Autophagy: Your Body's Anti-Aging Mechanism

Autophagy is a key process that keeps your body's cells in proper balance, or what we call homeostasis. A popular saying about sustainability for the environment is "Reduce, reuse, recycle." In a lot of ways, autophagy is the natural process that does all three of these things for your body. The term "autophagy" comes from the Latin word that means "self-eating." This is because the process of autophagy breaks down parts of your cells in order to recycle them in the creation of new cells.

Cytoplasm consists of fluid inside of a cell (excluding the nucleus). During autophagy, cytoplasm and organelles (small structures with specific functions) are removed and recycled. This process keeps your body in balance by self-removing cells that are no longer functioning optimally or appropriately.

While autophagy helps to keep your body in balance, there are also disorders that disrupt normal processes of autophagy, which leads to chronic illness. Neurodegenerative disorders like Parkinson's disease have genetic links to being related to dysfunction in autophagy.

Autophagy has important effects that occur both within the cell and outside of the cell. Within the cell, autophagy helps to decrease oxidative stress, increase genomic stability (which aids in the prevention of cancer), increase bioenergetic metabolism, and increase the elimination of waste.

Outside of the cell, autophagy helps to decrease the inflammatory response, increase neuroendocrine homeostasis, increase surveillance of cancer by the immune system, and increase the elimination of aging cells.

Autophagy is typically triggered by a cell's starvation of nutrients. It is believed that insulin suppresses autophagy while glucagon can activate the process.

After eating, your body releases insulin, while fasting causes a release of glucagon as your body's blood sugar starts to decrease. Glucagon signals your body to use glycogen in your liver to increase your blood sugar. Once autophagy is activated, the process occurs in four steps.

1. Sequestration: During this step, two membranes (called phagophore) elongate around and eventually enclose cytoplasm and organelles that are later to be degraded. This double-membrane becomes an organelle known as an autophagosome. Typically, the contents engulfed by the autophagosome are selected because they are within range. However, autophagosomes can be selective as the membrane can initiate autophagy when there is interaction with certain proteins in the cell.
2. Transport to a lysosome: The autophagosomes cannot directly connect to a lysosome, so it first fuses with an intermediate structure called an endosome. The autophagosome that is fused with an endosome is now referred to as an amphisome, which can readily fuse with a lysosome.
3. Degradation: This can begin after fusion with a lysosome occurs. Upon fusing with the amphisome, the lysosome releases enzymes (known as hydrolases) that degrade the materials that were in the original autophagosome. This structure that is full of degraded cellular material is now known as either an autolysosome or an autophagolysosome.
4. Utilization of degradation products: This can occur after all cellular materials are degraded down to amino acids. After being exported out of the autolysosome into the cellular fluid, the amino acids can then be reused.

The fourth and final stage is ultimately related to the starvation of cellular nutrients. The utilization of degradation products is ultimately needed for providing amino acids for gluconeogenesis (a process in which the body synthesizes glucose from non-carbohydrate sources). The amino acids serve as an energy source for the tricarboxylic (TCA) cycle, and these amino acids can be recycled into synthesizing new proteins.

There are three types of autophagy. Although similar, they each have distinct features to differentiate each type.

1. Macro-autophagy refers to the process of autophagy described above. This term is synonymous with autophagy.
2. Micro-autophagy is similar to autophagy in that it can engulf and degrade many different structures in the cell. The difference in this process is that it does not use a phagophore to sequester cellular contents. Instead, the lysosome draws the cellular contents in and engulfs the material around its membrane to then degrade the contents into amino acids for reuse.
3. Chaperone-mediated autophagy is a more specific method of targeting proteins to be degraded. In this process, chaperone-proteins help translocate the protein across the lysosome membrane, where it can be degraded into amino acids for reuse.

There is a lot of research dedicated to methods to activate autophagy due to the many health benefits including cancer prevention and homeostatic properties in the nervous system. However, it also appeals to many people due to the anti-aging properties and increased metabolic effects.

