Interview with Vadim Zorin on skin rejuvenation

With age, our health begins to deteriorate. To some extent, our bodies can cope with these changes, but after 35 many of them become noticeable. For us, living in a world where youth and beauty are considered an advantage, this gradual loss of a young appearance can be painful - if we do not know how to slow it down or turn it around.

It's not that beauty is valuable to me personally, but I often hear people say that anyone who promotes life extension technologies should be a good example; and wrinkles, dull skin and hair, overweight discredits not only the activist, but also the movement in general.

I follow what happens in aesthetic medicine - especially when it is based on rejuvenating biotechnology. Last week, I went to one of the leading research organizations in Moscow - the Institute of Human Stem Cells - for an interview with Dr. Vadim Zorin, the SPRS therapy project leader and the developer of a unique approach to skin rejuvenation.

Interview

Milova : Our community is interested in different approaches to slowing the aging process. If we recall the publication of 2013, The Hallmarks of Aging, skin aging (and other types of epithelium, as I understand it), is due to three mechanisms of aging: depletion of the stem cell pool, impaired proteostasis (that is, the cell produces less proteins for its normal function), cellular aging. Please tell us how SPRS therapy counteracts these mechanisms of aging?

Zorin : SPRS therapy (Service for Personal Regeneration of Skin) - a set of personalized treatment and diagnostic procedures for skin restoration with signs of age and other structural changes. SPRS therapy is based on the use of autologous patient's skin fibroblasts.

Fibroblasts are the main cellular component of the skin, providing its homeostasis and morphofunctional organization. They perform a variety of complex and complex functions in the skin: they control the composition and structure of the extracellular matrix of the dermis (collagen, elastin, proteoglycans and structural glycoproteins), and their function includes not only the production of these substances, but also their catabolism. Thus, fibroblasts are a key element in skin biology - they not only maintain the homeostasis of the extracellular matrix of the dermis, ensuring its remodeling and renewal, but also play a significant role in maintaining the physiological state of other skin layers.

As the population of skin fibroblasts ages, the number of cells decreases (according to J. Varani et al., 2006, in the skin of old people, compared with young, the total number of fibroblasts is reduced by an average of 35%), their biosynthetic activity decreases (according to Fisher G. et al., 2002, collagen production in the skin of old people, compared with young people, is on average reduced by 75%; the balance between the processes of synthesis and degradation of the extracellular matrix of the dermis is disturbed. A natural consequence of these processes is a reduction in skin thickness, a decrease in its elasticity and elasticity, and the formation of wrinkles. Those. The aging process of the skin is reduced to a decrease in the population of fibroblasts and a decrease in their proliferative / synthetic activity, which is naturally manifested in a decrease in the quantitative and qualitative composition of the extracellular matrix of the dermis.
The use of cultured autologous dermal fibroblasts (autoDP) allows you to replenish the population of fibroblasts that have decreased with age due to the introduction of specialized functionally active cells into the patient's skin.

(Back in 1994, American scientists showed that the introduction of autoDP into the skin contributes to the effective correction of wrinkles. Further, both American and Russian scientists conducted a number of clinical studies that confirmed the efficacy and safety of the use of autoDF in aesthetic medicine, thanks to which This technology has received worldwide recognition. For example, in 2010, the JSC “Institute of Human Stem Cells” (HSCI) in Russia received permission from the Federal Service for the Supervision of Health For the correction of age and cicatricial changes of the skin (technology "SPRS therapy"), from the English Service for Personal Regeneration of Skin), and in the USA - in 2011, the FDA issued Fibrocell Science permission to use auto-DF for the correction of wrinkles in the nasolabial folds (LAVIVTM technology, azficel-T)).

The changes we identified in the skin using instrumental and morphological studies (increasing the thickness, elasticity and elasticity of the skin, reducing the number and depth of wrinkles) indicate that after transplantation, the cultured autoDP fully integrates into the dermis, their biosynthetic activity lasts for at least 12 months. As a result, remodeling of the dermis microstructure is observed, which is expressed in an increase in the content of collagen fibers in it, an increase in skin hydration, an increase in its density and thickness. The clinical effect has an increasing character throughout the year and lasts for at least 2 years. The results we obtained are consistent with the results of studies conducted by American companies Fibrocell Science, which also showed a significant decrease in the number of wrinkles and an increase in skin thickness after the application of auto-DF.

Milova : Of course, when a person is seriously engaged in restoring a young appearance, he undergoes not one therapy, but a complex. These include contour plastic surgery, plastic surgery, and other injection methods, for example, plasma-lifting, which is currently popular. But your therapy was undergoing clinical trials where only its effect was monitored. What did your patients say, how old they looked after the course of treatment? How exactly do you measure results?

Zorin : It is difficult to say how younger the patients are after SPRS therapy, since no such studies have been carried out by anyone, but we can state with high certainty the change of parameters that are “responsible” for the youth and beauty of the skin - this is the thickness / density and hydration of the skin, the severity of pigment spots , the number and depth of wrinkles. So, our clinical analysis of the skin condition (on a 5-point scale) showed that if a month after the injection, 88% of patients evaluated the “good” and “excellent” clinical results, then after 3 and further (6,12,24) months - all 100%.

