Photo Aging of Skin

Photo aging is the effect of chronic ultraviolet exposure on the skin, and the term was first used by Kligman, back in 1986(1). Incidence of Photo aging is increasing in year by year. Photo aging is premature aging of skin, which is a very complex process which causes progressive functional and aesthetic changes in the skin. Photo aging is mainly due to Ultraviolet (UV) radiation that is UVa and UVb radiation and can also be due to genetic factors. Apart from UVa and UVb other rays like infrared and visible rays are also responsible for Photo aging (2). Photo aging is entirely different from chronological aging. Chronological aging, which is a natural phenomenon and cannot t be reversed or prevented like Photo aging and they differ clinically and histologically from Photo aging.

Photo aging is characterized by wrinkling of skin, loss of skin tone, loss of resilience due to loss of skin strength and skin elasticity. Photo aging appears mostly in areas which are exposed to sunlight like face, neck and back of the hands and is clinical presentation is with deep coarse wrinkles mostly around the eyes, then the mouth and on the forehead, next feature is uneven skin color and dryness, various spots which are pigmented like age spot, liver spots that are mottled pigmentations and freckles can also be seen, skin tone will be lost and will be leathery, spider vein can be seen on the nose, cheek and neck (4).

The mechanism behind Photo aging relating to UV rays is by producing an in balance between TGF β2 and AP1 damage, TGF β2 is an activator protein, which promotes collagen production and AP1 is a transcription factor which inhibits collagen production by increasing production of Metalloproteinase which break down collagen and there is another enzyme TIMP which inhibit MMP. In normal skin TIMP and MMP are in balance (5) (6). Whenever we are over exposed to UV rays there is an increased activity of AP1, which in turn increases MMP causes an imbalance between MMP and TIMP. Apart from increase increased activity of AP1 there is also decreased expression of TGF β2. This imbalance leads increased proteolytic activity leading to damage to collagen which will be corrected if not further exposed to UV rays, but if the skin is further exposed to UV rays damage to collagen will remain as such and skin will be formed abnormal in the form of wrinkles (6).decreased expression of TGF β2 causes decreases production of collagen . This damaged collagen and lack of new normal collagen formation altogether will lead to decrease in quantity of collagen forming leathery skin (fig.)

MMPs is induced by UV rays that induces by both UVa and UVb. UVa and UVb act by different mechanisms. UVa act by indirectly activating ROS, which intern produces other effects like lipid peroxidation, transcription factor activation, formation of DNA strand breaks, unlike UVa, UVb induce MMP by directly producing DNA damage and by ROS(7). Whether it’s UVa or UVb, ROS generation is the important factor in Photo aging.

SUN

AP1 ROS Generation TGF β2

MMP procollagen production

Collagen break down Imperfect repair

Invisible solar scar

Repeated UV injury

Visible solar scar

(Wrinkling of photo aging

Mitochondrial cells main function is to produce energy for the cell ,which is generated by a process called oxidative phosphorylation ,which is commonly known as electron transport chain .this oxidative phosphorylation usually have some error ,resulting in production of ROS which produces oxidative reaction. When human skin is exposed to uv rays ,it produces ROS .this ROS will cause damage to mitochondrial DNA which in turn leads to reduce of capacity for oxidative phosphorylation which accelerates production of ROS which again will cause mitochondrial DNA damage and the cycle is repeated resulting in conditions like photo aging (oxidative damage to mite dna)

UVa

ROS

Mutations of mitochondrial DNA

Acceleration

Reduced OXPHOS capacity

With the understanding of mechanism of photo aging, many strategies has been put forward for the prevention and treatment of photo aging .photo aging can either be prevented by using substances which the action of uv rays on skin or by giving treatment to reverse photoaging.it is well known that dark people develop less photo aging compared to white skin people which is thought to be due presence of increases melanin. So artificial tanning of skin by using thymine dinucleotide is a way to protect from photo aging (telomere mediated effects).another highly used way of protecting skin against uv rays is by using organic and inorganic uv filters as sunscreen creams however there is a controversy regarding effectiveness of this sunscreen formulations.( Coenzyme Q10, a cutaneous antioxidant and energizer.

