Sun Damage and Pigmentation

Ultraviolet light accounts for the majority of the symptoms of early onset aging. The repeated exposure to excess UV light can cause DNA damage, inflammation and oxidative stress. The sun’s UV rays are important for life on Earth, yet some have genetic predispositions that keep them from having an effective protective barrier. Genetic predispositions also allow for free radical production from UV radiation to accumulate faster than it can be removed.

Optimal Functioning

DNA repair genes help bring DNA repair components together at the site of action to help repair DNA damage and clean up oxidative-induced DNA damage caused by ionizing radiation/UV rays. Repair of DNA is always ahead of the rate of DNA damage.

Dysfunction

Dysfunction occurs when damage is dominant over repair. This can be caused by too much exposure to UV radiation or a defective gene. You may have a genetic inefficiency causing a lack of working enzymes or proteins to clean up the damage left accumulating in DNA and to protect from further damage.

Symptoms include:

• Blemishes and freckles
• Pigmentation
• Skin thinning and fine lines
• Redness
• Broken Capillaries
• Rough Surface Area

Supplements

• D3 Active 5000 helps protect and repair the DNA. You need a healthy source of vitamin D3 without the harmful effects of UV rays over-stimulating DNA damage and accumulating free radicals. Absorption of vitamin D3 from the sun decreases with age.

• Arctic Omega Krill helps with inflammation and the astaxanthin is a very powerful antioxidant that helps defend against UV. Reduces damage caused by UV.

• Pycnogenol (sold at Medical Detective store) protects skin from UV-induced damage.

• ALAmed CR  helps to improve collagen protective mechanisms along with promoting optimal mitochondrial function (ATP). Improved ATP production promotes collagen synthesis. When you have ingredients that promote ATP production, you must have adequate antioxidants to quench the free radicals produced by the mitochondria. This product is a powerful antioxidant and will neutralize the free radicals.  Other benefits include blood glucose and insulin support, detoxification of plastics and heavy metals, and antioxidant support.

• Beta Carotene (sold at Medical Detective store) protects against sunburn, a sign of DNA damage that has been accelerated past its repair mechanisms.

• Lycopene (sold at Medical Detective store) protects against sunburn, a sign of DNA damage that has been accelerated past its repair mechanisms.

• E-ssential has photoprotective properties.

• Omega Platinum EC helps to inhibit the inflammatory cytokines such as (IL1, IL6, and TNF a1) that can be activated by ionizing radiation. It upregulates anti-inflammatory cytokine IL-10 and suppresses TH17 cells that negatively affect the immune system.

• ResveraTri protects against UVB radicals.

• Circuvasc protects and supports blood vessels from indirect damage caused by sun-induced oxidation.

• CollaGENerate supports and protects collagen from indirect damage of MMP’s caused by sun-induced oxidation.

• Synovial Active supports and protects hyaluronic acid from indirect damage of MMP’s caused by sun-induced oxidation.

• BioFlav C supports and protects collagen and blood vessels from indirect damage of MMP’s caused by sun-induced oxidation.

• Acetyl GSH

Types of UV- Induced DNA DAMAGE

There are three bands of UV rays emitted by sun: UVA, UVB and UVC. We will only be discussing UVB and UVA because UVC cannot penetrate through the ozone layer.

UVA

UVA causes indirect damage (lesions) to the DNA by way of Reactive Oxygen species (ROS). (See section below about 8oxoG.) UVA penetrates the deeper parts of the dermis and the rays can be intensified by cloudy and overcast days. The effects of these rays become more apparent years down the road as they go deep into layers of skin, damaging the dermis. Fluorescent lighting emits light energy in the range of UVA and can cause darkening of freckles. It is important to wear UVA sunscreen in fluorescent-lit buildings to prevent any damage from the UV light energy emitted. [1]

UVB

Direct absorption of UVB generates DNA photoproducts that cause lesions to DNA. For example, this causes cross-linking between adjacent cytosine and thymine bases in DNA (creating pyrimidine dimers that damage DNA). UVB effects are more immediately visible. The rays do not travel as deep into the skin because the spectrum isn’t strong enough. It does its damage more superficially and causes sunburns, peeling, pigmentation, swelling, and browning of the skin.

“DNA photoproducts generated upon direct absorption of UVB (280-320nm), UVA (320-400nm) can indirectly cause oxidative DNA damage in the form of oxidation of guanine (8-hydroxyguanine) and single-strand breaks via reactive oxygen species generated after the absorption of light energy by cellular chromophores.” [2]

DNA 101

DNA, deoxyribonucleic acid, is the hereditary material in humans and other living organisms. DNA is found in the nucleus (nuclear DNA) and mitochondria (mitochondrial DNA) of cells.

