NK cell therapy

Cellular aging is a phenomenon originally discovered by Dr. Leonard Hayflick in 1961. Dr. Hayflick discovered that human fetal fibroblasts stop proliferating after a certain number of cell divisions, that the cells do not die even after they stop proliferating, and that they maintain metabolic activity (i.e., survival) even after long-term culture. (continued) and named this phenomenon cellular senescence. It is now widely known that normal cells, with some exceptions that have stem cell-like properties, have a limited number of divisions. Cells that have unlimited proliferation include germline cells, somatic stem cells, and embryonic stem cells (ES cells), and those created under controlled conditions in vitro include iPS cells (induced pluripotent stem cells). . It is easy to misunderstand this, but cellular aging is not an aging phenomenon. Cellular aging is a phenomenon that can occur during the entire life span, even in young people, and also occurs during the process from a fertilized egg in the mother’s body to an individual. Aging is a phenomenon that occurs progressively over time. Although the number of senescent cells inevitably increases with age, it is now known that cellular senescence also plays an important role in the process of development (cell differentiation and formation of tissues) and wound healing. Ta. Aging cells secrete factors called SASP (Senescence-associated secretory phenotype) (inflammatory cytokines, chemokines, extracellular matrix degrading enzymes, growth factors, exosomes, etc.), which repair damaged tissue and complete the repair process. and senescent cells disappear. However, as the immune function of macrophages declines with age, senescent cells cannot be eliminated and accumulate in the body, and excessive release of SASP factors causes chronic inflammation, leading to cardiovascular disease, arteriosclerosis, and diabetes. , chronic kidney disease, nonalcoholic fatty liver disease, osteoporosis, chronic obstructive pulmonary disease, autoimmune diseases, neurodegenerative diseases such as Parkinson’s disease and dementia, sarcopenia, and cancer. It is suggested. Therefore, if aging cells can be removed from the body or SASP factors secreted from cells can be suppressed to an appropriate level, it may be possible to prevent diseases caused by aging.

Currently, the development of drugs (Senolytics) that remove aging cells is underway, but many of them were originally developed as anticancer drugs, and there may be problems with long-term use. Therefore, flavonoid polyphenols (quercetin and fisetin), which have weak effects but are less toxic, are considered promising. On the other hand, focusing on SASP factors, several candidates have been proposed for drugs (Senomorphic) that block SASP secretion. Among these, the diabetes drug metformin and SGLT-2 inhibitors are attracting attention. Although much remains unknown about their mechanisms of action, large-scale clinical trials are being conducted in the United States. However, since it is necessary to combine multiple drugs to block all SASP factors, it is expected that it will be difficult to obtain a certain effect when administered alone. In addition, many drugs that target SASP itself are already in clinical use for rheumatoid arthritis, and are expected to be used as anti-aging drugs due to their mechanism of action to suppress chronic inflammation.

At this stage in the development of drug therapy, we focused on stem cells that have self-renewal and differentiation abilities. There are 6 billion stem cells at birth, but they decrease with age, dropping to 1 billion in your 20s, 300 million in your 40s, and 30 million in your 80s. Specifically, mesenchymal stem cells are cultivated from one’s own adipose tissue, and the number of stem cells increased from 100 million to 200 million is returned to the body through an intravenous drip. The injected stem cells will further proliferate within the body, and the secreted cytokines will activate the existing stem cells, promoting the removal of aged cells and rejuvenating the tissue. The effects are said to last for 2 to 3 years. However, stem cells themselves age with age, so if you are over 65 years old (although there are individual differences), the effect is expected to be rather limited. Of course, it would be better to inject young people’s stem cells (allogeneic), but this is not allowed in Japan, so at present we are not giving injections of cytokines to elderly people from young people’s stem cell culture. The recommended method is to extract a supernatant containing exosomes and inject this into the body.

Recently, rejuvenation treatments using your own natural killer cells (NK cells) have also been developed. NK cells are a type of white blood cell and are immune cells that account for approximately 10-30% of lymphocytes. When these cells discover bacteria, viruses, or cancer cells, they exhibit a biological reaction that quickly attacks them with extremely strong killing ability. This is called innate immunity, which attacks foreign substances on its own without instructions from other immune cells. Acquired immunity, on the other hand, is a biological reaction in which T cells (cytotoxic, helper cells) that have produced antibodies against the antigens of bacteria or viruses that have invaded the body once again attack the body when they invade again.

Until now, NK cell therapy has utilized the properties of innate immunity and has been mainly used for cancer prevention and treatment, but recent research has revealed the function of NK cells in eliminating senescent cells. It is known that NK cells recognize and attack various senescent antigens presented on the surface of senescent cells. However, when the function of NK cells becomes impaired due to aging, senescent cells accumulate rapidly, which induces organ aging and malfunction, eventually leading to the death of the individual. Our idea is to replenish NK cells, remove senescent cells, and rejuvenate the body to avoid this condition. In fact, although the data is from animal experiments, it is assumed that by removing senescent cells using NK cells, aging-related diseases can be prevented, and as a result, lifespan is expected to be extended by 20 to 30%.

It is said that the number of senescent cells will decrease by half in about 2 to 4 months unless the immune function of NK cells has decreased. In addition, the lifespan of NK cells is said to be approximately 10 days to several weeks, so in conditions where immune function has decreased or senescent cells have increased, the interval between NK cell treatments may be once a month. We recommend that you perform this treatment 2 to 4 times in total.

At our hospital, we measure the therapeutic effects of NK cells by measuring NK cell activity before and after treatment, age estimated from telomere length, which reflects the degree of cell aging, TAQ test that analyzes mRNA genes related to senescent cells, which are indicators of senescent cells. Evaluate using Telomeres are involved in cell lifespan and are associated with aging cells. Telomeres are the ends of chromosomes that shorten each time a cell divides. When telomeres shorten, cells begin to age, and cells stop dividing and become senescent cells. Telomere length is thought to function as one of the lifespan clocks in cells.