Introduction

"Modulation of autophagy may represent a promising therapeutic approach for extending human lifespan and healthspan." Click To Tweet

Homeostasis, a cell's ability to maintain a constant internal environment, is essential to cell survival. It is predicated on achieving an equilibrium between the production and degradation of cellular components. One major pathway for degradation is autophagy, an intracellular program involved in the disassembly and recycling of unnecessary or dysfunctional cellular components.

Autophagy (pronounced "aw-TAW-fuh-jee"), or "self-eating," is a highly conserved adaptive response to stress. This ancient defense mechanism sequesters protein aggregates, pathogens, and damaged or dysfunctional organelles into vesicles – bubble-like structures inside the cell called autophagosomes – and then delivers them for destruction to release macromolecules such as proteins, fats, carbohydrates, and nucleic acids for energy and re-use. The primary goal of autophagy is to allow the cell to adapt to changing conditions and external stressors.

Autophagy differs from apoptosis, a type of cellular self-destruct mechanism that rids the body of damaged or aged cells. However, the two processes are governed by shared signals and regulatory components, blurring the lines between their activities. In a simple analogy where autophagy is the first responder and apoptosis is the executioner, autophagy attempts to mitigate cellular damage, but if it is unsuccessful, apoptosis steps in to kill the cell.

The process of autophagy is activated by cellular stressors such as nutrient depletion, hypoxia, and toxins and involves myriad genes, proteins, receptors, and signaling pathways. Although autophagy occurs at the cellular level, its activation at the whole-body level may improve metabolic fitness and extend lifespan.^{[1] [2]}

Categorization and types of autophagy

In general, autophagy is either non-selective or selective.

Non-selective autophagy

Non-selective autophagy can occur as part of the cell's normal physiological functioning (referred to as basal autophagy) or in response to nutrient deprivation or other stressors to maintain homeostasis. In this way, non-selective autophagy performs a general housekeeping role and maintains cellular quality control.

Selective autophagy

Selective autophagy targets specific entities in the cell for destruction and removal and helps improve overall cellular function. This discriminatory form of autophagy relies on cues from damaged organelles, pathogens, or protein aggregates that demarcate them for destruction. It serves as a targeted cleansing program that removes slightly damaged or aging parts of the cell.

Types

"Failures in autophagy are implicated in the pathogenesis of cancer, autoimmune disease, infectious disease, and neurodegenerative disease." Click To Tweet

Several types of autophagy have been identified, and they differ based on how and when they are triggered, the method of sequestration they employ, and the target of their destruction. Two selective forms of autophagy are of particular interest: mitophagy and xenophagy.

Mitophagy

Mitophagy involves the selective degradation of mitochondria. It helps ensure that the body's cells are metabolically efficient without excessive production of reactive oxygen species – a type of oxidative stress that naturally occurs during metabolism, the effects of which are enhanced by damaged mitochondria. Mitophagy ultimately serves as a trigger for mitochondrial biogenesis, the process by which new mitochondria are produced. Failures in mitophagy are associated with several chronic diseases, including cardiovascular disease, kidney disease, and Alzheimer's disease.^{[3] [4] [5]}

• Related clip: Mitophagy: a signal for mitochondrial biogenesis, metabolic adaptation, and cellular differentiation

Xenophagy

Xenophagy is a function of the innate immune system. It targets foreign pathogens (such as bacteria or viruses), regulates antigen presentation, and induces innate immune memory – a vital process wherein immune cells "remember" threats. Xenophagy may also modulate cellular levels of non-microbial entities, such as iron.^[6]

Triggers of autophagy

Three primary signals trigger autophagy, all of which involve nutrient sensing. Critical to each of these pathways is the decline in cellular levels of acetyl CoA, an end product of nutrient metabolism. Acetyl CoA alters the acetylation status of key proteins involved in autophagy (such as mTOR and AMP kinase), thereby serving as a common regulator for the many pathways that lead to its induction or inhibition.

Starvation

Nutrient-sensing pathways signal the body to build new components and store excess nutrients when food is abundant. Food scarcity, however, and the accompanying reduction in acetyl CoA switch on homeostatic mechanisms – such as the mobilization of stored nutrients through autophagy. When mice or human volunteers experience starvation, autophagy occurs on the whole-body level.^[7]

Calorie restriction mimetics

Acetyl CoA levels can also be modulated via nutrient deprivation or via calorie restriction mimetics, compounds that "trick" cells into inducing autophagy even in the setting of sufficient nutrient levels.^[8] Examples of calorie restriction mimetics include resveratrol, metformin, and rapamycin.^[9]

• Related clip: Caloric Restriction Mimetics in Aging, Improved Cancer Chemotherapy, Autophagy, and Anti-obesity Effect

Learn more about resveratrol in this overview article.
Learn more about metformin in this overview article.