As per above explained mechanism of photo aging it’s clear that giving an antioxidant will have high amount of benefit and many studies are done with antioxidants. All these strategies are for prevention of photo aging. There are also studies with vitamin a, all Trans’ retinoic acid for repair of already existing damages to the skin. (. (New and emerging treatment for photo aging)

It’s a known fact that Skin photo aging is caused by the solar rays induced oxidative stress. Apart from the mechanism of imbalanced mmp and action on mitochondrial DNA there are other mechanisms involved in skin photo aging .In a in vivo study it was shown that when skin get exposed to ultraviolet rays cholesterol undergo O₂ oxygenation reaction with the help of free radicals and or O₂ to form a peroxidation product cholesterol 5 αhydro peroxide which form cholesterol aldehyde .cholesterol aldehyde modify proteins to form various pathological conditions including photo aging(formation of cholesterol).in another study it was reported that apart from cholesterol another target of 02 oxygenation reaction is unsaturated fatty acids like oleic acid and linoleic acid (age related ).this animal studies proved that 02 produced from type ii photosensitized reaction is involved in the injury of skin exposed to chronic UVa by oxidative stress.

From above its clear that free radical and or O2 is involved in the process of photo aging, so using an O2 quenching substance like carotenoids will help in prevention of photo aging (singlet oxygen quenching).

The normal skin itself has antioxidant protective effects .this antioxidant protective effect are produced by endogenous enzymatic antioxidants like GSH peroxidase ,SOD and catalase as well as non-enzymatic antioxidants like vitamin E ,vitamin C ,GSH, Uric acid and ubiquinol.when most there is an attack of ROS ,the skin will itself form an antioxidant defense complex the most important one among them is manganese superoxide dismutase (mnSOD) which a mitochondrial enzyme (antioxidant defense mechanism.)whereas when the skin is exposed to uvrays repeatedly this endogenous enzymes has less as evidenced by the less concentration of antioxidant enzyme in photo aged skin ,especially in the epidermis and stratum cornuem. Which makes it mandatory to use an external source of antioxidant when skin is exposed repeatedly to UV rays. (pandet et al)

On over all its known that main pathology involved in process of photo aging is oxidative reactions .with the understanding of that many studies have been done with different exogenous antioxidants since 30 years .different has been tried by different researchers .elmore et al studied with topical vitamin C cream .which has shown improvement.boelsma et al in 2001 reported vitamin E compliment the photo protective effect. Ribaya-Mercadoet al.in a study established that lycopene protect against UV induced photo aging in humans. Stahl and Krutmann, 2006 reported in a study that carotenoids gives basal protection against UV induced photo aging. Effect of carotenoids particularly beta carotene was studied by cho et al in 2010 and proved that dietary beta carotene has effect on photo aging. There are several studies done on photo aging with topical tretinoin and most of them has shown positive results one among them is study done by voorches in 1990 where he proved that topical tretinoin reduce the effects of photo aging. Hoppe et al studied with topical coenzyme q10 ,it has shown positive effect in preventing photoaging.richard et al done in vivo study with zinc treated fibroblast ,which showed a positive result in uvr resistance .in 2002 a study was done with resveratrol by afaq and mukhtar ,which showed effective prevention of induced increase in skin thickness .another antioxidant used in study was green tea ,green tea proved to reduce uv induced oxidative stress in a study done by katiyal et al.lu et al done a study with caffeine ,caffeine showed increase in p53 ,slowed cell cycling . Singh and Agarwal, 2002 reported that silymarin prevent photo carcinogenesis. Cocoa was proved to have photo protective effect against uv induced erythema in a study done by Heinrich et al.,

Ultraviolet rays

UV rays are electromagnetic rays which are naturally emitted from the sun along with other electromagnetic lights like visible and infrared rays. Electromagnetic spectrum of UV rays extends between x-rays and visible lights that is 40 to 400 nm. UV rays are classified into three types depending on its wavelength as UVc (220-290 nm), UVb (290-320) and UVa (320-400 nm). UVa having longer wavelength and the least energy and UVc have short wavelength and high energy, having high energy means its most hazardous but fortunately it doesn’t cross ozone layer where as UVa and UVb cross ozone layer in small quantity.