Pharmaceutical research is growing to identify ways to selectively activate autophagy with certain drugs. In particular, there is pharmaceutical interest in identifying ways to stimulate the induction of autophagy to help with neurodegenerative disorders.

• Huntington's Disease: Resveratrol, latrepirdine, and lithium are being investigated to stimulate autophagy for patients with Huntington's disease.
• Alzheimer's Disease: Resveratrol, nilotinib, lithium, latrepirdine, metformin, valproic acid, statins, nicotinamide, and hydroxychloroquine may help to stimulate autophagy in Alzheimer's disease.
• Parkinson's Disease: Nilotinib and statins may stimulate autophagy in Parkinson's.
• Amyotrophic Lateral Sclerosis (ALS): Lithium, tamoxifen, and valproic acid may stimulate autophagy in patients with ALS.

Outside of pharmaceuticals, fasting either intermittently or for more prolonged periods of time induces autophagy as well. It does this by depleting cellular nutrients. In order to maintain cellular function, autophagy is induced to produce amino acids that are no longer present.

Additionally, dieting that involves low carbohydrate intake deprives the body of easy-to-access sugars. Autophagy is activated to participate in the generation of amino acids. Amino acids can then be used to provide energy through gluconeogenesis and the TCA cycle since carbohydrates are not readily available. Before starting any diet, however, you should consult your doctor to ensure your safety and proper nutrition.

Autophagy-related genes (ATG) were first identified in the 1990s. Since that time, dysfunctional genes have been linked to disorders related to abnormal function of autophagy in the body. 

• Static Encephalopathy of Childhood With Neurodegeneration in Adulthood (SENDA) was the first neurodegenerative disorder to be identified with relation to autophagy dysfunction. This became important in identifying autophagy's role in the potential to treat other neurodegenerative disorders with autophagy-targeted therapies. The gene associated with SENDA affects the formation of autophagosomes. While the association has been identified, how autophagy dysfunction relates to the accumulation of brain iron has not been determined.
• Vici syndrome is a progressive neurodegenerative disorder that is a recessive gene (meaning both the father and the mother have to pass the gene on for the child to have the disorder). The gene associated affects how autophagosomes mature and are degraded.
• Hereditary spastic paraparesis is another recessive gene disorder that is neurodegenerative in nature, and it affects the lower limbs. While autophagy's role in the disorder is not well understood, it has been identified that it impairs the formation of autophagosomes as well as impairs the fusion of the autophagosome with the lysosome.
• Parkinson's disease is a neurodegenerative disorder and is affected differently than other disorders. In this case, the associated gene is believed to cause selective degradation of mitochondria (a cellular structure associated with the generation of energy) by autophagy, commonly referred to as mitophagy.
• Crohn's disease differs from the other disorders listed, as it is an inflammatory bowel disorder. There are several genes known to affect autophagy as it relates to Crohn's disease; however, these same genes are also related to many other processes. Therefore, it is unclear if Crohn's disease is an autophagy-related disorder and whether autophagy-targeted therapies would be viable treatment options.
• Cancer is different from the other disorders as autophagy is not genetically-related, but rather has demonstrated benefits and risks associated with it. Autophagy has cell-protective properties to try to prevent cancers from forming. However, once a tumor is established, autophagy is believed to demonstrate the same protective properties but for the cancerous cells. In other words, once a tumor is established, autophagy helps to keep the tumor from being destroyed by normal processes your body has to fight cancer.

Targeting the inhibition of autophagy in cancer patients would remove the tumor-protective properties that autophagy is believed to have established in cancer. Therapies being investigated target the lysosome portion of the autophagy process and include the medications chloroquine and hydroxychloroquine.

Autophagy is your body's natural process by which it "recycles" cells and maintains homeostasis. Its benefits include managing inflammatory responses as well as increasing cancer surveillance. However, when autophagy does not function properly in the body, it has been linked to various disorders such as Parkinson's disease. Though autophagy can be protective against cancer, in certain cases, it may actually protect the cancer cells once they are established in the body.