We carried out measurements using the following methods: histological studies (simultaneously with the introduction of autoDP into the skin of the face, were injected into the skin behind the auricle for subsequent biopsy after 1.3, 6.12 and 24 months) - morphometric estimation of the dermis thickness, impregnation with silver nitrate (to identify newly formed collagen fibers), immunohistochemistry, which revealed a prolonged biosynthetic activity of transplanted autoDF for at least 12 months, expressed in the synthesis of components of extracellular etochnogo matrix and increase in dermal thickness by an average of 63% during the year; microcirculation assessment - using laser Doppler flowmetry (laser blood flow analyzer), elasticity - using cutometry (Cutometer MPA 580, Courage + Khazaka Electronic GmbH), skin texture and wrinkles - using a VISIA photo system (Proctor & Gamble Co), wrinkle depth - by means of optical profilometry (PRIMOS, GFMesstechnik GmbH).

As a result of the conducted research, a significant increase in the elasticity and thickness of the skin, a decrease in the severity of pigment spots, a decrease in the number and depth of wrinkles were revealed.

Milova : It is wonderful that we have a way to achieve external rejuvenation. Moreover, it concerns not only the condition of the skin, but also such a common problem as hair loss. As I understand it, this is especially important for men - what is the proportion of men among your patients?

Zorin : Men among our patients make up 1/3.

Milova : Is it possible to restore hair pigmentation in people who have already turned gray?

Zorin : Today, no, it is impossible. This is a very complex process, since physiological graying is associated with the natural aging of melanocytes, and early gray hair is usually caused by their death or decreased activity due to hormonal disorders. As a result, hair loses its pigment, acquires a porous structure, and the air layers that have appeared give it a silvery-white tint. Stop the process of "graying" can not be, because Melanocyte cells begin to work even in the prenatal period of human development and gradually regress with age. Every 10 years after 30 years of age, their function diminishes by 10–20% and hair begins to appear with a lack of pigment in keratin. When all the melanocytes, which supply melanin to the hair shaft, die off, the hair becomes completely gray.

Milova : But the more difficult question is, is this approach applicable in order to repair other tissues and organs, or does SPRS only restore skin? If restrictions exist, what are they related to?

Zorin : SPRS therapy is aimed at restoring only the skin, because it is based on the use of certain cells - skin fibroblasts. But in the arsenal of our company there is another technology approved for use - SPRG therapy based on the use of oral mucosa fibroblasts, which allows restoring soft periodontal tissues.

Milova : Last year, our community was agitated by news from the Salk Institute, where, by reprogramming the cells of an adult organism, the Yamanaki factors partially reversed age-related changes in mice, such as muscular dystrophy or age-related metabolic disorders. What do you think about combining SPRS and the short-term use of Yamanaki factors on cell culture? Can the further development of SPRS therapy go in this direction?

Zorin : Yes, of course, reprogramming of autologous skin fibroblasts will allow you to get personalized iPSC patient cells that can be considered as innovative technologies for autogenic therapy of a wide range of diseases, including drug screening. However, it should be noted that, despite the promising possibilities of therapy based on autologous iPSC cells, it is still at the initial stage of development. It is necessary to conduct further studies with a detailed study of the bio-and onco-safety of the use of these cells, an analysis of their chromosomal stability, both in the early and late passages, as well as a comprehensive analysis of the differentiation potential.

Milova : At the moment, SPRS therapy is quite expensive, the price for one course of treatment can be more than $ 5,000. In order for this approach to slowing down aging to be available to the broad masses, the price must drop significantly. HSCI has a very good history in reducing the price of innovative products. I'm talking about gene therapy, which is developed at the institute. Your Neovasculgen drug is designed to stimulate the growth of the vessels of the lower extremities in order to replace the vessels lost as a result of severe ischemia. Over the past couple of years you have managed to reduce the price for Neovasculgen more than 2 times. How have you achieved this and can we expect similar breakthroughs for SPRS?

Zorin : Here we need to understand that in the case of SPRS therapy, we do not work directly with patients, the final price to the patient is set by the clinic with which we work within the framework of a bilateral agreement and, often, to our great regret, this price exceeds our cost price (ie The price at which we offer the clinic service is 3 times, and in some clinics 5 times! Now we are trying to work with new clinics in the direction of an adequate final price for the patient.

Milova : Can automating the process of cell cultivation help reduce the price? What are the main obstacles to more rapid implementation of automation?

Zorin : Automation of the process is real with the use of allogeneic cells; in the case of autologous cells, automation, on the contrary, will make the procedure even more expensive.

Milova : In addition to helping people become younger, you often write to your blog about your personal health strategy. What elements, in your opinion, should be the basis of such a strategy? What methods of slowing down aging do you think are sufficiently scientifically based, and what do you personally use?