UVa is the one responsible for production of tanning with the help melanin pigments when exposed to the sun, which is actually a defense mechanism to protect human skin from further exposure to UV rays (2), it’s also used in vitamin D synthesis, having said so over exposure of UV rays may cause erythema , toughening of skin and inflammatory reaction to eyes and over exposure for a long term leads to cataract formation ,immunosuppression , Photo aging of skin and skin cancers(3). Artificial UVA lights are widely used in health science for phototherapy in case of certain skin conditions like psoriasis for sterilization and disinfection and tanning booths (4)(2) (5).

Among skin cancers, non-melanoma skin cancers like basal cell carcinoma and squamous cell carcinoma are more common, but rarely fatal. Melanoma and non-melanoma combined leads to 66,000 deaths per year. Another hazard of long term of UV ray exposure on the skin is premature skin aging, photo dermatomes and Actinic keratosis which are due to degenerative changes in cells of the skin, fibrous tissue and blood vessels (6).

Mixed carotenoids

Mixed carotenoids are a combination of different types of carotenoids, in a particular combination. Carotenoids are plant pigment which are having 40 carbon atoms in a molecule (1). Carotenoids are mainly of two type’s one containing carbon, hydrogen and oxygen containing and other with carbon and hydrogen, which are named xanthophylls and carotenes respectively (2). Carotenoids are plant pigments which are synthesized by plants in higher amount and partly by algae and bacteria(2). Carotenoid is abundant in animals also, which they acquire by eating plants. Carotenoids are of different types around 700 carotenoids have been identified, most commonly available (3). Carotenoids like lycopene, beta-Cryptoxanthin, beta carotene, lutein, zeaxanthin. Alpha carotene, echinenone. Capsanthin, astaxanthin, canthaxanthin and all are commonly available fruits and vegetables like tomato, mango, carrot, citrus lime, green leafy vegetables, mushrooms and all, some of the carotenoids are well absorbed and are present in plasma (4) (5) .

Carotenoids were considered to be just as provitamin A, and importance of carotenoids in that case is itself considered to be the nontoxic reserve of vitamin- A (6)(4) .Recently its discovered that carotenoids are not just provitamin A it has other actions as well, from that point on immense research has been going on with carotenoids in almost all the system and all over the world (7).

Carotenoid is normally present in tissue and blood of humans. Adipose tissue is the most abundant one in carotenoids followed by liver and muscle, apart from this tissue carotenoids are also present in other tissues like corpus lithium, adrenal gland, macula lutea (8).

Among carotenoids lutein, Cryptoxanthin, lycopene, alpha carotene, beta carotene are the ones which are commonly available in serum and other tissues like adrenal gland (4)(3). Human skin contains carotenoids like α-, γ-, β-carotene, lycopene, lutein, and zeaxanthin (9)

Carotenoids are proved to be useful in many diseases and its many research is in process also, one of the most important research work related to carotenoids is its useful in cancer, especially in skin cancer, it’s been found that carotenoids acts in case of cancer by several mechanisms, one is that it protect against nuclear damage and sister chromatid exchange and another is that it when fibroblast are exposed to x rays, UV rays or to any chemicals like Cholanthrene it undergo transformation leading to cancer, carotenoids inhibit this transformation (4). In UV induced skin tumor it proved that carotenoid helped in delaying skin tumors induced by UV rays, over all carotenoids seems to inhibit development of cancer in the initial stage itself (10) (4). Another field or research with carotenoids is in ageing related, immune system, fertility, ischemic heart disease, and diabetes mellitus.