The DNA structure can be compared to a ladder. The backbone of the DNA would be the two parallel sides. In between the side structures of the DNA are rungs that run up and down it. If you were to twist this ladder you would get something that looks like the formation of the double helix of DNA.

DNA is made of repeating subunits called nucleotides.

Nucleotides contain:

1. Phosphate and 2. Sugar (Deoxyribose)

Appearing as the sides of the ladder.

3. Base Pairs

Found between the sides of the ladder.

Nitrogen Base Pairs, ATGC, are held together by hydrogen bonds. Base pairs are joined by a connection of adenine to thymine, and guanine to cytosine. Bases make up the code of your genetics. Bases are very sensitive to chemicals, carcinogens, and ROS induced by UV and other sources. The bases can form lesions (adducts), which can lead to trouble down the road. It’s known as DNA base modification.

Types of DNA Damage

Hydrolysis of Bases

Deamination
When a cell accepts a mutant base pair because repair wasn’t completed properly before DNA replication.

Depyrimidination
This is a loss of Pyrimidine Bases, cytosine and thymine. A baseless sugar results in an AP-site called apyrimidinic site. AP-sites can be lethal to cells and they block DNA replication. They are repaired during Base Excision Repair (BER). See types of DNA repair below. [3]

Depurination
This is a loss of Purine Bases, guanine and adenine. As in depyrimidation, depurination causes baseless sugar that results in an AP-site called apurinic site. The apurinic sites block DNA replication but are repaired during BER. [3]

Alkylation

The nitrogen atoms of the Purine Bases, guanine and cytosine, are susceptible to alkylation in form of methylation. Methylation of DNA bases can come from exogenous sources or endogenous sources.

Exogenous Sources
“Exogenous chemicals such as dimethylsulfate, used in many industrial processes and formed during the combustion of sulfur-containing fossil and N-methyl-N-nitrosoamine, a component of tobacco smoke, are powerful alkylating agents.” 3

Endogenous Sources
Methylation of the purine bases can occur from normal metabolic processes within the cells. S-adenosylmethionine (SAM) is a molecule that is a methyl donor during normal cell metabolism. The adenine base is also affected by alkylation damage induced by the molecule SAM. [3]

Photoproducts (Cross-Linking Agents) from Ionizing Radiation (Accumulation of Oxidation)

Below are UV-induced photoproducts that can cause Double Strand Breaks (DBSs) and Single Strand Breaks (SSBs):

(6-4PP) 6-4PP-pyrimidine (6-4) pyrimidine photoproduct
UV radiation causes thymine nucleotide bases on DNA strands to become covalent and bond together. This is not supposed to happen and it causes lesions in the DNA, damaging its structure. “More direct evidence that 6–4PPs may play a dominant role in UV-induced mutagenesis has been obtained from Escherichia coli (12, 13, 14) .” [4]

(CPD) Cyclobutane pyrimidine dimer
UV radiation causes thymine nucleotide on DNA strands to become covalent and bond together. Cytosine and thymine bind together, destroying normal base-pairing., i.e., the loss of pyrimidine bases cytosine and thymine. This is not supposed to happen and it causes lesions in the DNA, damaging its structure. You need exonuclease to cut out this lesion. If you have this genetic defect, your body will have a difficult time repairing this DNA damage.

8-oxoG

8-oxoG-7, 8-dihydro-8-oxoguanine is generated by ROS from endogenous and exogenous sources. Exogenous sources come from UVA and they create mostly free radicals. UVA provides main source of free radicals, while UVB provides more direct damage. This attacking is on DNA by UV-induced ROS and results in DNA adducts/lesions. (Adducts are lesions that form on the DNA when it has been damaged.) 8-oxoG is the most widely studied and well-known oxidative DNA base adduct. It can block DNA replication. [5]

When too many of these 8-oxoG radicals (8-oxoguanine) accumulate, you need an enzyme to clean up the damage to prevent DNA mutations from occurring. We need the enzyme 8-oxoguanine-DNA glycosylase (Ogg1) to remove the oxidized base from the DNA.

Your body must also be able to break down photoproducts caused by UV exposure. One such gene responsible for cleaning up and removing indirect and direct damage is 8-oxoguanine-DNA glycosylase(Ogg1). [5,6,7]

If someone has a defect in this pathway from a genetic variance causing less production of 8-OGG1, oxidation of the DNA bases will occur because of the accumulation of the 8-oxoguanine (8-oxoG) radicals.

