A cell must engage in autophagy in order to continue to exist and thrive. This entails converting the malfunctioning parts of the cells back into healthy ones or eliminating them. This frees up space and increases efficiency. This process also eliminates bacteria and viruses that are pathogens and can cause damage to the cell. Additionally, autophagy has a significant impact on the cell lifespan. Age-related reductions in autophagy can result in an accumulation of cellular waste products and, that is why cells start to slow down their functioning and do not perform as well as they once did.
Autophagy and Different Illnesses:
Autophagy was previously considered by scientists to be the cells’ means of grooming themselves so they could live and operate properly. In the past two decades, it has been concluded that autophagy could be crucial for both preventing and treating a vast variety of diseases.
For instance, autophagy can help deal with Crohn’s illness, diabetes, cardiovascular problems, Huntington’s disease, problems in the kidney and liver, Parkinson’s and even certain types of cancer.
However, autophagy isn’t a definite good or bad procedure in terms of preventing or treating illnesses. The majority of research on the connection between autophagy and illness has been done on rodents, who, just like every other mammal, undergo autophagy, and not on humans, yet. It also remains to be seen how this procedure will play out in long term health.
Autophagy is currently being discussed a lot as a health fad, a way to get more youthful and stronger cells. Autophagy isn’t exactly that easy. Indeed, it is necessary for cells to function properly but certain disorders are also linked to it. There is currently insufficient evidence to suggest autophagy induction as a wellness tactic.
Depending on whether or not you have certain underlying medical conditions, it could be risky to fast, or cut calories- basically altering your diet drastically, or even starting an intense exercise regimen. If you have any questions regarding conducting a lifestyle change that might interfere with the way your body performs normally, visit your healthcare professional first.
Almost all cells engage in autophagy at low basal levels to carry out homeostatic processes such as organelle and protein turnover. Whenever cells have to produce intracellular nutrients, such as during fasting, or withdrawal symptoms, or high energy demands, autophagy gets quickly activated. Additionally, autophagy is increased in response to both cytoplasmic component removal during oxidative stress, getting ill, or excess protein aggregation and also structural remodeling which happens during developmental transitions. Autophagy regulation is influenced by a number of variables, including hormonal balance, nutrition levels, and environmental signals like the climate, oxygen levels, and density of cells.
The Life and Death Decision of the Cell:
Autophagy is primarily a stress adaptation mechanism that also helps cells live longer. The fact that autophagy is also regarded as “Type II” or “cell death” as in, it is a sort of planned cell death, presents quite a juxtaposition. Historically, morphological factors have been used to characterize this form of cell death.
Whether autophagy is toxic or protective, and whether that results from self-cannibalism, the particular breakdown of such factors, are still not fully known. Self-cannibalism is the method that makes the most sense for now. Nevertheless, cells that are subjected to extended deprivation of the growth factor or glucose and oxygen, they can lose a great deal of their mass through autophagy and recover only when exposed to optimal culture conditions. This suggests that cell death via autophagy could be more than just a quantitative limit of self-digestion. Despite the fact that autophagy can independently trigger survival or death of a cell, it has also been linked to planned death pathways.
Pathologists have been observing autophagy’s ultrastructural characteristics in a wide range of human illnesses for many years, such as nerve diseases, heart attack, cancer and others. Previously these results were mostly disregarded or taken to suggest that autophagy plays a causal role in cellular deterioration and illness. Further complicating the pathological analysis of autophagosome development in specimens of tissue was the inability to differentiate between faulty autophagy and higher autophagic activation. Now that evolutionary conserved gene products that govern autophagy have been identified, along with signaling networks that regulate autophagy, the influence of autophagy in treatment or prevention of human diseases can be studied and refined further.
1. Liver Diseases:
An essential organ for the body’s synthesis of proteins is the liver. Autophagy plays a crucial role in many hepatic disorders and is necessary for maintaining hepatocyte stability.
