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I would imagine that, to most people in the health and fitness sphere, autophagy is not a completely novel term. Defined by Christian de Duve in the 1960’s, the term autophagy can be broken down into two parts to reveal its meaning: ‘auto’ and ‘phagy’ are both derived from Greek, and may be translated as ‘self’ and ‘to eat’, respectively (1). In other words, autophagy is the process of self-eating whereby damaged cells are cleared and their contents recycled (2). Autophagy most commonly refers to macroautophagy, or macromolecule digestion. This mechanism is initiated in times of acute stress, especially nutritional inadequacy, as a means of improving efficiency and providing building blocks for healthy cells to continue functioning. Autophagy is thus critical in preserving cellular homeostasis and metabolism while preventing build-up of distressed organelles and dysfunctional proteins. 

Autophagy is triggered mainly as a result of limited nutrient supply, whether that be in the form of hypoinsulinemia (low levels of circulating insulin), insufficient ATP availability (the primary energy substrate in the cell), a dearth of amino acids (derived from protein breakdown), or hypoxia (lack of oxygen) (3). Autophagy is one method by which the amino acid pool is restored as a result of ingestion of abnormal proteins and peptides (4). Regular turnover of proteins through a robust autophagic system is necessary to maintain cellular growth and development. Autophagy further plays a role in innate immunity by facilitating recognition via protein tagging of sinister invaders. Such tagging instigates uptake of pernicious molecules into autolysosomes for destruction.

Broadly speaking, autophagy is characterized by the formation of autophagosomes, double-membrane, spherical organelles that engulf and sequester potentially threatening cellular components (2). This process is regulated by the presence of autophagy-related (ATG) proteins. ATG proteins initiate autophagosome formation and promote their fusion with lysosomes (4). Lysosomes are organelles that contain acidic lysosomal hydrolases which denature and dissolve proteins. The outcome is the creation of autolysosomes and the subsequent contact of autophagosome contents with lysosomal enzymes for protein digestion. A baseline level of autophagy is important in decreasing the burden of sluggish or toxic cellular components that might otherwise instigate a decline in cell function and metabolism. 

It may help to think of autophagy as a ‘hunkering-down’ in anticipation of a crisis, a protective process whereby older, less capable cellular components are sacrificed in order to save the young and healthy. This evolutionary process has allowed for human survival in a number of less than ideal conditions such as starvation. For better or for worse, we as a species rarely encounter these types of situations in our modern environment. Autophagic housekeeping is thus infrequently stimulated, exacerbating the build-up of damaged organelles and proteins that wreak havoc on metabolic processes. We will dive deeper in the next few blog posts, describing the fundamental functions of autophagy, its involvement in disease processes, and how we might go about preserving this critical evolutionary adaptation for the sake of longevity and healthspan. 

References

1. de Duve C, Wattiaux R. Functions of Lysosomes. Annual Review of Physiology. 1966;28(1):435-492. doi:10.1146/annurev.ph.28.030166.002251
2. Vargas JNS, Hamasaki M, Kawabata T, Youle RJ, Yoshimori T. The mechanisms and roles of selective autophagy in mammals. Nature Reviews Molecular Cell Biology. Published online October 27, 2022:1-19. doi:10.1038/s41580-022-00542-2
3. Ichimiya T, Yamakawa T, Hirano T, et al. Autophagy and autophagy-related diseases: A review. International Journal of Molecular Sciences. 2020;21(23):8974. doi:10.3390/ijms21238974
4. Saha S, Panigrahi DP, Patil S, Bhutia SK. Autophagy in health and disease: A comprehensive review. Biomedicine & Pharmacotherapy. 2018;104:485-495. doi:10.1016/j.biopha.2018.05.007