Every time you expose yourself to harmful UVB rays you impair your OGG1 and adducts increases occur that are harmful to your DNA. Nitrogen bases of DNA are subject to oxidation. In Figure 4 above, you will see OGG1 sending out for enzymes that will help to clean up the oxidized base.

DSBs and SSBs That Occur From The Above Sources of Damage

Single Strand Breaks (SSBs)

SSBs are caused by bulky DNA adducts and UV radiation. Not as serious as a double strand break, because it can use the template of the strand that is not damaged to repair the damaged strand by duplicating its template. When the DNA strand cannot be successfully duplicated, there has been an error in the transcription. This is DNA synthesis. DNA polymerases are proteins that are involved during resyntheis of DNA and DNA glycosylase are enzymes that are involved. In SSBs, there is a change in a single nitrogenous base. See Figure 5.

When the balance of damage and repair is past the tipping point, the DNA becomes damaged beyond repair and mutations occur. When DNA repair mechanisms are dysfunctional or you have OCDLs, the result is cytotoxic or mutagenic effects. It is important to make sure you stay away from sources that damage your DNA (create DNA lesions) and take preventive measures to eliminate this issue. [7]

Sources of DNA Damage

Endogenous. Reactive Oxygen Species (ROS) from normal metabolic process (i.e., mitochondria production of ATP creates ROS), byproducts of spontaneous mutation, oxidative deamination, and replication errors. ROS causes hydrolysis of bases in processes such as depurination, deamination, depyrimidination, and single and double strand breaks. [8]

Exogenous. Found in UV radiation, x-ray and gamma rays (radiation), viruses, hydrolysis or thermal disruption, plant toxins, man-made mutagenic chemicals and aromatic compounds. ROS causes hydrolysis of bases in processes such as depurination, deamination, depyrimidination, and single and double strand breaks. [8]

Types of DNA REPAIR

Base Excision Repair (BER) and Single Strand Repair (SSR)

One of the two most dominant pathways in DNA repair.

Found in repair of SSBs. This type of repair removes simple lesions in DNA that cause minimal structural changes.

Multiple enzymes work together to excise and replace a single nitrogenous base (ACTG). The first enzymes to be deployed are called glycosylases, which will help to excise or remove the damaged DNA base. This will create an AP-site.

Next, the second enzyme in the BER pathway, AP endonucleases (APE1), is activated. APE1 will nick the backbone of the damaged DNA at the AP-site so the next enzyme can remove it. The next enzyme, DNA polymerase, will remove the damaged section using its 5’ to 3’ exonuclease and will synthesize DNA by inserting the correct nucleotide. The next enzyme, called DNA Ligase (DNA Ligation), seals the nick by joining the DNA strands to create something called phosphodiester bond between them. [8]

(NER) Nucelotide Excision Repair

One of the two most dominant pathways in DNA repair.

Found in repair of cyclobutane pyrimidine dimer (CPD), single strand breaks and adduct formation from ROS such as 8-oxoG. Removes bulky lesions in DNA. Repairs UV-induced photoproducts. Repairs crosslinking agents.

The process for release of enzymes to repair is similar to those in the BER section:

• Damage recognition
• Damage base excision
• AP-site excision
• DNA repair synthesis and DNA ligation

Double Strand Break Repair (DSBR)

Below are pathways involved with this type of repair.

Homologous recombination (HR)

Requires an identical or nearly identical genome sequence to use as a template for repair. The damaged chromosome will be repaired using a sister chromatid or homologous chromosome as the template. [8]

Nonhomologous end-joining (NHEJ)

Enzymes are involved to help rejoin two ends together. These enzymes are called DNA Ligase IV, XRCC4, and DNA Protein Kinase (DNA-PK). When sister chromatids are not available to use as templates for broken DNA strands, repair will take place without the template and genome-sequencing information will be lost during this process. “NHEJ is inherently mutagenic as it relies on chance pairings called microhomologies, between single stranded tails of the two DNA fragments to be joined.“ 8 There has been a loss of the base pairs present in the original wild-type sequence.

Mismatch Repair MMR

This pathway is of particular interest in relation to cancer, as it represents an error in DNA replication. It occurs when the wrong DNA base is inserted or substituted during repair to form a new DNA strand or when a DNA base has been deleted during DNA synthesis repair. The incorrect base pairs are known as mismatches or mispairs. [9]

Mutations occur when DNA cannot be repaired before Mitosis (cell division). When cells lose ability to repair DNA damage, they respond in one of three ways.

