The key to long life: the "super strong" immune system of super centenarians

The secret of longevity has always been a topic of great concern to the academic community and the public. Generally speaking, with the aging process, the probability of ordinary people suffering from cancer and infectious diseases increases greatly, which leads to the limitation of human life span. How do centenarians, or even super centenarians, "go against the grain"?

Recently, a joint study on super-centenarians by the RIKEN Center for Biomedical Sciences and the Keio University School of Medicine's Longevity Research Center has provided a possible answer: super-centenarians may have an immune system that is different from that of ordinary people. So, what is so special about the immune system of super-centenarians?

How difficult is it for a centenarian to live another ten years?

At what age can one be called a long-lived or super-long-lived person?

Looking at the world, the average life expectancy of humans is no more than 70 years old. According to statistics from the World Health Organization (WHO), the average life expectancy of Japanese men and women in 2018 was 84.2 years, ranking first in the world in terms of longevity. It is not easy for an old person to live to be over 100 years old, and they are worthy of being called a centenarian. People who can live to be over 110 years old are even rarer, and they also have an exclusive English name, called supercentenarian, which means super long-lived people.

Don’t underestimate the ten years from 100 to 110. For an old man whose body has aged in all aspects and whose functions may have deteriorated, it may be more difficult to withstand the test of natural factors and safely cross another decade than to climb Mount Everest. The results of Japan’s national census in 2015 showed that there were about 20,000 people who exceeded 100 years old (this figure had increased to more than 60,000 in 2017), and there were only 146 super-long-lived people who perfectly exceeded 110 years old.

Image from RIKEN Distribution of the Centenarian Population in Japan in 2015

The secrets of the immune system of super-centenarians

However, due to the limitation of the number of experimental samples, there was almost no research on super centenarians. It was not until November 12, 2019 that the RIKEN Institute of Physical and Chemical Research and the Keio University Longevity Research Center published a study on super centenarians in PNAS (Proceedings of the National Academy of Sciences of the United States), which initially revealed the secrets hidden in their bodies.

The secret is that they seem to have a special immune system.

The researchers drew blood from seven super-centenarians and five normal people aged 50 to 80, and conducted an in-depth and detailed analysis of immune cells such as T cells and B cells in their blood.

They tested the gene expression of individual immune cells and found that the number of CD4+ cytotoxic T cells in the blood of super-centenarians is much greater than that of ordinary people (as shown in the figure below, the arrows represent CD4+ cytotoxic T cells; the left figure is super-centenarians, and the right figure is people aged 50-80). At the same time, they found that more CD4+ cytotoxic T cells contain the same surface recognition molecules, which means that their T cells may have targeted the same antigen and produced a large number of clones.

Distribution of immune cell numbers (Image from the RIKEN Institute of Physical and Chemical Research)

Killer T cells may be the secret weapon to longevity

So, what are CD4+ killer T cells? Let's first understand the human immune system. If the human body is compared to a country, the immune system is the army that maintains the security of the country and can resist the invasion of foreign enemies (bacteria, viruses, etc.). The lymphocytes in the immune system are like the vanguard troops, playing the role of distinguishing between the enemy and ourselves and eliminating pathogens.

Immune cells, image from wikipedia

Among lymphocytes, there are two main brothers with different "personalities", one is called T and the other is called B. Academically, they are called T lymphocytes and B lymphocytes. The two brothers originally came from the same predecessor - hematopoietic stem cells, which were formed in the bone marrow. Later, due to the needs of the "country", T cells, as the eldest brother, were forced to leave their homeland and migrate to the thymus (Thymus), so they were referred to as T for short. T cells complete more refined training there and finally develop into mature T lymphocytes. B is different. He is more like a younger brother who stays at home. Because he was first discovered in the bursa of birds (Bursa), he is referred to as B for short. B cells continue to grow and develop in the bone marrow in the later stage, and finally develop into mature B lymphocytes.

The two brothers T and B were separated since childhood. Naturally, they had different divisions of labor when they grew up, but they were inseparable.

B is slightly introverted and only participates in humoral immunity. It cannot directly attack infected cells, but it can identify enemy forces invading the body - pathogens, produce antibodies, make them circulate in the blood, surround the invaders, produce immune responses, and achieve the effect of "hijacking".

T is the "big brother", so it is naturally more powerful and has a heavier task. It plays a role in both humoral immunity and cellular immunity. T cells have more skills and can transform into multiple forms as needed when encountering an enemy, including CD4+T cells and CD8+T cells. Especially when B encounters pathogens and needs to produce antibodies, CD4+T cells first transform into helper CD4+T cells to assist B cells in completing the production of antibodies.

On the battlefield, fighting against the most ferocious enemies - viruses and cancers - requires CD8+T cells to transform into CD8+killer T cells (CD8+ killer T cells) to directly eliminate cells invaded by viruses or cancer. However, under the condition of long-term chronic infection, the lethality of CD8+ killer T cells will gradually weaken, and the combat effectiveness will begin to decline. At this time, part of the CD4+T cells will transform into CD4+killer T cells (CD4+ killer T cells) and join in the activities of eliminating tumors and other malignant diseases. This means that the more CD4+ killer T cells there are, the more effective the human body will be in resisting viruses, cancer, and even chronic diseases, and it may live longer.

Ultra-high resolution image of killer T cells surrounding cancer cells, source: Wikipedia T cells, public domain

Unfortunately, under normal circumstances, there are only a very small number of CD4+ cytotoxic T cells in the blood, which may be the reason why most people only have a normal lifespan. According to a joint study by the RIKEN Institute of Physical and Chemical Research and the Keio University School of Medicine, these seven super-centenarians all have extremely high levels of CD4+ cytotoxic T cells in their bodies. It must be said that this may be their secret weapon to resist external pathogenic induction and overcome the internal risk of cancer, achieving super longevity.

What determines longevity? Research on longevity has a history of many years. Scientists in various fields have made many attempts, but almost no one can give a definite answer. The research described in this article has opened up a new research perspective, which is eye-opening - it turns out that the reason for longevity may be that there are many killer T cells in the body! However, this is still just a small step in the long journey of exploring the secrets of longevity. In the future, scientists will continue to uncover deeper mysteries about longevity.

References

1. T cell wikipedia

2.https://www.riken.jp/press/2019/20191113_1/index.html

3.https://memorva.jp/ranking/unfpa/who_whs_life_expectancy.php

4． Kosuke Hashimoto, Tsukasa Kouno, Tomokatsu Ikawa, Norihito Hayatsu, Yurina Miyajima, Haruka Yabukami, Tommy Terooatea, Takashi Sasaki, Takahiro Suzuki, Matthew Valentine, Giovanni Pascarella, Yasushi Okazaki, Harukazu Suzuki, Jay W. Shin, Aki Minoda, Ichiro Taniuchi, Hideyuki Okano, Yasumichi Arai, Nobuyoshi Hirose, Piero Carninci, "Single-cell transcriptomics reveals expansion of cytotoxic CD4 T-cells in supercentenarians", Proceedings of the National Academy of Sciences (PNAS)

5.https://www.riken.jp/press/2015/20151221_1/index.html

6.Arata Takeuchi, Mohamed El Sherif Gadelhaq Badr, Kosuke Miyauchi, Chitose Ishihara, Reiko Onishi, Zijin Guo, Yoshiteru Sasaki, Hiroshi Ike, Akiko Takumi, Noriko M. Tsuji, Yoshinori Murakami, Tomoya Katakai, Masato Kubo and Takashi Saito, "CRTAM determines the CD4+ cytotoxic T lymphocyte lineage", Journal of Experimental Medicine