The use of therapeutic plasmapheresis in preventive and sports medicine

. Maintenance of active longevity, preservation of physical activity, and prevention of decreased mobility associated with injury or age of patients are among the most urgent tasks for modern healthcare. The suppression of pathological processes and activation of defense systems at the cellular and organismal levels are the main routes for solving these problems. Several initial anti-aging therapy approaches are detoxification, rheocorrection, and immunocorrection. In these areas, methods of extracorporeal hemocorrection, in particular, therapeutic plasmapheresis, are effective. This study aimed to evaluate the effectiveness of hardware plasmapheresis with albumin compensation by assessing the dynamics of circulating age-related biomarker levels in randomly selected patients. Twenty human subjects of both sexes aged 40–55 years with an increase in one or more aging-related biomarkers participated in this study. The patients were randomly divided into two groups with ten people each. Patients from Group 1 underwent therapeutic plasmapheresis with albumin replacement (four procedures with a 2-day interval). Patients from Group 2 were offered plasmapheresis treatment with saline replacement. The levels of aging-related biomarkers were determined in the blood of patients before and 30 days after starting treatment. Preliminary data showed that plasmapheresis with albumin replacement in randomly selected male and female patients was accompanied by normalization of the selected aging biomarkers. Thirty days after the start of the plasmapheresis treatment, a decrease in both biological and phenotypic age was determined. Further studies are needed to investigate the effects of nutritional factors on aging biomarkers with and without plasmapheresis treatment. Based on the obtained results,


Introduction
Due to an increase in the average age of the population, prevention of premature aging and treatment of age-related diseases are among the most urgent tasks for modern healthcare [1]. Modulating the molecular mechanisms of aging can solve these problems. This approach aims to suppress pathological processes and activate the protection systems of cells and even the entire body [2]. López-Otín et al. showed that the main cellular and molecular signs of aging might include genome instability, shortening of telomeres, epigenetic alterations, disruption of proteostasis and nutrient sensing, and mitochondrial dysfunction, cellular senescence, depletion of stem cell pools, and changes in cell cooperation [3].
Currently, both non-pharmacological and pharmacological methods are used to prevent premature aging. Thus, initial approaches to anti-aging therapy include detoxification, rheocorrection, and immunocorrection. Extracorporeal hemocorrection has a particularly good track record [4]. For example, therapeutic plasmapheresis can be efficient during prophylaxis, treatment, and rehabilitation after various diseases and injuries-its major effects are associated with the removal of endo-and exotoxins including the products of lipid peroxidation [5]. Its effects are also related to a draining effect resulting from an enhanced inflow of interstitial fluid (containing products of pathometabolism) into the bloodstream within a concentration gradient. This leads to a "dynamic equilibrium" among the concentrations of different substances in intracellular, interstitial, and intravascular compartments [6,7].
The methods of extracorporeal hemocorrection have been used for a long time. In 1902, Hedon washed and transfused autologous red blood cells for dogs and rabbits. In 1909, Fleig described a case of treatment of a patient with uremia via bloodletting with subsequent return of red blood cells washed in saline [8].
In the early 20th century, research groups at the Department of Infectious Diseases, St. Petersburg Military Medical Academy, and the Pharmacology Department at Johns Hopkins University School of Medicine carried out studies that laid the foundations for current methods of extracorporeal detoxification. In Russia, these studies were done by V.A. Yurevich and N.K. Rosenberg [9]; the US team was led by J. Abel [10,11]. In the 1940s and 1950s, plasmapheresis was adopted for the treatment of hematological patients. In the late 1950s, plasmapheresis was first carried out for Waldenstrom's macroglobulinemia [12] described in 1944 [13].
Since the 1970s, many countries have used plasmapheresis as an additional method of intensive treatment [14]. Blood was initially separated via a centrifuge and plastic containers. A special blood cell separator was created in the late 1960s in the USA to automatically separate blood into components. Since 1976, there has been the ability to separate plasma via filtration through semipermeable membranes made of polyvinyl diacetate and lavsan filters. This is the basis for membrane plasmapheresis [9].
Literature analysis indicates an accumulating positive experience in using extracorporeal hemocorrection for the normalization of aging-related biomarkers. In 2018, Li et al. [15] described the efficiency of double filtration plasmapheresis in the prevention of premature aging and extension of active aging. The study comprised 915 subjects: 584 (63.8%) men and 331 (36.2%) women. The age of the male subjects reached 50.94 ± 10.60 years, and the age of the female subjects was 51.20 ± 11.84 years; 34 blood biomarkers were assessed. Comprehensive analysis and blood tests were used to screen aging biomarkers and develop formulas for biological assessment of male and female age. The authors studied the elimination of aging biomarkers via double filtration plasmapheresis. It was shown that double filtration plasmapheresis can lower aging biomarkers. On average, men lowered by 4.47 years after plasmapheresis and women by 8.36 years.
Mehdipour et al. [16] described the impact of plasmapheresis on body rejuvenation in experimental conditions. Here, 5% albumin solution was used as a blood substitute. The results confirmed theories that plasmapheresis with substitution of 5% albumin boosted muscle recovery, decreased liver fibrosis and steatosis, and positively affected hippocampal neurogenesis in old (22-24 months) mice.
This study aimed to assess the effectiveness of hardware plasmapheresis with albumin compensation in terms of the dynamics of circulating aging biomarkers in randomly selected middle-aged patients.
The patients were randomly divided into two groups of 10 people each. The patients underwent four procedures with a 2-day interval between treatments. Patients from Group 1 underwent plasmapheresis with albumin replacement (5% albumin solution). Patients from Group 2 (control) were offered plasmapheresis treatment with saline replacement.
This study was approved by the Local Ethics Committee of the National Medical Research Center for Rehabilitation and Balneology (Moscow). Each participant signed an informed consent form. The levels of age-related biomarkers in the blood of patients were determined before and 30 days after starting treatment.
Ten markers were used for these estimates: albumin, creatinine, glucose, C-reactive protein, percentage of lymphocytes, MCV, RBC distribution width, alkaline phosphatase, WBC count, and patient's chronological age.

