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Dr. Xiaodong Wang laboratory declassified the mystery of aging in mouse male reproductive system

Publication Date:2017/08/22

On Augest 15th, 2017, Dr. Xiaodong Wang’s laboratory published in eLife a paper titled " RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system ". Their paper told of a signal pathway in mice that controls the aging of the male reproductive system. And they worked with the Dr. Zhiyuan Zhang lab to develop an RIPK1 inhibitor,  feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs could blocked the aging of mouse male reproductive system. When the mice in the control group who ate normal food lost basic fertility, the fertility of the mice taking the medicine remained essentially unchanged. Results show that mice fed with RIPK1 inhibitor have the same tissues and organs as young mice, the male hormone levels are maintained, hypotrichosis phenotype are inhibited, such as weight gain. To the best of our knowledge, this is the first senescence pathway found in mammals that is fully described at the molecular, cellular, organ, and integral animal levels. Like many scientifically important discoveries, the discovery of the aging pathway is also full of accidents. Dr.Xiaodong Wang's lab has not studied aging in the past, they has been focusing on programmed cell death for more than two decades. Much attention was focused on apoptosis in the early stage, and recently focused on necrosis.

Figure 1. Ripk3-/- mice maintained their reproductive system function at an advanced age.

They find that RIPK3 and it’s substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. Necroptosis is a form of programmed necrotic cell death caused by the tumor necrosis factor family of cytokines. In response to the activation of TNF receptor family members, receptor-interacting kinase 1 (RIPK1) is recruited to the cytosolic side of the receptor and its kinase activity is activated. RIPK1 then interacts with and phosphorylates a related kinase, RIPK3, leading to its activation. Once active, RIPK3 then phosphorylates a pseudokinase called mixed lineage kinase domain-like protein (MLKL). MLKL normally exists as an inactive monomer in the cytosol. Upon RIPK3 phosphorylation on serine 357 and threonine 358 of human MLKL or the mouse equivalent of serine 345, serine 347, and threonine 349, MLKL forms oligomers and translocates to the plasma membrane, where it disrupts membrane integrity, resulting in necrotic cell death.

While conducting a study investigating the impact of necroptosis on the progression of atherosclerosis, Lingjun Meng from Dr.Xiaodong Wang’s lab serendipitously found that the male reproductive organ of mice with Ripk3 gene knockout looked remarkably young even at advanced ages. The discovery was interesting at the time, but it didn't attract much attention in the following years. The main factor is how to find the molecular mechanism that was not clear at that time.

The subject was on a fast track after Dianrong Li joined the laboratory. He worked with Lingjun Meng and another animal expert, Tao Xu, find that Mlkl deficient mice had the same phenotype. They also detected phosphorylation of RIP3 specifically activated MLKL in normal senescent mouse testicular germ cells. To directly demonstrate that necroptosis in testes is sufficient to cause the aging of the male reproductive system, they also injected a combination of TNF-a, Smac mimetic, and caspase inhibitor z-VAD-FMK (henceforth ‘TSZ’), a known necroptosis stimulus to the testes of young mice, and found that induction of necroptosis in testes accelerates aging of the male reproductive system. Finally, they worked with the Dr. Zhiyuan Zhang lab develop an RIPK1 inhibitor, feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs could blocked the aging of mouse male reproductive system.

Although Ripk3- and Mlkl-knockout mice or fed RIPK1 inhibitor had longer reproductive abilities, their offspring were much more deficient than offspring of young males with a high proportion of pre - and post birth mortality rates.

Therefore, old mice can effectively remove accumulate damaged reproductive cells (spermatozoa) by the aging of the reproductive system of animals from the breeding population to ensuring the evolutionary vitality of the population.

Therefore, this aging program plays an important role in animal population health.

Figure 2. An RIPK1 inhibitor blocks aging of the male reproductive system.

Human beings are the only creatures that separate reproductive activity from reproduction. If the reproductive senescence pathway is conserved between mice and humans, we can block the aging pathway in human, thereby maintaining male reproductive activity and preventing male diseases such as prostate hyperplasia, and will play an important role in the health of mankind.

Dr.Dianrong Li from Xiaodong Wang’s laboratory is the first authors of the study; other contributors include Dr. Lingjun Meng and Tao Xu from the Xiaodong Wang’s laboratory. Dr. Zhiyuan Zhang. Yaning Su and Xiao Liu from Dr. Zhiyuan Zhang laboratory. Dr. Xiaodong Wang is the corresponding author. The study was supported by the Chinese Ministry of Science and Technology 973 Grants, and was conducted at the National Institute of Biological Sciences, Beijing.