Selective autophagy: a therapeutic target for healthy aging?

Manastireanu, Denisa Mihaela#; Salazar, Nicolle Andrea#; Bejarano, Eloy*; Nieto-Torres, José Luis*

Department of Biomedical Sciences, School of Health Sciences and Veterinary, Universidad Cardenal Herrera-CEU, CEU Universities, Valencia, Spain

*Correspondence to: Eloy Bejarano, PhD, eloy.bejaranofernandez@uchceu.es; José Luis Nieto-Torres, PhD, jose.nietotorres@uchceu.es.

#Both authors equally contributed to the work.

Abstract

At the molecular level, aging is characterized by the accumulation of unresolved damage to essential components of cells, such as DNA, proteins, and organelles, which over time contributes to cellular malfunction and the onset of age-associated diseases. To counteract this detrimental process, cells are equipped with protective mechanisms that prevent or reverse molecular damage. Arguably, the cellular recycling process of autophagy is one of the most versatile repair pathways that cells display. Autophagy allows the degradation and recycling of surplus and/or damaged cytosolic components, which otherwise may pose a threat to cellular homeostasis. This is achieved via the delivery of cytoplasmic components to lysosomes, which are organelles equipped with a sophisticated set of degradative enzymes that eliminate cellular waste and transform it into building blocks to maintain cellular function. There are different autophagic routes, known as macroautophagy, microautophagy, and chaperone-mediated autophagy, via which a variety of cellular components, ranging from organelles, DNA, proteins, and lipids, can be delivered to lysosomes for proper turnover. While these autophagy pathways operate to maintain cellular homeostasis over time, an overall deficit in autophagic function leads to aging acceleration and is correlated with the onset of age-related diseases. However, the extent to which specific autophagic pathways and the selective degradation of cellular components contribute to aging, as well as the molecular interplay among the different routes, remain elusive and constitute a main research direction. This narrative review summarizes the implications of autophagy subtypes in aging, focusing on the contributions of each pathway to select cargo degradation and their interaction, and highlights future lines of research toward identifying potential therapeutic routes for the amelioration of selective autophagy to promote healthy aging.

选择性自噬：健康衰老的治疗目标？

摘要

在分子水平上，衰老的特点是细胞的基本成分（如 DNA、蛋白质和细胞器）中的损伤累积，随着时间的推移，其会导致细胞功能失调和老年相关疾病的发生。为了抵御这一有害过程，细胞具有防止或减轻分子损伤的保护机制。可以说，自噬这一细胞循环过程是细胞所表现出的最重要的修复途径之一。自噬可以降解和回收多余和/或受损的细胞膜成分，否则这些成分可能会对细胞平衡构成威胁。溶酶体是一种配备有复杂降解酶的细胞器，可消除细胞废物并将其转化为维持细胞功能的构件。自噬有不同的途径，被称为大自噬、微自噬和伴侣介导的自噬，通过这些途径，细胞器、DNA、蛋白质和脂质等各种细胞成分可以被运送到溶酶体进行适当的周转。虽然这些自噬途径的作用是维持细胞的长期稳态，但自噬功能的整体缺失会导致衰老加速，并与老年相关疾病的发病有关。然而，特定的自噬途径和细胞成分的选择性降解在多大程度上导致衰老，以及不同途径之间的分子相互作用，仍然难以捉摸，这也是该领域的一个主要研究方向。文章总结了自噬亚型对衰老的影响，重点关注每种途径对选择性自噬的贡献以及它们之间的相互作用，并强调了未来的研究方向，即确定选择性自噬改善的潜在治疗途径，以促进健康的衰老。