1. Senescent-mitosis. Cell division stops. The cell becomes irreversibly dormant. This protects you from cancer because it stops the growth of mutations. It’s the body’s last resort.
2. Apoptotic. This is when the cell is programmed for death to stop mitosis. It’s the body’s last resort.
3. Malignancy. When cells begin uncontrolled division after taking on immortal characteristics. This is how cells turn into cancer. [8]

Inflammation Induced by ROS from UV Radiation

Some genes can be over-expressed and can cause inflammation via upregulation of NFKB (responsible for signaling of inflammatory cytokines). You need repair enzymes and proteins to repair ROS-induced DNA lesions, but too much can cause a flood of cytokines. Your body will constantly be on alert and since inflammation generates free radicals and free radicals cause inflammation, you create a constant source of damage.

One example of inflammation caused by UV exposure is that it causes Versican, a component of the Extra Celluar Matrix (ECM), to release inflammatory cytokines that interact with ECM molecules such as collagen, proteoglycans, hyaluronan and glycoproteins.

The ECM houses fibrous structural proteins, including collagens, elastin and laminin, that are very important for skin integrity and strength. [6] The more you are exposed to UV radiation, the more expression of Versican and this leads to inflammation that can age the dermis. This is yet another example of expression of inflammation markers from UV radiation DNA damage.

The most important inflammatory cytokines ILB and IL6 were increased during accumulation of 8-oxoG radicals from UVB and resulted in inflammation.

“Continuous accumulation of UVB ROS-induced 8-oxoG in the skin by UV leads to damaged DNA and inflammatory cytokines IL-B IL6 and this leads to overexpression of Versican and photo aged skin. The over expression of Versican promotes further inflammation.” [6]

PARP-1 repairs damage from ROS-induced DNA lesions but can lead to increased inflammation by activation of PARP-1 signaling of NFKB. The body needs to be able to repair itself, but when you are consistently signaling for repairs, you cause more damage from the persistent inflammation. [7] “Parp-1 signaling, where it is participating in DNA repair but may also induce DNA damage through inflammation if chronically activated for repair processes.” [7]

You must figure out the source of your aging as it relates to your genetics and environment. If you have a genetic variance predisposing you to ineffective DNA repair and protection, you should use protection such as SPF when exposed to UV in the sun. You should take supplements that will inhibit the genes that cause your body to be on fire and promote certain genes to effectively repair your DNA lesions. Also something interesting to note is that some fluorescent lights can cause damage in the same way UV can so it is important to wear SPF when you are exposed to certain fluorescent lighting. [10]

References

1. “Physiology of the skin Draelos, D., pugliese, p. 2011. Page 100
2. Br J Cancer. 2004 Oct 18;91(8):1604-9. Genetic variation in XRCC1, sun exposure, and risk of skin cancer. Han J1, Hankinson SE, Colditz GA, Hunter DJ.
3. Encyclopedia of aging. 2002. Bohr, Vilhelm. The gale group.
4. Respective Roles of Cyclobutane Pyrimidine Dimers, (6–4)Photoproducts, and Minor Photoproducts in Ultraviolet Mutagenesis of Repair-deficient Xeroderma Pigmentosum A Cells. Eriko Otoshi, Takashi Yagi, Toshio Mori, Tsukasa Matsunaga, Osamu Nikaido, Sang-Tae Kim, Kenichi Hitomi, Mituo Ikenaga and Takeshi Todo
   Published 15 March 2000
5. Topical Treatment with OGG1 Enzyme Affects UVB-induced Skin Carniogenesis.
6. Increased Expression of Versican in the Inflammatory Response to UVB- and Reactive Oxygen Species-Induced Skin Tumorigenesis. Kunisada M1, Yogianti F, Sakumi K, Ono R, Nakabeppu Y, Nishigori C.
7. PARP-1 Friend or Foe of DNA Damage and Repair in Tumorigenesis. Amanda F. Swindall 1, Jennifer A. Stanley 1 and Eddy S. Yang 1,2,3,*
8. DNA Damage and Repair. Sigma Aldrich.
9. Encyclopedia.com/topic/DNA_repair.aspx#1
10. The risk of ultraviolet radiation exposure from indoor lamps in lupus erythematosus. Rachel S. Klein,1 Robert M. Sayre,2,3 John C. Dowdy,2 and Victoria P. Werth1,4. Autoimmun Rev. 2009 Feb; 8(4): 320–324.
    Published online 2008 Nov 6. doi:  10.1016/j.autrev.2008.10.003