HuR Inhibition in Platelets Attenuates Degenerative Aging in Mice
Platelets play a vital role in blood clotting. A population of hematopoietic cells known as megakaryocytes spawn platelets by pinching off parts of their membrane and cytosol, forming what are essentially mini-cells that lack some of the usual components, such as a nucleus, but retain many of the others, such as mitochondria. As such platelets are capable of many of the functions of a full cell, such as secreting factors that influence other cells. Unfortunately, platelets become problematic with age in ways that contribute to greater inflammatory behavior and increased risk of the inappropriate clotting of thrombosis. Researchers here identify a specific protein, HuR, that regulates inappropriately inflammatory behavior in platelets in aged tissues. Suppressing HuR in only the platelets of aged mice reduces inflammation, burden of cellular senescence, and loss of physical and cognitive function characteristic of aging.
Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in systemic aging. In response to physiological or pathological stimuli, platelets synthesize and release many different growth factors, cytokines, chemokine, vasoactive substances, and other bioactive factors. During aging, platelet reactivity generally increases, even though the number of platelets decreases. As components of the blood, platelets penetrate the entire body, permitting platelets to affect the entire body. However, the role of platelet activation and platelet-secreted pro-inflammatory factors (PSPF) in aging is unclear.
In aged mice, the levels of platelet-secreted pro-inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in the brain, liver, lung, kidney, and aortic root. The RNA-binding protein HuR/ELAVL1, a major regulator of RNA metabolism, promoted the production of PSPF in platelets. Platelet-specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in the brain, liver, lung, kidney, and aortic root, and delayed systemic aging. By using single-nucleus sequencing, platelet-specific HuR ablation was found to alleviate p53 and pro-inflammatory signaling pathways in liver, lung, and brain tissues in aged mice. Our findings highlight a role of platelets in coordinating aging traits across organs.