Bloom Samuel I, Karlseder Jan
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
The Salk Institute for Biological Studies, La Jolla, California 92037, USA
Genes Dev. 2025 Aug 1;39(15-16):920-922. doi: 10.1101/gad.353122.125.
Aging is the greatest risk factor for most diseases. We propose that aging manifests as disease as a function of tumor-suppressive capabilities. Adequate tumor suppression results in cell death or an accumulation of damaged cells leading to inflammation and tissue dysfunction that underlies diseases such as cardiovascular disease, neurodegenerative diseases, or type 2 diabetes. Conversely, inadequate tumor suppression leads to cancer. Telomeres are central to this process because they oppose hyperproliferation that is required for cancer initiation by enforcing two potent tumor suppressor mechanisms: senescence and crisis. Although senescent cells promote age-related diseases via inflammatory signaling, crisis cells have lost the p53 and RB pathways, have more unstable genomes, and harbor shorter telomeres, all of which could increase inflammation to a greater degree than is seen in senescence. This model emphasizes the intimate relationship between aging, telomeres, tumor suppression, and inflammation and suggests that crisis cells may represent an unexplored driver of inflammation in advanced age.
衰老是大多数疾病的最大风险因素。我们提出，衰老作为一种疾病表现，是肿瘤抑制能力的函数。充分的肿瘤抑制会导致细胞死亡或受损细胞的积累，从而引发炎症和组织功能障碍，而这正是心血管疾病、神经退行性疾病或2型糖尿病等疾病的基础。相反，肿瘤抑制不足会导致癌症。端粒在这个过程中至关重要，因为它们通过强化两种强大的肿瘤抑制机制——衰老和危机，来对抗癌症起始所需的过度增殖。虽然衰老细胞通过炎症信号促进与年龄相关的疾病，但处于危机状态的细胞已经失去了p53和RB通路，基因组更不稳定，端粒更短，所有这些都可能比衰老状态下引发更严重的炎症。该模型强调了衰老、端粒、肿瘤抑制和炎症之间的密切关系，并表明处于危机状态的细胞可能是老年炎症未被探索的驱动因素。
