In the face of the inescapable natural law of aging, for a long time, the entire time school has been committed to popularizing cutting-edge scientific progress and interventions to the public, such as senescent cell clearance and immune cell therapy, which can be called "regular customers" in the number. At the same time, it is gratifying that with the continuous development, a variety of anti-aging means have become more and more mature, and even began to join hands to break into the world.
Just last week, two heavyweight players in the field of anti-aging, immune cell therapy and senescent cell clearance, joined forces to bring us a new research result. Mainland scholars used NK cells (natural killer cells), one of the immune cells, to carry out infusion therapy, successfully killed mouse or human senescent cells, and found that after combining with a dopamine-releasing peptide, the senescent cell clearance ability of NK cells was significantly improved [1].
Note: On April 5, the study was published online in Nature's sub-journal Cell Death & Disease
Powerful combination:
Immune cell therapy and senescent cell scavenging dream linkage
As we age, it is inevitable that the body will experience a decline in immune system function and the accumulation of senescent cells, and numerous studies have shown that both can significantly accelerate aging [2-5]. It is for this reason that immune cell therapy and Senolytics therapy( which target senescent cells) aimed at improving immune aging are particularly hot in the increasing field of anti-aging.
Then, the faction that is at the forefront of the anti-aging campaign day by day will naturally not miss these two "capable officers".
In earlier historical tweets, we systematically analyzed the details of current immune cell storage and reinfusion therapy, and discussed the great potential of immune cell infusion in improving immunity, treating cancer and intervening in aging. Moreover, with the development and maturity of the therapy's own categories (CAR-T, CAR-NK, etc.) and practical applications, the author sincerely looks forward to the future human life extension revolution realized by it. (Review: Freeze today, use it tomorrow!) An article to understand immune cell storage and reinfusion therapy)
For another leader in the industry, Senolytics Therapy, whether it is the "exhaustive pursuit" of the daily science popularization tweets of the Time School, or the exchange event of the Time School at the end of each year, from research reports to the on-site sharing of big names in the field, it can be said that every Senolytics therapy and material development is enough to make us worship it. (Review: Dialogue author| PCC1 leader Sun Yu: 5 in 10,000 is a significant decline!) Regular, effective removal of senescent cells or beyond the 120-year-old lifespan limit)
But what is even more gratifying is that these two aging intervention therapies, which are extremely optimistic about the time school, have not only been deeply cultivated in their respective fields in recent years, but also gradually embarked on the road of strong and powerful alliance.
Here, it is necessary to mention a blockbuster study published in Nature, a top international scientific journal in June 2020: scholars engineered T cells according to specific receptors on the surface of senescent cells, and successfully eliminated senescent cells in mice after infusion [6]. In addition, follow-up studies have found that CAR-T cell therapy can also significantly improve off-target toxicity in Senolytics treatment and improve the scavenging effect of senescent cells [7].
In addition, many studies have shown that a large number of immune cells, including macrophages and NK cells, have the potential to effectively eliminate senescent cells, which lays a more solid theoretical foundation for the joint anti-aging application of immune cells and Senolytics therapy [8-10].
NK cell infusion to clear senescent cells,
Both mice and humans achieved positive results
Senescent cells can be recognized and eliminated by the immune system, but as the immune system ages, these "guards" in the body who defend against foreign enemies are naturally not as alert as before, and there is a gap in the hundreds, and the senescent cells have "immune escape" [11]. So, can exogenous back-infusion supplement a sufficient amount of fresh immune cells improve the situation?
In order to explore this problem, the scholars selected NK cells (natural killer cells) that have a certain research basis, and cultured them together with mouse aging fat progenitor cells (radioactivity or doxorubicin induction), and found that senescent cells may activate NK cells (marker CD69, IFN-γ, etc.) by upregulating activated molecules in the immune response [12][12], and then NK cells "performed their duties" and greatly promoted the apoptosis of senescent cells.
Subsequent in vivo tests also yielded positive results similar to those in cell tests. After the infusion of NK cells into the "forced premature aging" mouse, the senescent cells in the body were successfully killed, the effect was so good that how to evaluate it, the control mouse may look red for a few points - NK cells are activated in large quantities, to the body to do a "deep cleaning", after treatment, the number of senescent cells in the premature aging rat body is less than the normal mice in the control group. Sure enough, killing you that can't kill you will make you stronger.