Results and Discussion
Here we evaluated the effectiveness of hardware plasmapheresis with albumin compensation by assessing the dynamics of circulating age-related biomarker levels in randomly selected patients. The biological and phenotypic ages were estimated before and 30 days after the start of plasmapheresis treatment.
The phenotypic age was estimated for selected patients using the equation available in the literature [16]: The following ten markers were used for these estimates: albumin, creatinine, glucose, C-reactive protein, percentage of lymphocytes, mean corpuscular volume, RBC distribution width, alkaline phosphatase, WBC count, and chronological age. Table 1 shows the clinical and biochemical blood analyses of a 50-year-old man, which were used to determine his biological age before and 30 days after the start of plasmapheresis treatment. The patient presented with general weakness and fatigue.
Before treatment, his biochemical blood analysis revealed raised cholesterol, HDL cholesterol, LDL cholesterol, lactate dehydrogenase, creatine kinase, and glucose levels. All the main indices in the clinical blood test were within normal limits. Thirty days after the start of plasmapheresis, his blood glucose, (LDL) cholesterol, and lactate dehydrogenase levels had decreased to within normal limits and there was also a decrease in his cholesterol and creatine kinase levels, albeit still higher than normal. Table 2 shows the clinical and biochemical blood analyses of a 42-year-old woman who presented with general weakness and rapid fatigability. Before treatment, all the main clinical blood test indices were within normal limits, but the biochemical blood test showed decreased total protein, apolipoprotein B, cholesterol, and low-density lipoprotein (LDL) cholesterol and elevated urea and lactate. After 30 days of treatment, her urea and lactate had decreased to normal, while total protein, cholesterol, and LDL cholesterol levels remained below normal limits. Thirty days after the start of plasmapheresis, a decrease in both biological and phenotypic ages was determined in randomly selected patients. Our studies have shown that plasmapheresis may lower the biological and phenotypic ages of an individual and as a result, lead to a reduction in the risks of developing age-related diseases and disabilities and contribute to prolonging life and improving its quality.
Given the role of nutrition in healthy aging [19,20], further studies are needed to investigate the influence of nutritional factors on aging biomarkers with and without plasmapheresis treatment.

Conclusion
In this study, the effectiveness of hardware plasmapheresis with albumin compensation was evaluated by assessing the dynamics of circulating age-related biomarker levels in middleaged patients. Male and female patients with an increase in one or more of the aging biomarkers were randomly selected for the study. The biological and phenotypic ages were estimated before and 30 days after the start of plasmapheresis therapy (four procedures with a 2-day interval). After plasmapheresis treatment, a decrease in both biological and phenotypic age was determined. It has been shown that plasmapheresis may lower the biological age of an individual and is a promising anti-aging therapy that could help to increase lifespan and quality of life.
Further studies are now needed to investigate the effects of nutritional factors on aging biomarkers with and without plasmapheresis treatment. Based on the obtained results, recommendations will be made on the use of plasmapheresis in preventive and sports medicine.