Let the immune system "rejuvenate", the latest research may be able to "reverse" aging!

Aging is a phenomenon that each of us needs to face, and its impact is reflected in all aspects of our body, including the aging of the body's immune system. On the one hand, the aged immune system has difficulty recognizing subtle changes in cells or molecules in the body, resulting in immune "loopholes", which leads to a higher incidence of malignant tumors in the elderly than in their youth; on the other hand, its ability to respond to external stimuli decreases, and it cannot effectively resist the invasion of pathogens, which means that the elderly are prone to infectious diseases caused by pathogens such as bacteria, viruses or fungi, and the effectiveness of vaccination is often significantly lower than that of young people. In addition, the level of chronic inflammation in the elderly is often higher, because the aged immune system is more inclined to stimulate inflammatory responses rather than clear them. This phenomenon of high inflammation levels not only damages normal tissues, but may also promote the development of a variety of age-related diseases.

A 2023 study on the immune system and aging of Chinese adults, which included 43,096 participants (aged 20-88 years old), found that after the age of 35, the immune system of Chinese adults gradually began to "go downhill" [1]. In order to effectively alleviate the aging process, people have proposed many methods, such as maintaining a fixed daily routine, adopting a balanced diet and maintaining healthy exercise and other good living habits, or through mindfulness meditation and acupuncture. It is undeniable that these methods do play a certain role. However, aging is still rolling forward like a wheel. Can we find a way to stop this "wheel" or even reverse it?

Recently, the research team of Irving L. Weissman from Stanford University and the team of Kim J. Hasenkrug from the National Institute of Health in the United States collaborated to publish a research paper titled Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity in the journal Nature [2]. The research team developed an antibody therapy that can target and eliminate myeloid-biased haematopoietic stem cells in mice, allowing the aged mice to restore the characteristics of their young immune systems, including increasing the number of lymphocyte progenitor cells, new T cells and B cells, while reducing the expression of related markers of the aging immune system. In addition, this antibody therapy increased the immune response of aged mice to viral infections, improving the effectiveness of vaccination.

Hematopoietic stem cells (HSCs) are a vital cell type in the human body. They reside in the bone marrow and are responsible for generating blood cells to ensure physiological functions, as well as various immune cells such as T cells, B cells and natural killer cells. At the same time, hematopoietic stem cells have a strong self-renewal ability. They can generate stem cells identical to themselves through division, maintain the stability of their own number, and allow the body to quickly recover and adapt even when facing external pressure or internal damage. Generally, hematopoietic stem cells can be divided into two categories: HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) and HSCs with myeloid-biased output (my-HSCs). With age, the main type of hematopoietic stem cells will gradually change from bal-HSCs to my-HSCs, thereby reducing the production of lymphocytes and increasing the production of myeloid cells. The latter is also the culprit of many elderly problems - immune decline, chronic inflammation, and even myeloid-related diseases. Theoretically, if my-HSCs can be eliminated, it is possible to restore the level of bal-HSCs in the body and thus restore the "youth" of the immune system.

To achieve this goal, the research team first had to find antigens that are specifically expressed on my-HSCs, so as to design targeted antibodies to eliminate my-HSCs. Through omics analysis and flow cytometry, the research team found that compared with bal-HSCs, in my-HSCs, the two genes CD62p and NEO1 had the highest expression levels (Figure 1). Based on CD62p, NEO1 and CD150 (known markers to distinguish my-HSCs from bal-HSCs), the research team was able to distinguish my-HSCs from other hematopoietic stem cells. The research team designed specific antibodies anti-CD62p, anti-NEO1 and anti-CD150 for these three antigens, respectively, and found that any one of the antibodies can reduce the number of my-HSCs in animals, but because the antigen proteins distributed on the surface of each cell are not exactly the same, the effect of eliminating my-HSCs by targeting only a single antigen protein is not good. After optimization, the research team combined any of the antibodies with anti-CD47 and anti-KIT (both of which are related to anti-macrophage phagocytosis and are abnormally active in diseased or aged organisms) and found that they could significantly improve the efficiency of my-HSCs clearance.

Figure 1 Schematic diagram of the process of identifying and validating my-HSCs surface antigens, and the cell surface antigen content of bal-HSCs and my-HSCs.

The research team then used these antibody therapies on aged mice (Figure 2). They found that the number of my-HSCs in aged mice decreased significantly after the first week of injection, and this downward trend was further consolidated and improved during the subsequent treatment. Correspondingly, the number of bal-HSCs and their progeny cells also increased significantly, and these cells are the key to the "youth" of the immune system. These data further confirm the strong potential and authenticity of the antibody therapy designed by the research team. Thanks to the addition of new forces, the immune phenotype associated with lymphocyte aging in aged mice injected with antibody therapy was also suppressed, and the resistance to infection and the effect of vaccination were significantly improved. At the same time, the level of inflammatory factors associated with chronic inflammation in aged mice also decreased.

Figure 2 Comparison of the immune system status of young and old mice after 1, 8 and 16 weeks of treatment

Even more exciting is that after analyzing the expression of human hematopoietic stem cell surface antigens, the research team found that the expression of CD62p and NEO1 in human hematopoietic stem cells was also increased in my-HSCs and could be recognized and screened by the same antibodies. This conservation between different species suggests that this preclinical research can be transformed into clinical treatment plans to help restore the human immune system to a youthful state.

At the same time, Nature also published a review article by Professor Robert AJ Signer, a well-known stem cell scholar, titled "Anti-ageing antibodies revive the immune system." While praising the antibody therapy, Professor Signer also pointed out its potential risks, such as antibody injection may reduce the total amount of hematopoietic stem cells, thereby exacerbating the emergence of clonal hematopoiesis, and may also force hematopoietic stem cells to expand compensatorily, which may lead to the occurrence of related cancers. He warned people not to overuse this antibody therapy in the future.

"This is a true paradigm shift -- a new way for researchers and clinicians to think about the immune system and aging," said Jason B. Ross, lead author of the study. "The idea that it might be possible to modulate the entire immune system simply by affecting the function of such a small number of cells is surprising and exciting."

In any case, this research not only opens up a new way to revitalize the immune system and alleviate the effects of aging by targeting specific cells, but also provides us with hope to fight aging. Through this innovative antibody treatment, we may be able to move towards a healthier and longer life in the future.

References:

[1] Jia Z, Ren Z, Ye D, et al. Immune-Ageing Evaluation of Peripheral T and NK Lymphocyte Subsets in Chinese Healthy Adults. Phenomics. 2023;3(4):360-374. Published 2023 May 23. doi:10.1007/s43657-023-00106-0

[2] Ross JB, Myers LM, Noh JJ, et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature. 2024;628(8006):162-170. doi:10.1038/s41586-024-07238-x