ABSTRACT

Macroautophagy/autophagy is a sophisticated quality control program that limits cellular damage and maintains homeostasis, being an essential part of several lifespan-promoting interventions. However, autophagy is also necessary for full establishment of cellular senescence, a causal factor for many age-related diseases and aging. What lies ahead of us to unravel such a paradoxical role of autophagy in senescence is to identify specific targets degraded by autophagy during senescence and determine their importance in the senescence regulatory network. Recently, we developed the “Selective autophagy substrates Identification Platform (SIP)” to advance these goals, providing a rich set of autophagy substrate proteins involved in senescence. Our study demonstrated that selective autophagy coordinates the stress support networks in senescent cells by degrading multiple regulatory components, echoing its homeostatic roles in normal cells. Targeting this type of selective autophagy might provide a unique opportunity to develop non-senescence addiction-based therapeutic strategies for senotherapy by disturbing the homeostatic state of senescent cells.

摘要

巨自噬/自噬是一种复杂的质量控制程序，可限制细胞损伤并维持体内平衡，是几种促进寿命的干预措施的重要组成部分。然而，自噬对于细胞衰老的完全建立也是必要的，细胞衰老是许多与年龄相关的疾病和衰老的原因。摆在我们面前的要解开自噬在衰老中的这种自相矛盾的作用是确定衰老过程中自噬降解的特定靶标，并确定它们在衰老调控网络中的重要性。最近，我们开发了“ S选择性自噬底物I识别Platform (SIP)”来推进这些目标，提供一组丰富的与衰老有关的自噬底物蛋白。我们的研究表明，选择性自噬通过降解多种调节成分来协调衰老细胞中的压力支持网络，与其在正常细胞中的稳态作用相呼应。针对这种类型的选择性自噬可能会提供一个独特的机会，通过扰乱衰老细胞的稳态状态来开发基于非衰老成瘾的治疗策略。