Note: In the presence of senescent cells, NK cells are significantly activated, and the senescent cells in the body can be greatly removed after infusion
The mouse trial was so successful, so what about human clinical? To this end, the scholars recruited 26 healthy adult male and female subjects (aged 36-71 years) and performed autologous NK cell refusion for them. Although the purity of NK cells varies greatly due to age, the proportion of senescent CD3+ T cells and a number of inflammatory indicators were significantly improved after cell reinfusion.
Note: The back-infusion of NK cells significantly improved the subjects' aging status
Coincidentally, similar to those occurring in mouse senescent fat progenitor cells, NK cells also reduced the aging markers of adipose tissue (p16 and p21) and pro-inflammatory cytokines in obese people, and did not exhibit any cytotoxicity.
Note: NK cells reduce multiple markers of aging in adipose tissue in the body
Dopamine "enters the game",
Combined with dopamine-releasing peptides enhances senescent cell scavenging
The good aging improvement effect of NK cells in the previous article depends on the activation of senescent cells at the beginning, so are there other activation methods? In order to enhance the efficacy of NK cells, the researchers went deeper again and found a good helper to help NK cells kill senescent cells, which is dopamine.
When it comes to dopamine, everyone is not too unfamiliar. As a neurotransmitter, dopamine plays a vital role in the regulation of brain activity and movement, regulating human behavior, cognition, and mood, and when dopamine-releasing neurons (dopaminergic neurons) are gradually lost due to aging (5-10% per decade), insufficient dopamine secretion may induce a variety of geriatric diseases such as Parkinson's disease [13-15].
When the researchers tried to add different concentrations of dopamine and co-culture with mouse NK cells and senescent muscle cells, it was found that dopamine can enhance the killing effect of NK cells on senescent cells by upregulating its receptor D1, and there is a dose dependence within a certain range (the optimal concentration shown in the trial is 10^-9 M).
Note: Dopamine enhances the toxicity of mouse NK cells to senescent cells through D1-like receptors
One question is followed by another, when dopamine gradually declines with aging, or even insufficient, the additive effect on NK cells will no longer exist, then what should be done?
It is said that the organism is really cleverly constructed, and the dopamine deficiency affects the downstream effect, and under the premise of not choosing violent dopamine supplementation (long-term supplementation with dopamine precursors may lead to neurotoxicity and shorten life [16]), the upstream pro-release factor of dopamine is a fulcrum that can be leveraged.
When a heptapeptide molecule called Acein is injected into mice, this substance that targets cerebral angiotensin-converting enzymes [17] significantly induces the release of dopamine. After Acein was combined with NK cells, the senescent cells in the mice, including fat, were eliminated to a greater extent than in the control group, and a number of aging-related indicators returned to a youthful state.
Note: Acein enhances NK cell activation and reduces senescence of adipose tissue
After the "enhanced version" of NK cells was reintroduced, the senescent cells that hindered the cause of life extension were finally "cleaned up", and four months later, the group of mice was tested again, which confirmed the excellent reversal effect of the combination therapy on the aging state of mice: in multiple tissues (liver, lungs, kidneys, adipose tissue and eyes), the expression of aging markers such as p16, p21 and SASP (aging-related secretion phenotype) was improved, and the content of key coenzyme NAD+ that was essential to the body and changed significantly with aging was also significantly increased.
Note: NK cells in combination with Acein reversed the age-related phenotype of older mice
Time Pie reviews
On the whole, in addition to the safety of human clinical application of Acein combined with NK cell therapy, the anti-aging potential of immune cell infusion has been confirmed again.
At the same time, in the process of research, mainland scholars also found that there is obvious age dependence on the quality of the autologous infused NK cells, which means that the NK cells extracted when we have aged, even after in vitro purification, expansion and other treatments, but due to the decline in cell quality, the potential anti-aging effect of the therapy may be greatly reduced.
Therefore, in the future, the early storage of immune cells in the early stages of individual life, as well as the continuous improvement of stem cell induction differentiation technology, are likely to be an important way to solve the above problems. In time, the golden age of immune cell therapy intervention in human aging may indeed come.
The study was led by Professor Xu Hanmei of Jiangsu Provincial Engineering Research Center for The Discovery and Evaluation of Synthetic Polypeptide Drugs and the Key Laboratory of Natural Medicines of the Ministry of Education of China Pharmaceutical University, with doctoral students Bai Zongke and Yang Peiwei as co-first authors.
—— TIMEPIE ——
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