Aging is a physiological process of the time-dependent accumulation of cellular damages and accompanied by gradual functional decline. Aging is directly linked to lifespan and it is a driving force for all age-related diseases, such as cardiovascular musculoskeletal disorders and diseases, arthritis, neurodegenerative diseases, metabolic disorders (e.g. diabetes), and cancer.

Currently, there has been an increasing amount of interest in healthy aging. Healthy aging or “healthy aging phenotype” is a term for an extension of health period span avoiding major age-related chronic disease. People with healthy aging could also look younger than their chronological age (CA). To evaluate the biological age (BA) of an individual, many researchers have tried to develop methods that are based on a standard laboratory analysis data. Good methods for determining BA can accurately predict the degree of organism aging, and this BA estimation allows a person to assess the state of his body and how the aging process correlates with his real chronological age. Currently, there are many online services and tests that allow you to quickly determine your biological age with varying accuracy.

Likewise, many research groups are investigating the causes, hallmarks, and mechanisms of aging to understand how to slow down the aging process and develop appropriate therapies. Simplified, the mechanisms of aging can be divided into several strongly interconnected groups. These are the following :

1 Accumulation of DNA structure changes

Generally, aging is the result of an accumulation of the DNA damages, telomeres shortening, chromosomal gains and losses, and different epigenetic modification of DNA and its linked protein. All these forms of DNA structure modification affect the essential genes functioning and transcriptional pathways, leading to senescence or apoptosis of cells followed by tissue and organismal homeostasis impairment.

This is especially relevant when DNA changes occurred in the stem cells, lowering their ability in tissue regeneration. During evolution, organisms have obtained a complex network of DNA repair mechanisms that reduce genetic changes and therefore slow down aging processes. It was shown that deficiencies and defects in DNA repair mechanisms cause accelerated aging in mice and underlie several human progeroid syndromes such as Werner syndrome, Bloom syndrome, xeroderma pigmentosum, trichothiodystrophy, Cockayne syndrome, or Seckel syndrome. Disorders of DNA repair mechanisms are generally inherited or appeared during life.

In regard to the epigenetic mechanism regulations of DNA structure, it include different DNA methylation modification of and other patterns, histones, chromatin proteins. These epigenetic modifications are needed for right DNA organization, like special stuff to keep your closet neatly organized. Hence, dysregulations of epigenetic modifications during the aging process have effects on gene expression and cell proper functioning.

One of the chromatin-modifying protein families is Sirtuin. Proteins of this family have various activities and they interact with histones, transcription factors, and metabolic enzymes. Sirtuins are shown to take part in DNA repair and genomic stability, and thus contribute to healthy aging processes. As a result, their activator and inhibitor ways are investigated as possible targets for anti-aging therapy, although there is limited success in the development of sirtuin specific drugs to date. Some of the known and investigated ones are Resveratrol, Selisistat, and Quercetin.

Having said that, further nuclear DNA changes, mutations, and deletions in mitochondrial DNA (mtDNA) could cause mitochondrial dysfunction, leading to reduced ATP generation and increased ROS production. When this occurs, it results in disruption of cellular homeostasis, cell senescence, and stem cell exhaustion.

2 Impairment of protein homeostasis (proteostasis)

For protein homeostasis to work accurately, the proteins must fold and assemble into precise three-dimensional structures. The proteostasis mechanisms assist proteins to adopt and maintain their correct folding state during and after synthesis. Once achieved, the proteostasis mechanisms ensure that misfolded proteins are degraded by special cell structures (the proteasome or the lysosome), thus preventing the accumulation of damaged components and the continuous renewal of intracellular proteins.

Aging and some aging-related diseases are linked to impaired proteostasis. Chronic expression of unfolded, misfolded or aggregated proteins lead to the development of Alzheimer's disease, Parkinson’s disease, and cataract.

3 Dysregulation of cell metabolism, oxidative damage (oxidative stress) of cells

DNA structure changes and proteostasis impairments lead to the dysregulation of cell metabolism, energy loss, and accumulation of ROS, which could further contribute to more genetic lesions and protein damages.

