近日，日本东京大学Makoto Nakanishi等研究人员合作发现，阻断PD-L1-PD-1可改善衰老监测和衰老表型。该项研究成果于2022年11月2日在线发表在《自然》杂志上。

研究人员表明，衰老细胞异质性地表达免疫检查点蛋白程序性死亡配体1（PD-L1），并且PD-L1⁺衰老细胞在体内随着年龄的增长而积累。PD-L1-细胞对T细胞监视敏感，而PD-L1⁺细胞则有抵抗力，甚至在存在衰老相关的分泌表型（SASP）情况下也是如此。体内p16⁺细胞的单细胞分析显示，PD-L1的表达与较高水平的SASP相关。

与此相一致的是，对自然衰老的小鼠或具有正常肝脏或诱导的非酒精性脂肪性肝炎的小鼠模型给予程序性细胞死亡蛋白1（PD-1）抗体，以激活CD8⁺T细胞依赖的方式减少体内p16⁺细胞的总数以及PD-L1⁺群体，并改善各种老化相关表型。

这些结果表明，PD-L1的异质性表达在衰老相关的衰老细胞积累和炎症中具有重要作用，通过免疫检查点阻断消除PD-L1⁺衰老细胞可能是一种有前景的抗衰老治疗策略。

据了解，衰老细胞的积累是与年龄有关的炎症的一个主要原因，并容易导致各种与年龄有关的疾病。然而，人们对这种积累的分子基础以及它作为改善衰老过程的靶标潜力知之甚少。

附：英文原文

Title: Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes

Author: Wang, Teh-Wei, Johmura, Yoshikazu, Suzuki, Narumi, Omori, Satotaka, Migita, Toshiro, Yamaguchi, Kiyoshi, Hatakeyama, Seira, Yamazaki, Satoshi, Shimizu, Eigo, Imoto, Seiya, Furukawa, Yoichi, Yoshimura, Akihiko, Nakanishi, Makoto

Issue&Volume: 2022-11-02

Abstract: The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1 cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.

DOI: 10.1038/s41586-022-05388-4

Source: https://www.nature.com/articles/s41586-022-05388-4