Free radicals and the aging process

Free radicals are highly reactive chemical species carrying an unpaired electron in their outer orbit. They abstract electrons from the surrounding molecules (lipids, proteins, DNA) in order to complete their own electron structure, thus inducing cellular damage. Such reactions are strongly implicated in the development/ pathogenesis of chronic diseases as atherosclerosis, diabetes, rheumatoid arthritis, skin and neurodegenerative disorders, cancer, as well as in the aging process.

To the free radical family belong Reactive Oxygen Species (ROS) like superoxide, hydrogen peroxide, hydroxyl radical and singlet oxygen, lipid peroxides, Reactive Nitrogen Species like nitric oxide and peroxinitrite as well as Reactive Chlorine Species like the hypochlorite anion.

Important internal and external sources of free radicals contributing to the aging process of human tissues are described in Figure 1, but reactive oxygen species (ROS) are also generated in cell-free systems including O₂, H₂O₂, transition metals as Fe²⁺/Fe³⁺, Cu¹⁺/Cu²⁺, thiols, ascorbate, xanthine/ xanthine oxidase, chelating agents, xenobiotics and others.

The Free Radical Theory of Aging formulated by Dr. Denham Harman, in 1956, postulates that aging is caused by free radical reactions associated with environmental influences, disease, failures of the antioxidative defence and the intrinsic aging process. It predicts that the life-span of an organism can be increased by slowing the rate of initiation of free radical reactions and/ or decreasing their chain lengths. In accord to this theory, several mechanisms related to the aging process have been described:

• The endogenic and exogenic free radical generation factors related to disease and aging.
• The pathways of the lipid, protein and DNA oxidative damage induced by the free radical attack and antioxidant strategies to slow down or block these reactions, as well as;
• The patterns of glycation / oxidation and cross-linking reactions of lipoproteins involved in the aging progression.

Skin aging triggering factors

As already reported at the 3^rd Monte Carlo Antiaging Conference ™ in September 2002, [Ed.- Audio tapes are available from International Antiaging Systems, or see www.antiaging-conference.com], the intrinsic (genetically determined) and the extrinsic (UV- and toxic exposure mediated) skin aging processes are overlapped and strongly related to an increased generation of free radicals in the skin.

Generally, the intrinsic skin aging process is characterized by:

• Increased cellular catabolic activities.
• Deficient antioxidant defence mechanisms, (genetic polymorphism).
• Deficient melanin synthesis, (genetic polymorphism).
• Deficient detox capacity, (genetic polymorphism).
• Decreased sexual hormones supply, (age related).
• Low blood perfusion, (arteriosclerosis, lack of exercise).

Biomarkers of the intrinsic skin aging include the hyaluronic acid depolymerisation, a reduced melanogenesis and estrogen dependent collagen synthesis, lowered ATP generation and wound repair capabilities, impaired antioxidant defence and increased lipofuscin generation, (age spots).

On the other side, the extrinsic skin aging is closely related to:

• The photoaging process induced by sunlight or artificial UV-exposure, which has the major impact on skin appearance through an obvious free radical generation in the skin. [Ed.- Referring to Dr. Kyriazis article in this issue of the Bulletin, remember that as much as 90% of skin damage could be caused by photoaging].
• Toxic environmental exposure via smoking, industrial exhausts, heavy metals, detergents, all of which are known to be potent free radical inducers.
• Chronic infection/ inflammatory states associated with an increased free radical attack, (superoxide, peroxinitrite, hypochlorite).
• Inappropriate nutrition, (excess of refined carbohydrates, fats, food additives, alcohol, low water intake) and last, but not least;
• Sleep deficiency and stress.

Biomarkers of the extrinsic skin aging processincludes products of lipid peroxidation, collagenase activation, glycation/ oxidation of proteins (AGE products), activation of p53 transcription factors, low DNA repair capacity and cumulative DNA damage/ mutations leading to skin cancer and others (Figures 2a+b).

The photoaging process, (in the presence of natural sunlight or artificial UV sources) happens continuously and leads in time to dryness, deep wrinkles, sagging, lost of elasticity, mottled pigmentation and skin telangiectasia.

