Autophagy in Aging: A Simplified Perspective PDF

ILOs 1. Describe the Conserved Process of Autophagy 2. Classify the different types of autophagy 3. Appraise the relationship between cellular Autophagy and Aging 4. Explain the link between ROS Generation, Autophagy and Aging 5. Identify Loss of Proteostasis in aging 6. Discuss Mitochon...

ILOs 1. Describe the Conserved Process of Autophagy 2. Classify the different types of autophagy 3. Appraise the relationship between cellular Autophagy and Aging 4. Explain the link between ROS Generation, Autophagy and Aging 5. Identify Loss of Proteostasis in aging 6. Discuss Mitochondrial Dysfunction in aging 7. Recognize Nutrient Sensing Deregulation and the role of intermittent fasting 8. Review the Genomic related to autophagy and aging 9. Describe Telomere Attrition 10. Appraise Current and Future Autophagic Treatments in Aging and Age-Related Diseases 40  The Conserved Process of Autophagy Autophagy “Self – Eating” An intracellular catabolic pathway concerned with lysosomal degradation and turnover of cytoplasmic organelles and proteins. A highly conserved process that enables cells to degrade and recycle cytoplasmic components which are sequestered in double-membrane vesicles and degraded on fusion with the lysosome. It was first coined by Christian de Duve in 1963 to describe a process of lysosomal degradation of cytosolic components. In 2016, Nobel Prize was awarded to Yoshinori Ohsumi for discoveries of the mechanisms for autophagy after 27 years of research hoping it would have an impact upon human health. 41 Types of autophagy Selective and non-selective autophagy 42 Cellular Autophagy and Aging Overexpression of ATG5 in mice lead to enhancement of the autophagy process and anti-aging features, suggesting the importance of autophagy in the longevity of mice. In addition, these mice showed a better resistance to age-related obesity and enhanced insulin sensitivity, exhibiting an improved metabolism. Autophagy and Hallmarks of Aging ROS Generation In the most important work that links an overexpression of a single Atg gene with an increment in mammals' lifespan the authors 43 Mitophagy: Mitochondrial ROS, activate Atg4 , and this in turn leads to mitophagy activation in order to reduce the ROS levels by limiting the number of mitochondria per cell. Mitophagy activation upon cellular stress helps avoid detrimental effects of ROS Loss of Proteostasis Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction. Autophagosomes and lysosomes decline in an age-dependent manner in muscles, heart, and several other tissues. Moreover, CMA has also been implicated in removing oxidized and potentially dangerous proteins by direct lysosomal degradation. 44 Mitochondrial Dysfunction in aging 45 age‐related decline mitochodrrial dysfunction >>> decline in autophagic capacity as a cause for accumulating altered molecules resulting from damaged and dead cells, which triggers inflammation response. Nutrient Sensing Deregulation and Intermittent Fasting The mammalian target of rapamycin (mTOR) kinase is the main negative regulator of autophagy and is exquisitely sensitive to dietary amino acids. When mTOR is activated, it shuts down autophagy. The main positive regulator is 5′ AMP-activated protein kinase (AMPK) which detects the AMP/ATP ratio and when this ratio is high signifying low cellular energy levels. When AMPK is activated, it activates autophagy. 46 Genomic Instability related to autophagy and aging 47  POSSIBLE ALTERATIONS THAT MAY CONTRIBUTE TO GENOMIC INSTABILITY IN AUTOPHAGY-DEFECTIVE CELLS: Failure to control the damage of checkpoint or repair proteins, Deregulated turnover of centrosomes, Insufficient energy for proper DNA replication and repair Excessive generation of reactive oxygen species due to inefficient removal of damaged mitochondria Telomere Attrition Repetitive sequences TTAGGG at the end of chromosomes. Telomerase is the special polymerase. Somatic cells of mammalian species lack the expression of telomerase. In each cell cycle, the telomere becomes shorter. This process is called telomere attrition. Aging leads to functional decline of telomerase in most of somatic cells. 48 Immortalized cells, such as germ cells and cancer cells, telomerase can sustain its activity. It is difficult to restore telomeres with the DNA repair machinery and this results in cellular senescence. In cells undergoing crisis, cells undergo cell death through autophagy activation, which is triggered by chromosome breakage. Current and Future Autophagic Treatments in Aging and Age- Related Diseases Induction or restoration of autophagy could alleviate aging symptoms. Three major anti-aging therapies evaluated over the last 30 years: - Autophagic inducers - Antioxidants - Caloric restriction AUTOPHAGY ACTIVATORS Rapamycin, an immunosuppressive macrolide, is a well-known autophagic activator via inhibition of mTOR. - Proved to increase lifespan - Rapamycin added during reperfusion after heart infarction in a myocardial ischemia mouse model improved the survival and cardiac functioning - Rapamycin improves whole metabolism. 49 Caloric restriction /Intermittent Fasting One of the most effective therapies in Reducing oxidative stress Prolonging lifespan 50