Non-Canonical Autophagy in Aging

Autophagy is the name given to a complex collection of processes that recycle broken and unwanted proteins and cell structures. Autophagy declines in effectiveness with age, while upregulation of autophagy is a feature of many of the approaches shown to slow aging in laboratory species. The ability of calorie restriction to slow aging appears to depend on autophagy, for example. So far, little meaningful progress has been made towards therapies that can greatly improve on the ability of exercise to improve autophagy, though mTOR inhibitors could be argued to be somewhat better than exercise on this front, given their greater effect on longevity in short-lived mammals. As mentioned, autophagy is complicated, and the paper here is an example of that complexity, diving into what is known as non-canonical autophagy, some of the less well explored interactions taking place during cell maintenance.

Macroautophagy requires the conjugation of members of the ATG8 family, ubiquitin-like proteins including LC3 and GABARAP, to phosphatidylethanolamine (PE). This enables double-membrane vesicles termed autophagosomes to recruit ATG8 proteins, which mediate loading and maturation of cargo. More recently, autophagy-independent functions of ATG8 proteins have been discovered. Several recent studies have highlighted these additional roles of ATG8 proteins leading to alternative fates of their cargo in degradation and secretion, together referred to as non-canonical autophagy (NCA). With age, there is a general decrease in efficiency of degradative autophagy, both canonical and NCA. Additionally, in what is likely a response to age-associated decreased degradation through the lysosome is the shift to "secretory autophagy" (SA), release of material into the extracellular space. However, owing to the overlap of the initial steps of autophagosome formation, SA also decreases with age. Understanding the mechanisms that differentially initiate and regulate NCA will help identify how defects in these pathways contribute to aging and disease.

One of the defining hallmarks of aging is altered intercellular communication, with a prominent example being "inflammaging", or the chronic inflammation that further amplifies the aging process. Growing evidence identifies inflammaging as the driver for NCA in aged microglia. SA has been shown to maintain proteostasis when autophagy is inhibited by blocking fusion with the lysosome in vitro. However, the downstream effect of this is the release of cargo into the extracellular space, and, depending on what was targeted for degradation but is now in the extracellular space, can itself induce an immune response. Hyperactivation of macrophages will lead to increased phagocytosis of the discarded cargo, bringing it back into the cell to attempt to be cleared. However, if the limitation is at the lysosome, the effort is futile and will lead to deposition of aggregated proteins both intracellularly and in the extracellular space. Thus, chronic inflammation seen with aging is a likely driver for aggregation-associated diseases, including many neurodegenerative diseases.

The role of NCA in aging and age-related diseases is still under intense investigation. It is still not clear how cargo is recruited for NCA, whether NCA and canonical autophagy coexist, if differential signals direct the decision to complete canonical versus NCA, and whether the cell has a preference for either type. Alternatively, NCA may only be initiated when canonical autophagy cannot meet cellular requirements, and thus becomes the dominant response for cargo clearance. Furthermore, the molecular pathways and vesicular trafficking in SA are not fully described, but canonical autophagy machinery is required for the initiation. So, if the same machinery is needed, but there are different outcomes, what determines if degradation occurs in the lysosome or if SA is induced? Moreover, with so many pathways to deliver cargo to the lysosomes for degradation, does everything come down to functional lysosomes? This seems to be the case, since the switch from degradation to SA does not solve the overall problem in neurodegenerative diseases.

Link: https://doi.org/10.3389/fcell.2023.1137870