Recently, Professor Qiu Yifu and his team at Peking University have for the first time detailed the occurrence of macrophage aging and analyzed the molecular mechanism. In addition, they also applied the enhancement of type II immune signals to anti-aging treatment, conceptually proving the great potential of this treatment.   Through this, they also clarified the molecular mechanism of macrophage aging and revealed that the aging of immune cells themselves is sufficient to promote the aging of the body.   Interestingly, in 2023, several papers showed that immune cells aged and accelerated the progression of various diseases such as tumors and obesity. The above research by the research group and peers jointly clarified the key role of the immune system in aging.   Therefore, they hope that this study will encourage relevant scholars to pay more attention to the role of the immune system in the systemic biological process of aging.   Since the results of this experiment show that targeted enhancement of type II immune signals can promote healthy aging in elderly mice. Therefore, this anti-aging regimen is comparable to the efficacy of the classic anti-aging drug Senolytics (Dasatinib + Quercetin), and the combination of the two regimens will be even better.  It can be seen that this anti-aging program has great potential and is expected to be used to delay aging, healthy aging, and alleviate senile diseases.   However, the experimental subjects this time are limited to mice, and there is still a long way to go before clinical application. In addition, over-activating type II immunity can lead to more serious side effects such as allergic reactions.   Therefore, directly activating type II immunity to fight aging requires more comprehensive considerations. However, their research shows that at least in mice, low doses of interleukin 4 can achieve ideal anti-aging effects without causing allergic reactions.   At the same time, this study has just unveiled the veil of type II immunity regulating aging, and there are still many unknowns to be explored, which requires them and their peers in the field to work together.   The academic community has been exploring the causes of aging for many years, and various mechanisms have emerged one after another: from free radical theory, telomere theory, to the metabolism and information theory that have been popular in recent years.  However, these theories have some limitations to a greater or lesser extent. For biological individuals, especially complex higher organisms such as humans, the body obviously has a variety of cell types, which also suggests that various previous aging theories may only describe the state of some cells in the body.   In early 2023, Cell published a review article summarizing the twelve major characteristics of aging. Do these characteristics converge in a certain direction?   Professor Qiu Yifu and his team thought about this for a long time. Based on their years of accumulation in the field of immune metabolism, they speculated that the immune system has an important regulatory role in aging. Immune cells are generally believed to act as monitors in the aging process, mainly responsible for clearing harmful senescent cells. And the immunity of the elderly has declined significantly, which is simply defined as immune aging.   In addition, over the past two decades, scholars in the field have gradually paid attention to a phenomenon called "inflammaging", which is closely related to the immune system, and this chronic inflammation can aggravate a variety of aging-related diseases.   There are three types of cell-mediated immunity: Type I immunity usually fights against intracellular bacteria and viral infections; Type II immunity targets parasitic pathogens and induces allergic reactions; and Type III immunity defends against extracellular bacteria and fungi, etc.  Type I and III immunity have been reported to regulate immunosenescence, but whether type II immunity is involved is unclear. This study showed that type II immunity decreased significantly with age. And they used mouse models to show that defects in type II immunity accelerate aging and significantly shorten the lifespan of mice.   Therefore, they started this project, which is to explore the changes in the immune system itself and to decipher the mystery of body aging from the perspective of the immune system.   After researching the literature, they found that the field of aging at that time did not pay enough attention to the immune system. Many studies only regard immune system dysfunction as an accompanying phenomenon of aging, and their causal relationship with aging is not clear.   The team found through long-term observation that mice with type II immunodeficiency will develop white hair and oligotrichosis earlier. Is this a sign of aging? How do we understand the role the immune system plays in the aging process? So I decided to use this as a starting point to conduct in-depth research.   In the study, they first explored the phenotype of the gene knockout mice, and only after determining the stable phenotype, they began to study the follow-up mechanism.  Regarding the mouse phenotype, they used middle-aged mice aged 8-11 months, at which time the mice can show accelerated aging caused by genetic defects, such as the aforementioned less white hair and reduced athletic ability.   The mouse lifespan data was also collected after a long wait. The subsequent molecular mechanism analysis was relatively smooth. Thanks to high-throughput sequencing and public database mining, they quickly locked the DNA repair pathway of macrophages.   When the type II immune signaling pathway in macrophages is defective, the DNA repair ability of macrophages becomes poor and aging is more likely to occur. And aging macrophages are enough to cause inflammation and promote the overall aging of animals.   After confirming that interleukin 4 signaling can promote DNA repair in macrophages, they naturally want to apply it to aged mice to test the anti-aging effect.   Considering that the half-life of interleukin 4 is very short, they use adeno-associated viruses to continuously express and secrete interleukin 4 in the liver instead of directly injecting recombinant interleukin 4. This method can ensure that the experimental mice can maintain a high level of interleukin-4 for a long time.  Yi-Fu Qiu said: "When it comes to the promotion of research, I am fortunate to have an outstanding student, Zhou Zhao, who is the first author of this paper. Zhou Zhao is a very creative master-doctoral student who is good at applying the concepts and methods he reads in the literature to his research topics. Many of the ideas in the research were proposed by him and were implemented after our joint discussions."

Although the entire research process had smooth parts as well as tough nuts to crack, the completion of the research ultimately could not have been achieved without Zhou Zhao's tenacity and the academic collisions he had with everyone during the communication process.

Since the team had no precedent for studying aging, Zhou Zhao started from scratch, reviewed the research methods of predecessors, and with the help of Qiu Yi-Fu's another student, Yao Jingfei (the second author of this paper), he established a relatively complete experimental system.

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It is worth mentioning that Yao Jingfei was the first to observe the aging phenomenon in type II immune-deficient mice, which was mainly due to his meticulous observation.

After the paper was submitted to Immunity, it received positive feedback and high praise from the journal editors and reviewers. The reviewers said their research was a "comprehensive study" and believed "This is a very strong finding".The reviewer particularly pointed out that the study provided a detailed description of the accelerated aging phenotype in type II immune-deficient mice, which left a very deep impression on them, and appreciated that the study provided a "promising therapeutic opportunity" for healthy aging.

At the same time, the reviewer also raised very meaningful questions. For example, whether there is a similar mechanism in human macrophages? Is the aging of macrophages due to polarization?

Subsequently, Qiu Yifu's team answered these questions through supplementary experiments and received high recognition from the reviewers. "Here, I also thank the editors of Immunity and the reviewers, their professional opinions have made our article more perfect," said Qiu Yifu.

Recently, the related paper was published in Immunity with the title "Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging" [1].

Zhou Zhao is the first author, Yao Jingfei is the second author, and Qiu Yifu serves as the corresponding author.However, this study is just the beginning, and there are still many related issues that need to be further resolved. For example, how is the decline of type II immunity triggered during the aging process? In terms of functional expansion, their current results mainly focus on physiological aging, and whether there are similar situations in the progression of age-related diseases? This is also what they hope to explore. In addition, to achieve clinical transformation, further promotion is also needed.