Exercise

"Exercise induces autophagy in the brain and several organs involved in metabolism..., which may explain how exercise benefits the whole body." Click To Tweet

Exercise is widely recognized for its many health benefits, including lifespan expansion and protection against cardiovascular diseases, diabetes, cancer, and neurodegenerative diseases. Exercise induces autophagy in the brain and several organs involved in metabolism in mice, including the liver, pancreas, adipose tissue, and muscles, which may explain how exercise benefits the whole body.^[10] Endurance training, in particular, induces autophagy in mice, mediating the harmful effects of diabetes and obesity.^[11]

Physiological roles of autophagy

Immunosurveillance

"Autophagy serves as a trigger for immunosurveillance, the process by which immune cells seek out and identify foreign pathogens such as bacteria, viruses, and precancerous or cancerous cells in the body." Click To Tweet

In addition to its role as a manager of quality control and homeostasis, autophagy serves as a trigger for immunosurveillance, the process by which immune cells seek out and identify foreign pathogens such as bacteria, viruses, and precancerous or cancerous cells.

Immunosurveillance activates when autophagy facilitates the release of ATP from dying cells, which attracts the attention of myeloid cells, a critical arm of the body's immune system largely responsible for innate defense against an array of pathogens. The released ATP activates a special class of cellular proteins known as purinergic receptors, which switch on various immune system elements, including the inflammasome, a key player in the body's inflammatory response.^[12] Immunosurveillance suppresses tumor development and subsequent growth. Its activation predicts long-term success from chemotherapeutic treatments and may help to explain the complex relationship between autophagy and cancer.^[13]

Slowed aging

A growing body of evidence suggests that autophagy may contribute to longevity and healthspan. Caloric restriction, a potent inducer of autophagy, extends lifespan in many organisms but also reduces the risk of many age-related chronic diseases, such as diabetes, cardiovascular disease, cancer, and brain atrophy – likely attributable to the beneficial effects of autophagy.^{[14] [15]}

Pathophysiological roles of autophagy

Failures in autophagy are implicated in the pathogenesis of cancer, autoimmune disease, infectious disease, and neurodegenerative disease. A common factor among all of these conditions is inflammation. The relationship between autophagy and inflammation is complex. Autophagy influences the development, homeostasis, and survival of inflammatory cells, including macrophages, neutrophils, and lymphocytes.^[16] Induction of these proinflammatory mediators can lead to inappropriate immune activation and subsequent disease states in some contexts, such as cancer, autoimmune disorders, infectious disease, and neurodegenerative disease.

Cancer

Whereas autophagy promotes suppression during tumor initiation, it provides critical protection during tumor progression. In early-stage cancer, the initial suppression of autophagy may help prevent attracting undue attention from the immune system but may facilitate ongoing transformation. In later-stage cancer, autophagy may help cancer cells survive within the hostile tumor microenvironment. Metabolic stress is relatively well tolerated in cancer cell lines because of their capacity to activate the autophagic response.^[13]

• Related clip: Autophagy and cancer: a crucial role in immunosurveillance and chemotherapeutic treatment

Autoimmune disorders

Although autophagy is generally considered a beneficial process, it can have harmful effects in the setting of autoimmune diseases. In rheumatoid arthritis, upregulation of TNF-alpha, a proinflammatory cell-signaling protein, induces autophagy, promoting the differentiation of osteoclasts, a type of bone cell that breaks down mineralized tissue in the joint, destroying the joint architecture.^[17] Similarly, dysregulation of autophagy signaling has been implicated in lupus and Crohn's disease.^[18]

Infectious disease

Some pathogens have developed strategies to evade autophagy successfully. For example, M. tuberculosis, the bacterium responsible for tuberculosis, commandeers autophagic mechanisms by hiding inside the autophagosome, impairing the processes that break down the pathogen.^[19] The bacterium can also interfere with one of the steps involved in xenophagy, ultimately impairing the body's immune response.^[20] Similarly, human immunodeficiency virus, or HIV, reduces cellular levels of key proteins involved in xenophagy induction.^[21]

Neurodegenerative disease

Failures in mitophagy are strongly implicated in Parkinson's disease, a neurodegenerative disorder characterized by mitochondrial dysfunction and energy deficits in dopaminergic neurons in the brain. A growing body of evidence suggests that mitophagy is compromised in Parkinson's disease and promotes the accumulation of dysfunctional mitochondria. Impaired mitophagy likely contributes to the aggregation of misfolded proteins, which in turn impairs mitochondrial homeostasis.^[22]

• Related clip: Increasing general autophagy as a treatment for neurodegenerative diseases like Parkinson's Disease

Autophagy is a complex process that influences many aspects of health and disease. It plays a crucial role in maintaining cellular homeostasis by participating in cell metabolism, survival, and host defense. Failures in autophagy are associated with a wide array of chronic conditions, such as cancer, autoimmune disease, neurodegenerative disease, and aging. Modulation of autophagy may represent a promising therapeutic approach for extending human lifespan and healthspan.