Overnutrition is the cause of non-alcoholic liver diseases, which is frequently linked to metabolic conditions including dyslipidemia and diabetes mellitus. Hepatocytes with reduced autophagy in NAFLD accumulate lipid droplets and produce hepatotoxicity, all of which result in hepatocyte death. Overfeeding activates mTORC1, which controls the autophagy-starting complex and suppresses autophagy as a result. The overnutrition-induced hyperinsulinemia also triggers mTORC1 through the insulin receptor substrate pathway, hence impairing autophagy.
Another theory about the pathophysiology of nonalcoholic fatty liver disease is the presence of Rubicon protein, which prevents the fusion of autophagosomes and lysosomes. After a high-fat diet, autophagy inhibition is eliminated in hepatocyte-specific Rubicon protein mice, leading to improvements in hepatotoxicity, fatty droplet formation, and fatty liver. After receiving palmitic acid treatment, Rubicon expression rises in both NAFLD and cultured hepatocytes. These findings imply that delayed Rubicon degradation contributes to the pathogenesis of NAFLD by suppressing autophagy. It has also been noted that alcohol-induced liver damage also involves autophagy. Research using cultured liver cells and animals model for acute alcoholic hepatitis has shown that ethanol metabolism produces ROS while inhibiting mTOR. Consequently, ethanol-damaged mitochondria and lipid droplets are specifically targeted by autophagy, which increases and shields the liver from ethanol-induced damage . Long-term alcoholic liver injury in mice has been shown to inhibit autophagy at the lysosome as well.
2. Diabetes:
A metabolic condition called diabetes mellitus is typified by ineffective insulin secretion and activity, which raises blood sugar levels and causes systemic problems. Type 2 diabetes is a result of insufficient insulin secretion and insulin resistance, while Type 1 is a consequence of insulin deficiency brought on by the immune system’s eradication of pancreatic β-cells. Reduced β-cell proliferative ability and increased β-cell apoptosis have led to a decrease in the number of β-cells in the pancreatic cell-specific mice. As a result, there is less serum insulin in the blood, which leads to intolerance to glucose.
Furthermore, morphological alterations in the mitochondria, and vessels are associated with broken down protein clusters that are confined to p62 protein molecules that have both LC3 and ubiquitin binding domains. The autophagy of pancreatic β-cells got triggered and their number also increased in control mice when fed a high-fat diet, but autophagy-deficient animals have not shown any increase in the number of β-cells. This is quite in contrast to pancreatic cell-specific mice.
According to these findings, pancreatic β-cell autophagy disruption results in aberrant cellular organelle turnover and their functioning, which leads to inadequate levels of insulin and hyperglycemia. Furthermore, ER activity is also critical for β-cell activation and insulin production. β-cells experience ER stress continuously as a result of which, human islet amyloid polypeptide, a peptide implicated in blood glucose regulation, gets generated. This forms amyloid aggregates linked to β-cell death and triggers the onset of type 2 diabetes. The toxicity of hIAPP has also been found to increase when autophagy in pancreatic β-cells is blocked. in those that lack autophagy or hIAPP. So one can conclude that autophagy is a very necessary component to eliminate toxic materials in the pancreas and help prevent the onset of diabetes.
3. Kidney Fails:
By filtering blood in the glomerulus and reabsorbing usable nutrients, and water in the tubules, the kidneys eliminate toxins from the body. It was seen in mice lacking in inner tubule autophagy, that they developed inclusions in the cytoplasm and malformed mitochondria, which caused cellular degeneration and enlargement that has not been seen in wild-type controls. Serum levels of creatinine, urea and nitrogen also markedly enhanced in autophagy-lacking animals due to increased tubular cell death and a buildup of p62 and ubiquitin-containing cytoplasmic structures .
Because of tubular dysfunction brought on by an infection, exposure to drugs, or ischemia, acute renal injury develops. It is an impairment where internal homeostasis and waste excretion functioning suffer. The proximal tubular tissue is particularly vulnerable to these kinds of stimuli. Mice with cisplatin-induced nephrotoxicity have been shown to exhibit enhanced autophagy in tubular cells. By promoting autophagy, the mTOR inhibitor rapamycin delays the start of cisplatin nephrotoxicity.
