNAmutations>cancer
oxidations of polyunsaturated fatty acids in lipids (lipid peroxidation)>
Atherosclerosis, cardio-vascular disease
oxidations of amino acids in proteins>inflammation, neurodegeneration (AD, dementia, MS)

Regardless of how or where ROS are generated, a rise in intracellular oxidant levels has two potentially important effects:
Damage to various cell components and triggering of the activation of specific signalling pathways, leading to INFLAMMATION AND CANCER.
Aging and the development of age-related diseases.

THE IMPORTANCE OF BALANCE AND EQUILIBRIUM BETWEEN FREE RADICALS AND ANTI-OXIDANTS:

MORE FREE RADICALS>AGING>CELLULAR FATIGUE
MORE ANTIOXIDANTS>YOUTH AND HEALTH.

OXIDANTS/ANTIOXIDANTS

Internal antioxidants: SOD, catalase and glutathione peroxidase.
External antioxidants: ascorbate (vit C), pyruvate (vit B), flavonoids (green teas),
Carotenoids>beta carotene, vit A.
Mitochondria and aging

Several studies have shown that ageing cells and organisms accumulate increased levels of oxidant-damaged nuclear DNA. Perhaps because of its proximity to the main source of oxidant generation, or because of a limited DNA repair system, mitochondrial DNA is generally considered to be even more sensitive then nuclear DNA to oxidative damage. Increasing damage to mitochondrial DNA inevitably leads to compromised mitochondrial function and integrity. Damaged mitochondria are thought to release more ROS and set in motion a vicious cycle of increasing DNA damage leading to increased ROS production that in turn leads to more DNA damage.

Mitochondria, “nuclear” factory

Most estimates suggest that the majority of intracellular ROS production is derived from the mitochondria.

Nrf2 AND NF

Anti-inflammatory and proinflammatory protein complex

Telomeres

Aging happens deep in your cells in small structures called telomeres which are like the plastic tips on shoe laces that prevent chromosome ends from fraying and sticking to one another.  Telomeres are sequences of DNA – chains of chemical code. Like other DNA, they are made of four nucleic acid bases: G for guanine, A for adenine, T for thymine and C for cytosine.

Geneticist Richard Cawthon and colleagues at the University of Utah discovered that shorter telomeres are associated with shorter lives. Among people older than 60, those with shorter telomeres were three times more likely to die from heart disease and eight times more likely to die from infectious diseases. 

NRF2 and INFLAMMATION

The expression of many inflammation-related genes is similarly dysregulated with age. In fact, systemic chronic inflammation increases with age, even in the absence of risk factors or chronic disease.  The transcription factor NF-κB is a master regulator of inflammation and is consistently upregulated with aging.  Greater expression of NF-κB is associated with higher levels of inflammatory biomarkers in humans, including C-reactive protein (CRP) and proinflammatory cytokines (e.g., IL-6 and TNF-α).

Nrf2 is a positive regulator of the human Antioxidant Response Element (ARE) that drives expression of antioxidant enzymes

Nrf2-regulates genes, including antioxidant-related genes such as those involved in glutathione synthesis genes involved in limiting the inflammatory process, genes involved in limiting pulmonary fibrosis, and genes conferring protection against ischemia/reperfusion injury

The many roles of Nrf2

The Nrf2 signaling pathway is emerging as a critical and principal factor in the protection against cancer, Neurodegeneration, Inflammation, Cellular detoxification. The expression of many inflammation-related genes is similarly dysregulated with age. In fact, systemic chronic inflammation increases with age, even in the absence of risk factors or chronic disease.  

NRF2 and AGING

Cytoprotective pathways, including Nrf2 and vitagenes, are impaired with aging and ultimately controlled by age-related changes in gene expression. Studies in aged rats have reported as much as a ∼50% reduction in nuclear Nfr2 levels and ARE binding in liver.
Loss of Nrf2 with age is reversible and therefore an attractive target for antiaging interventions.
Nrf2 expression appears to decline with aging, leading to dysregulation of oxidative stress responses.
It seems more likely that oxidative stress merely reflects an imbalance between the quantities of oxidants our cells are producing and the quantities of antioxidant gene products (SOD, catalase, GSH peroxidases, etc.) required to restore balance. 

WHY ENDOGENOUS?
WE NEED WHOLE FOODS

Initial studies examining the effects of decreasing oxidative stress in several diseases, including cardiovascular disease, have used exogenous antioxidant supplements such as vitamins C and E. However, the protective effect of exogenous antioxidants has been disappointing and in some cases supplementation increased mortality. WHY?????

A novel approach to decreasing disease-associated oxidative stress involves augmenting endogenous antioxidant defense systems rather than relying on exogenous antioxidant supplementation,  a study which involved a group of people with coronary artery disease saw that those with the most Omega-3 EPA and DHA fatty acids in their bodies also had the slowest rate of telomere shortening over 5 years.  

We are probably all aware by now that fat has been the target of much scorn, but it is absolutely necessary for graceful aging and lowering inflammation in our bodies which is a key to aging successfully. Consuming the right fats and oils supplies the essential fatty acids (EFA’s) that our bodies are incapable of producing on their own, and these are highly important for preventing aging.  The right kinds of fats will also ferry fat soluble vitamins such as A, D, E & K around the body; delivering these much needed nutrients to your skin cells, resulting in a healthy complexion.

WHY WHOLE FOODS,
NOT SOD OR GLYTOTHIONE DRUG?

Much effort has been expended in the past several decades in attempts to turn SOD into a drug. Proteins and enzymes generally make very poor drugs for a variety of reasons: possible immunogenicity, high cost of production, problems associated with purification and stability, non-availability by oral administration, and poor pharmacokinetic properties.

CURCUMIN

NIHMS307506.html

Sulforaphane Glucosinolate

Intake of broccoli sprouts, a rich source of the glucosinolate glucoraphanin, has been associated with decreased incidence, multiplicity, and tumor growth in animal cancer models.1-3 In 1992, Paul Talalay, MD, and colleagues at Johns Hopkins University identified the isothiocyanate, sulfora- phane, a biologically active metabolite of glucora- phanin, as the compound in broccoli responsible for many of its health benefits.4 Since that time, more than 500 studies have been conducted on the mechanisms and biological activity of sulforaphane and its precursor, glucoraphanin.5 Glucoraphanin, also referred to as sulforaphane glucosinolate (SGS), is the most potent naturally-occurring inducer of phase 2 detoxification enzymes4,6 and is an indirect, long-acting antioxidant.7-9 Sulforaphane also exhibits broad-spectrum antimicrobial activity against numerous gram- positive and -negative bacteria,10 most notably Helicbacter pylori.11 In addition, sulforaphane possesses anti-inflammatory activity; it inhibits cytokine production in preclinical and clinical studies.12-14 Sulforaphane’s multiple molecular targets and promising early research have lead to 15 clinical trials currently underway to assess its effects on various cancers, cardiovascular disease, upper airway inflammation, radiation dermatitis, and vascular health.15

Can we help ourselves to young again?

Pathways activated by acute oxidative stress show diminished activity as a function of ageing. If oxidative stress and the ability to respond appropriately to it is important in ageing, then it follows that factors that increase resistance to stress should have anti-ageing benefits and lead to enhanced life span