One important observation of scientists is that mammals under calorie restriction produce fewer ROS and age slower. Such effects of calorie restriction rely on slow accumulations of age-associated oxidative damages and increased metabolic efficiency. Currently, the methods of calorie restrictions are quite common in anti-aging therapy.

4 Stem cell exhaustion and senescence

Cell senescence is a gradual process linked with DNA structure changes ROS and proteostasis loss The decline in the accumulation, damages, regenerative potential of tissues in aging is linked with stem cell exhaustion and senescence. For example, the reduced hematopoiesis abilities due to age result in a diminished production of adaptive immune cells (or immunosenescence), as well as increased cases of anemia and myeloid malignancies. Likewise, a similar functional loss of stem cells has been found in all adult stem cell compartments, which has a different influence on the whole organism state. In these cases, stem cell rejuvenation methodics may slow the aging process at the organismal level and be used as an anti-aging therapy.cellular proteins.

5 Inflammation and Autoimmune reactions

In aging, the amount of senescent cells have increased. These senescent cells provided an aging microenvironment, enriched in pro-inflammatory cytokines, matrix metalloproteinases, and transcription factors for proinflammatory genes. This senescence-associated secretory phenotype (SASP) leads to inflammation processes in various tissues (or inflammaging). As such, many age-related pathologies (including cancer, cardiovascular disease, arthritis, and a number of neurodegenerative diseases) are linked with tissue inflammation. Likewise, chronic inflammation (due to viral or bacterial diseases, or unhealthy food habits) can potentially accelerate the aging process. Equivalent to inflammaging, the function of the adaptive immune system declines. This results in difficulties for the immune system to clear different infectious agents, infected cells, and cells with malignant transformation.

The aging process of the immune system could also be expressed in elevated probability of different autoimmune diseases development (such as rheumatoid and inflammatory bowel arthritis, progressive systemic sclerosis, disease). Recently, it was shown that inflammation and stress are related to the aging process through the NF-kB signaling pathway. Activation of this pathway could result in reduced production of gonadotropin-releasing hormone (GnRH) by neurons. This GnRH decline in its turn contributes to numerous aging-related changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis. However, an interesting observation is that GnRH treatment could slow down aging development in mice. It was suggested that the hypothalamus may modulate systemic aging by GnRH-mediated neuroendocrine effects.

Therefore, aging depends not only from individual cell senescence processes but also its association with the general alteration in intercellular communication. Some anti-aging therapy options are directed on the regulation of this intercellular communication pathway.

6 Metabolism changes

Aging changes the whole body metabolism and the primary reasons for these changes are the enumerated mechanisms above. The metabolic changes in the body result in increased fat deposition, reduced muscle mass, and likelihood of developing metabolic diseases (such as type II diabetes mellitus, hyperlipidemia, and arteriosclerosis). Interestingly, that loss of voluntary (striated) muscle tissue mass throughout adult life depends on physical activity to a certain extent. Some investigations demonstrate that a large part of the loss of muscle mass during aging is the result of disuse and atrophy rather than loss of muscle fibers. Therefore, another anti-aging therapy method is moderate and regular physical activity.

7 The tissue structural integrity losing

With aging processes, extracellular deposits of elastin and collagen are disrupted along with the elevation of cross-links between these molecules. These changes lead to the reduction of elasticity of blood vessels, crystallinity and rigidity of the eye lens, appearance of wrinkles on the skin, loss of elasticity of the ligaments, and the development of osteoarthritis and others.

All the seven mechanisms of aging described briefly above are responsible for the dysfunction of the body and the manifestation of aging hallmarks. Significantly, slowing down the aging process and prolonging human life will be possible if technologies would be developed for: (1) accurately correcting all DNA structure changes; (2) providing proper operation of DNA repair mechanisms, and; (3) target regulation of the epigenetic status of DNA.

Under certain conditions, the biological age of a person could be less than the chronological one, which entails healthy aging and life extension.

How can you improve your well-being, slow down aging process, and reduce your biological age?