These results imply a protective function for autophagy and mitophagy activation in the tubules that are proximal during acute renal failure. Long-term deterioration of the kidneys brought on by diabetes mellitus, or chronic nephritis is known as CKD, or chronic kidney disease. Podocytes, glomerular basement membrane, and glomerular endothelial cells constitute the three strata that jointly make up the glomerular wall used in blood filtration. Podocyte autophagy is especially crucial for preserving renal function, and it has been shown that decreased podocyte autophagy is linked to age-related decline in renal functionality and diabetic nephropathy. It could also lead to glomerulopathy, which is characterized by the build-up of oxidized and broken down proteins, and proteinuria. Eventually, podocyte elimination and delayed glomerulosclerosis occur.
4. Cardiovascular Diseases:
Maintaining heart function through the quality assurance of organelles inside cells is facilitated by autophagy. Specifically, the myocardium’s mitochondria produces ATP, which facilitates cardiac pulsation. Mitochondrial failure results in cardiac dysfunction. Cluttered sarcomere framework, cardiomyocyte death and mitochondrial misalignment, have all been observed in the hearts of Atg5-deficient mice, who also show accumulation of proteins and increased ER stress. Knockout mice have also developed heart failure, and if not, the left ventricle size of the mutant mice significantly increased.
At this point, mitophagy and autophagy become active. But it’s only temporary, and eventually they become dormant due to a decline in heart and mitochondrial function. So by promoting autophagy and mitophagy, the autophagy-inducing peptide Tat-Beclin-1 slows the development of heart failure and mitochondrial dysfunction. Cardiomyocyte autophagy has a significant correlation with the severity of heart failure among individuals experiencing dilated cardiomyopathy. These results imply that autophagy plays a crucial role in cardiac health preservation and recovery following a heart failure.
5. Inflammatory Bowel Syndrome:
A complicated combination of circumstances, including an aberrant increase in inflammation in the intestines, dietary modifications that alter the gut microbiota, and genetic susceptibility, results in the chronic, almost-incurable illness known as IBD or inflammatory bowel disease. The link between IBD and autophagy-related genes has also been carefully investigated. Autophagy has been shown to be essential for intestinal immune system response, physiological adjustment, epithelial cell maintenance, and microbiota conservation.
According to reports, under stress circumstances like fasting, mutant autophagosomes get destabilized, which lead to decreased autophagy activity, decreased effectiveness against bacteria, and increased production of proinflammatory cytokines. LRRK2 has been found to be an at-risk gene for CD in addition to being a gene that causes the hereditary Parkinson’s. Because of their altered gut microbiota, LRRK2 knockout mice are less able to fight off infections and are more likely to get infected.
6. Neurodegenerative Diseases:
Autophagy deficit in neurons linked to gene mutation or deletion is the root cause of many neurodegenerative disorders. Such disorders associated with autophagy are varied. Parkinson’s is a disease characterized by symptoms that arise from degeneration of dopaminergic neurons in the mesencephalic neural network. Together, PINK1, carried by PARK6, and Parkin, which is a ubiquity ligase expressed by PARK2, act on the outer membrane of the mitochondria to stimulate the process of mitophagy. Now defective Parkin and PINK1 impair this autophagy, which causes mitochondrial metabolism to stall and reactive oxygen species (ROS) to build up. As a result, it is thought that this route has an intricate link to the onset of Parkinson’s disease.
The hallmarks for any neurodivergent disease are delayed mental development, reduced ability to move around, and epileptic fits starting in childhood itself. In later life, dementia starts to manifest. Wdr45, a gene associated with autophagy, has been found to be the culprit gene. Cellular apoptosis was avoided in the knockout mice genes only by the stimulation of autophagy or a decrease of stress in the ER. This phenomenon implies that one viable treatment option for this condition is to activate autophagy.