Carotenoids act by several mechanisms, but the entire mechanism of action is not yet proved in different part of the system, it has different action which is still on research, some of the mechanisms related to cancer has been discussed already. However, one of the well-known action of carotenoids is by an antioxidant mechanism, that is it act against oxidative stress(11). Oxidative stress is a result of reactive oxygen species (ROS) reaction or a free radical reaction (12). Reactive oxygen species are produced as an unfortunate byproduct of redox reaction which are a part of oxidative phosphorylation to produce ATP in mitochondria rays are produced by other redox reaction also, some of the examples of ROS are superoxide anions, hydrogen peroxide or hydroxyl radicals. This reactive oxygen species accumulation will lead to serious problems, which are inhibited by killing this race either by enzymatic mechanism or non-enzymatic mechanism. Enzymatic mechanism is by the help of enzymes and non-enzymatic approach is by the use of antioxidants like ascorbate and glutathione, tocopherol, flavonoids, alkaloids and carotenoids. So normally in human body oxidants are antioxidants are maintained in a balanced state, any break in that balance leads to trouble. But unfortunately the balance is disturbed in day to day life and so there is always a oxidative damage in the process (13) (14) (15).

Oxidative stress leads to many problems. Harman in 1956 itself has proposed that ageing is related to oxidative stress. According to him, rose will produce some irreversible deleterious changes to molecules, which was later on approved by many other researchers of past and present, a more elaborate finding was done by Halliwell B. He observed that the rays produced in mitochondria primary target is mitochondrial DNA itself, which leads to further production of Ross and this cycle is repeated leading to ageing. This case is similar when it comes to ageing of skin too, when skin is exposed to UV irradiation and oxidative stress is produced leading to ageing and as explained by Biesalski et al that oxidative stress can be prevented by antioxidants like carotenoids (17) (18). Another of the mechanism involved in photo aging o2 oxygenation of unsaturated lipids in the skin and cholesterol in the skin. This peroxidized cholesterol accumulation partly leads to activation of MMP9 (formation of cholesterol. (Age related when we use carotenoids it inhibit o2 oxygenation of unsaturated lipids and it also inhibit o2 oxygenation of cholesterol which in turn partly suppresses MMP 9 action. (Peroxide cholesterol induced)+participation of singlet oxygen.

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Advantage of taking carotenoids is that it accumulates in human skin which is commonly known as carotenoderma.carotenoids deposit more in palm of the hand and forehead. And the level of carotenoids present skin is proportional to the amount of carotenoids present in serum and its fortunate human absorb wide variety of carotenoids. (Carotenoderma a review).one of the reason for abundance of carotenoids in skin is that stratum cornea has a lipid layer which has more affinity to carotenoids. leading more amount of carotenoids in the stratum corneum .

Carotenoids protect sperm from the rose by its antioxidant property there by maintaining fertility. Carotenoids also has action female fertility by helping the formation of corpus luteum and many other aspects of reproduction as well, though a specific action of it is not known. Carotenoids have other actions like reducing risk of age related macular degeneration(20), they also reduce risk of age related cataracts (21), carotenoids reduce risk of hypertension and ischemic heart disease by lowering Tri acyl glycerol and increasing HDL (22).

Apart from this proved effects and mechanisms there are suggestions of many more of effects and mechanisms for carotenoids where immense researches are going on.

 

An intervention study demonstrated that dietary carotene

Protects the human skin from the UV light-induced erythema. (38)

Stahl et al.(39) found that combination of a relatively low dose of

total carotenoids (25 mg/day) and vitamin E (RRR-α-tocopherol;

335 mg/day) significantly diminished the erythema on dorsal skin

induced by illumination with UV light after 8 weeks. They also

revealed that the intensity of erythema 24 h after the irradiation of

UV light was diminished in a group receiving mixed carotenoids

containing β-carotene, lutein and lycopene (8 mg each/day) for

12 weeks.(40) In a separate study, intake of tomato paste rich in

lycopene (40 g/day) was also shown to be effective in the prevention

of erythema formation induced by UV light after 10 weeks.(41)

These studies strongly suggest that dietary carotenoids accumulate

preferentially in the skin and prevent it from UV-induced photooxidative

damage by acting as antioxidants