1 Calories restriction diet

GSome investigations demonstrate that individuals who consume a primarily plant- based diet tend to live longer than persons who regularly consume red meat and other animal products. Monkeys on calorie-restricted diets showed reduced likelihood of cardiovascular disease to raised on relative reasons unrestricted those these animals calorie The underlying why restriction All the seven mechanisms of aging described briefly above are responsible for the dysfunction of the body and the manifestation of aging hallmarks. Significantly, slowing down the aging process and prolonging human life will be possible if technologies would be developed for: (1) accurately correcting all DNA structure changes; (2) providing proper operation of DNA repair mechanisms, and; (3) target regulation of the epigenetic status of DNA. Under certain conditions, the biological age of a person could be less than the chronological one, which entails healthy aging and life extension. How can you improve your well-being, slow down aging diets. methodics work are due to the reduced ROS production that reduces stress on the digestive system and increases the efficacy of metabolism processes. However, it should be mentioned that while diet could restrict calories, it could also control nutritional value. For example, eating foods that are low in calories but deficient in iron, vitamins B, or some rare amino acids will not yield good results and may lead to some disorders.

2 Moderate, but regular physical activity

Light sport exercises or doing some work in the garden will help to maintain your muscle mass and reduce fat storages.

3 Mental activity

An active social life is a good prophylaxis for depression, different neurological disorders, and dementia.

4 Regularly check the health of your body

Control your weight, BMI (body mass index), WHR (waist to hip ratio), and blood pressure for evaluating basic physical parameters. Check your peak flow rate, a quick indicator of the functioning of the respiratory system, and have an electrocardiogram for the heart. Likewise, do some simple and useful lab tests regularly for glucose level, glycosylated hemoglobin (HbA1c), lipid profiles (at least total cholesterol, LDL cholesterol, and triglycerides), kidney profiles (at least creatinine and estimated glomerular filtration rate (eGFR) levels, as well as albumin in urine), main haematological indices, and C-reactive protein (CRP). Other additional lab tests would also be beneficial, such as thyroid function examination, bone and joint profiles, adiponectin, suPAR (soluble urokinase plasminogen activator receptor), vitamin D, folic acid, vitamin B12, Cortisol, and dehydroepiandrosterone sulfate (DHEAS).

These lab tests could help recognize deteriorating metabolic changes through time, which can be fixed by a special medication regimen, thereby preventing the development of serious complications and disorders and promoting healthier aging. To give an example, it was shown that dyslipidemia and hypertension are common precursors for the occurrence of type 2 diabetes and CVD, which are risk factors for all-cause mortality.

5 Regularly check the health of your body

Many investigations on animal models have shown that the selective elimination of senescent cells will lengthen the period of life that is free of chronic diseases due to aging. Senolytics, or the drugs targeting the senescent cell in the body, could help reduce the influence of senescent cells on the aging process, holding a great promise for the management of chronic age-associated conditions (such as diabetes, a number of cardiac disorders, and vision problems). There are several different groups of senolytics, some of them cause senescent cell apoptosis (Fisetin, Quercetin+Dasatinib, navitoclax, UBX1325), while others inhibit the SASP Secretion Pathway (Ruxolitinib, metformin, rapamycin). However, the use of senolytics could not only slow down aging, alleviate several disorders, and increase healthy life span, but also affect the metabolism of ordinary cells, causing various side effects such as thrombocytopenia, weight gain, slowing down wound healing, and promoting tumors, since they affect basic signaling pathways within and between cells.

Because of this, the decision to use senolytics should be considered with the recommendation of a healthcare provider and the expected positive effects should outweigh the possible side effects. It should also be taken into account that the drugs in the aging body tend to accumulate due to changes in pharmacokinetics and lead to a higher possibility of long term drug toxicity. In addition, the use of many drugs at the same time increases the possibility of interaction between clinically important drugs and senolytics, thereby elevating adverse drug effects.

Currently, the short-term and long-term side-effects of senolytic therapies are largely unknown. It is possible that a regimen of sinolytics that is carefully selected by a doctor and taking into account the medications already needed (such as lowering blood pressure), can give excellent results.