7. Cancer:
Tumor formation may result from the disruption of autophagic cell quality monitoring of the cell. The onset of autophagy in the development of tumors is also linked to the availability of nutrients to the cells. Thus, autophagy is involved in tumor genesis and progression through a variety of mechanisms, both of which are activated and inhibited.
Mice with impaired Atg5 mosaicism and mice lacking in Atg7 developed liver benign tumors. When broken down proteins attach to the selective autophagy protein, they are eliminated via autophagy. When this protein attaches to an adapter protein called Keap1, it significantly accumulates and prevents it from connecting to the transcription element called the NF-E2 factor. This leads to the inhibition of Nrf2 decay and the promotion of tumor development. Furthermore, after both p62 and Nrf2 have been eliminated at the same time, tumors brought about in the liver by autophagy suppression are significantly decreased. Renal carcinoma associated with local amplification of p62 on chromosome 5q also happens. P62 also controls the mTOR and nuclei factor-kappa B, the two factors that are crucial for the signaling networks leading to the onset of cancer. Therefore, it has been concluded that p62 might be involved in the autophagic mechanism that controls cancer.
In several mice models with autophagy gene deletions, autophagy promoted the progression of advanced lung tumors, pancreatic abnormalities, and also breast cancer. The pancreatic cancer usually exhibits a high level of autophagic activity, and autophagy restriction slowed down the growth of tumors.
Additionally, autophagy plays a crucial role in the inception and evolution of cell lung cancer, also known as NSCLC. In a mouse model of non-small cell lung cancer, removal of Atg7 has been shown to accumulate aberrant mitochondria and impede tumor cell proliferation. This suggests that both NSCLC activation and multiplication depend on healthy mitochondrial activity. Fresh findings have suggested that chemotherapy for non-small cell lung cancer may be beneficial.
By encouraging LC3 degradation, autophagic activity in cell lines arising from colorectal cancer can be stabilized by p53. Metastatic colorectal cancer has been reported to overexpress the autophagosome marker LC3-II protein. Lymph node infiltration and Atg5 expression were also found to be correlated in people with CRC after immunohistochemical examination of Atg5 expression. The degree of LC3 expression may indicate that autophagy plays a role in colorectal cancer.
Breast cancer has also been linked to autophagy. Accordingly, the development and spread of breast and other cancers are aided by the decreased expression of autophagy proteins. In the mouse model of breast cancer, it was discovered that the FIP200 deletion inhibited the genesis and growth of mammary tumors by preventing the formation of autophagosomes. Autophagy inhibition in latent cancer cells dramatically decreased cell survival and the burden of metastasis, and autophagy flux inhibition in inactive breast carcinoma cells led to cell apoptosis. So autophagy is very important for remedying breast cancer.
Higher autophagy can thus contribute to the development of colorectal cancer as well as the disease’s resistance to chemotherapy. As a result, the purpose of autophagy in CRC remains unclear, and more investigation is needed to clarify the role autophagy plays in the onset and progression of CRC.
CONCLUSION
We can conclude that the two basal levels of autophagy and stress-related boosts in autophagy are probably significant in improving health, based on recent insights into the physiological roles of autophagy. When faced with restricted food supply, autophagy preserves an energy equilibrium, eliminates cellular proteins and organelles that are damaged or could lead to aging, or even malignancies, and tissue degeneration. It also protects the mammalian cells from microbial invasion. Maybe this explains why so many societies have actually included autophagy-activating intermittent fasting into their healing customs, and use this to live a healthier life.
There are, however, certain possible hazards associated with autophagy activation. When autophagy is present in overabundance, it can kill cells that need to live while keeping alive those that ought to perish, such as cancer cells that have received chemotherapy.
The activation of autophagy can sometimes cause cellular congestion that can give rise to more illnesses should the lysosomal disposal of autophagosomes malfunctions. Parkinson’s and other neuro-related illnesses may be a result of this condition. The overwhelming body of research from mice has indicated that autophagy may primarily serve to maintain optimal longevity and welfare. However, it has not been fully understood how autophagy’s adaptable physiological tasks are balanced towards the possible hazards.