Zorin : What happens to us with increasing age? Increasing food intake - one time, reducing motor activity - two, reducing the body's ability to mobilize fat - three. Starting from the age of 30, alas, the body's fat content begins to increase, but the net body weight, due to a decrease in muscle tissue and demineralization of bone tissue, decreases. This is due to many factors, not least of which is the same decrease in motor activity due to metabolic processes that develop with age. And it turns a vicious circle. Therefore, the algorithm is very simple:

1. Increased physical activity, which leads to high energy costs. What kind of training is the easiest and most useful? Normal walking or, even better, Nordic walking - in the "cardiological" step (ideally, 5-6 km / h with a pulse rate of 120 beats / min). This is training in the so-called aerobic zone, i.e. low-intensity and long-term physical exertion.
   
   I am an adherent of Scandinavian walking (CX) (which uses up to 85% of the muscles of the body and, among other things, perfectly supports energy metabolism, pulmonary ventilation and muscle tone, which plays an important role in preventing the development of, in particular, coronary heart disease). But since any physical activity must be adequate to the age and state of health, for this purpose - control of the pulse is obligatory (heart rate, heart rate). I use the Runtastic PRO program installed on my mobile phone to control (in real time) heart rate, distance and speed. Standard training regime: at least 3 times a week with a walk duration of 30-40 minutes and more. By the way, physical exertion contributes not only to the strengthening and growth of muscle and bone tissue (and we have no more or less of them - 206 bones and more than 640 muscles (!), But also stimulate the activity of stem cells in the tissues responsible for maintaining the number of people their cells.
2. Conscious control of the diet. Restriction in food prolongs life (as it turned out, in any organisms - starting with yeast and ending with primates, including humans). And in 2007, evidence of this phenomenon appeared at the cellular level - when American scientists led by David Sinclair (published in the most prestigious scientific journal Cell) discovered the genes SIRT3 and SIRT4 (activation of which leads to an increase in the level of proteins of the same name - from the sirtuin family - which are important regulators of the slowing down of cell aging and the “longevity” of the body). In general, it happens this way. In the cytoplasm of cells there are “energy factories” - mitochondria. With a decrease in calories entering the cell, signals about this enter the mitochondria and activate the specific NAMPT gene in them, which leads to an increase in the production of certain molecules (the so-called NAD, the main energy carriers in the cell), which, in turn, activate the SIRT3 and SIRT4 genes . The proteins expressed by these genes lead to an improvement in energy metabolism in the cell, and this, in turn, leads to a delay in cell aging and the prevention of apoptosis (premature cell death). As a result, aging processes are slowed down in the body, development of “age-related” diseases is delayed and, accordingly, life expectancy increases.
   
   Proof of this can be the results of a 25-year study (Nature Communications magazine, 2014), conducted by a team of scientists from the University of Wisconsin-Madison on rhesus monkeys.
   
   These are the “bonuses” received by the macaques, who were on a low-calorie diet: 1) normal body weight; 2) decrease in the rate of loss of muscle mass (which is known to accelerate with age); 3) a significant reduction in the risk of diabetes and cardiovascular diseases; 4) extending life to 30 years or more (despite the fact that the average life expectancy in captivity for these animals is about 26 By the way, Sinclair and his colleagues say that physical activity has the same effect on the body as a low-calorie diet ...
3. And, of course, do not forget about the sauna (to those to whom it is not contraindicated for health reasons). Sauna perfectly relaxes, dilates blood vessels and ... reduces the risk of respiratory and cardiovascular diseases, senile dementia and even Alzheimer's disease.

Milova : We often ask researchers what their prediction is about medical technology for managing aging. Do you think science will succeed in defeating aging, and thereby preventing age-related diseases? What can we as a community do to make this happen faster?

Zorin : I think that sometime in the future it will happen. Although much has already been done in this regard. What kind of directions?

1. Gene therapy; have experimentally managed to extend the life of laboratory worms-nematodes, fruit flies, mice. The person also identified the genes responsible for the extension of life.
2. Cell therapy; Today, many clinical studies are being conducted on the treatment of so-called “classic age-related diseases”, when, when allogenic mesenchymal stromal cells are introduced into damaged areas of the brain and heart, they significantly improve the condition of patients who have had a stroke and heart attack. Recently, in clinical trials (phase I and II) with the help of cell therapy, good results were also obtained for the restoration of bones, joints, and skin. В настоящее время во многих ведущих лабораториях мира достигли успехов в изучении индуцированных плюрипотентных клеток (iPSC), на которые возлагают большие надежды, поскольку с одной стороны, они обладают свойствами эмбриональных стволовых клеток (ESC), то есть способны к дифференцировке в производные всех трех зародышевых листков, а с другой – их использование позволяет избежать этических проблем, связанных с применением ESC. Эти клетки дают возможность создания инновационных технологий для аутогенной терапии самого широкого спектра заболеваний, включая, естественно, и возрастные патологии.
3. Выращивание и пересадка органов. Уже сейчас научились выращивать в лабораториях не только хрящевую ткань и кожу, кровеносные сосуды, но и мочеточник, мочевой пузырь и иные полые органы. Работают над созданием искусственных сердца и легких. Одним словом, перспективы очень большие.

Что мы как общество можем сделать? Повышать свой уровень образования, развивать науку и медицину.