Clinically, the adverse effects of natural sunlight and other UV-sources on normal human skin may vary from sunburn with erythema, oedema and DNA damage (12-24 hrs. after UV-exposure) to polymorphic light reaction (eczema solare), solar actinic elastosis and actinic hyperkeratosis, (as common precancerous condition), up to different skin cancer forms like basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or malignant melanoma (MM)

Usually, photoaging and other extrinsic skin aging factors are superimposed on intrinsic aging processes, leading to complex morphological and biochemical changes of the skin.

As the photoaging through sunlight or artificial UV-exposure has the major impact on skin appearance, new defence strategies including the appropriate UVA+UVB sunscreen choice in addition to an antioxidant rich food, the induction of photo-protective melanogenesis through thymidine-dinucleotide (pTpT) formulations, the use of phytoestrogens and metal chelating agents to inhibit the collagenase activation, the avoidance of refined hyperglycaemic carbohydrates to slow down the glycation/ oxidation of proteins, the use of DPTT, aminoguanidine and carnosine formulations to inhibit the collagen cross-linking as well as retinoic acid to stimulate the DNA repair mechanisms and collagen synthesis, have been suggested (Figures 2a+b).

However, it is essential to understand that the above mentioned approaches must have an individual character, related to the metabolic, nutritional and clinical skin status of the individual person.

Of considerable interest for the aging subject or dermatological patient is the rapid evaluation of their free radical and anti-oxidant status, in view of an appropriate intervention. In this respect, the introduction of new, simplified redox and chemiluminescenece technologies in the Spezial Klinik at Neukirchen, Germany, has allowed the rapid routine investigation of the oxidative stress in blood and plasma samples of dermatological, chemical sensitive and cancer patients, as well as in geriatric subjects

As demonstrated in hundreds of clinical cases, these new technologies help the physician to choose the right drug or nutritional therapy for ROS mediated diseases and to monitor the efficacy of these treatments over time (Figure 3a+b).

New photoaging defence therapies

Research data indicate that the overlapped intrinsic and extrinsic skin aging mechanisms are leading to an accelerated collagen, elastin and hyaluronic acid degradation associated to low water retention, diminished antioxidant capacity, disrupted cellular structures, low energetic metabolism, sagging and wrinkled skin.

The study of the lipid, protein and DNA oxidative damage triggered by sunlight exposure and the subsequent free radical attack has conducted to appropriate strategies to slow down or block these reactions, and has made possible the design of appropriate skin care formulations. In order to minimize the intrinsic and the extrinsic skin aging processes innovative compounds addressing the low energetic metabolism and melanin synthesis, the increased carbonylated proteins and lipofuscin generation were introduced in the products. In this respect, the new Solaris ® Photoaging Defence Formula, which combines for the first time the double UVA + UVB protection (SPF 25) with melanin promoting factors, thus enhancing the natural tanning process. [Ed.- This makes Solaris ® very unique, not only does it have a very high sun protection factor of 25, therefore guarding against photoaging, but is also allows for tanning to take place, thus giving people the look they want without undergoing the damage it would normally do].

Solaris ® also contains free radical and metal blocking agents like Vitamin E, carrot oil and EDTA, respectively, are also preventing the sun exposure side-effects, together with immune stimulating plant extracts (ß-glucans) with anti- herpes virus activity. The proved moisturizing properties of the base emulsion are completing this ultimate anti-photoaging formulation.

To slow down the photoaging linked wrinkle formation efficiently, Energo ® Repair Complex provides for the first time a synergistic anti-aging combination of UV-light blockers, free radical quenchers, (Vitamin E and Coenzyme Q10) plus anti-glycation agents and collagen/ elastin synthesis promoters like soy bioflavonoids. All the active ingredients are incorporated in liposomes, (containing skin identical phospholipids) and ceramides by means of the patented DMS ^® nanoparticle technology. A rapid uptake in the epidermis cells is thus granted.

Energo ® Repair Complex shows evident firming and anti-wrinkle effects smoothing the skin around the eyes and fights against dark circles and puffiness. It nourishes, moisturizes and tonifies providing the skin a youthful radiant look. A visible, significant difference was noticed in more than 1000 tested persons after 2-3 weeks of Energo ® use.

The combined use of the products (day/ night) may lead to most surprising results in a relative short period (Figure 4). All these anti-aging products are clinically tested, free of preservatives, colours and fragrances and therefore hypoallergenic and suitable for sensitive or allergic skin.

Further research on this topic is in progress in our laboratories; the attached references are supporting to the scientific background of these very new anti-aging skin treatments described above.

References:

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