6 Mesenchymal stem cell transplantation

As mentioned above, stem cell senescence and exhaustion are major causes of the decline in tissue regeneration capacity during the aging process. Because of special therapies with mesenchymal stem this, cells anti-aging (MSC) transplantation have been developed recently. A growing body of evidence has shown that aged people's regeneration abilities can be improved by stem cell transplantation and slow down the aging process.

MSCs are naturally occurring, although they are rare cell types in our body. MSCs have multiple features and are used in regenerative and transplantology medicine to facilitate patient recovery and reduce graft versus host diseases. One particular feature is that the surface of MSCs is lacking MHC 2 type molecules, providing low immunogenicity of these cells when transplanted to patients. This means that MSCs transplantation will be as safe as possible with minimal side effects. Likewise, MSCs are capable of secreting a variety of growth factors, cytokines, and miRNA. All these molecules are responsible for the paracrine effects of MSCs. In particular, it has been shown that MSCs could demonstrate the following properties: immunomodulatory and anti-inflammatory, angiogenic, antifibrotic, and antiapoptotic.

MSCs are also capable of getting into the area of inflammation, and able to reduce it and activate the body's stem cells to proliferate and differentiate, which allows the damaged tissue to recover. An undoubted advantage of MSCs therapy is the absence of toxic side effects, as in the case of taking various pharmacological drugs that slow down aging, since MSCs secrete substances that are already naturally occurring in our body. Moreover, the process of secretion is gradual and depends on the environment. If there are no foci of inflammation in the body, then anti-inflammatory cytokines will be produced in a minimal amount. In other words, MSCs adapt to the needs of the micro environment after its transplantation to patients.

For some elderly people, however, the effect of stem cell therapy is mild. Why anti-aging therapy with MSC might not have excellent results as anticipated?

As mentioned earlier, a part of our own stem cells become senescent and F exhausted with reduced regeneration capabilities and secreted SASP (senescence-associated secretory phenotype) during the aging process. If the percentage of senescent stem cells in a particular patient is high, then there are fewer targets for the action of MSCs – the patient's stem cells that can be activated for tissue proliferation and regeneration. It has also been shown that SASPs cause inhibition of these factors could reduce the MSCs. Thus, effectiveness of MSCs therapy.

In some cases, MSCs therapy will not give any results if fast aging processes are associated with specific genetical, epigenetic changes, disturbances of DNA reparations functions, or complicated or advanced cases of metabolism disorders. Moreover, it should be mentioned that autologous MSCs transplantation (MSCs that are obtained from your body for therapy) as an anti-aging therapy have low effectiveness because mesenchymal stem cells appear increasingly senescent with age. MSCs of older people have lower capabilities to amplify in laboratory conditions to obtain high quality and quantity cells dose for therapy and lower levels of specific secretome molecules beneficial for health one’s improvement. That is why, MSCs provided from young donors could give better results.

With that in mind, Kintaro cells suggest a therapy with the highest quality bone marrow derived MSCs obtained from young healthy donors that ensures as good as possible results in each particular case. To reduce inhibitory effects from senescent cells and SASP of patients, Kintaro cells suggest therapy with MSCs, which are optionally preconditioned with melatonin. MSCs treated with melatonin are more resistant to inhibition by senescent cells and have a better survival rate after transplantation into a patient. This precondition procedure of MSCs with melatonin is performed during the cultivation process in laboratory conditions. After that, the cells are carefully washed from the melatonin residue. In doing so, this precondition procedure is absolutely safe for patients.

Overall, MSCs therapy cannot eliminate the causes of aging, but it can slow down the processes of functional tissue loss due to their secretome containing various growth factors and cytokines, and ability to reduce inflammation and activate melatonin. human stem cells to proliferate and differentiate. Together with careful monitoring of key metabolic parameters through laboratory tests and their timely correction, MSC therapy can reduce biological age and promote healthy aging.

Perhaps in the future, combination therapy protocols using senolytics and MSCs will be developed. Ideally, senolytics in the first stage of therapy would reduce the number of old cells that negatively affect the performance of MSCs. At the second stage, transplantation of MSCs would stimulate the processes of regeneration and renewal of the body. However, careful studies of possible side effects from taking senolytics and resolution of questions about the increased risk of cancer during combined therapy are needed.