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| FASTING, LONGEVITY AND AUTOPHAGY | | | Dr. Wahied Khawar Balwan
Fasting is ancient tradition in different religions and is willful calorie restriction. Fasting induces autophagy, a natural renewal process that occurs at cellular level in the body. It helps in reducing the possibility of some diseases as well as prolongs the lifespan of an individual. Fasting and calorie restriction induces the autophagy. Lysosomes have been identified as signaling organelles that sense nutrient availability and activate a lysosome-to- nucleus signaling pathway. They mediate the starvation response and regulates energy metabolism.
INTRODUCTION
Fasting is the willful self-discipline or reduction of the consumption of some or all food, drink, or both, for a period. Many cultures and religions around the world fast throughout the year. Religions and philosophies that practice fasting include Hinduism, Buddhism, Jainism, Islam, Christianity, Judaism and Taoism. Throughout the recorded history of mankind, fasting has been determined of traditional health and healing practices. Apart from religious practice, fasting is often used as a tool to make a political statement, to protest, or to bring awareness to a cause.
On October 3, 2016, the Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi for “discoveries of the mechanisms for autophagy”. Autophagy literally means “self-eating” and is a vital self-degradative clean-up process for the removal of misfolded or aggregated proteins, and recycling of damaged cell components. Dr. Ohsumi identified the genes that regulate autophagy and has linked disturbances of autophagy to a host of degenerative diseases. In his studies, he used starvation to activate autophagy. Starvation has long been identified as a cause for the breakdown and clean-up of toxic cells and debris.
Lysosomes are the main organelle involved in the autophagy. During autophagy, the cell embraces different routes to deliver the cytoplasmic substrates to lysosomes for degradation of unwanted or damaged material (e.g. macromolecules, organelles) that accumulate during aging.
Autophagy has been shown to possess important housekeeping and quality control functions that contribute to health and longevity. Lysosomes are present in all animal cell types (except erythrocytes) and are the main catabolic organelle of the cells. Lysosomes contain a large number of hydrolases, including proteases, nucleases, lipases, sulfatases or phosphatases, etc. whose optimum pH is usually low (pH 4.5–5). In yeast, methionine restriction positively influences the pH of vacuoles (yeast lysosomes) and extends lifespan by increasing the functional autophagy. As intra-lysosomal pH impacts the degradative and storage functions of the lysosome and thus it may serve as another aging- relevant signal associated with the fasting.
Besides their central implication in autophagy, lysosomes also contribute to lifespan control via a diverse array of other signals as shown in different model organisms. For instance, organization of active lipid molecules from the lysosomes to the nucleus results in altered gene expression that modulates lifespan in worms. In a cell, for the degradation of protein and organelle i.e. the autophagy occurs via the lysosomal pathway. Cytoplasmic material can be transported for lysosomal degradation along three pathways:
1. Macro-autophagy: It facilitates the eradication of damaged cell organelles or unused proteins. In this regard, the material that needs to be degraded is engulfed by the phagosome, which forms a double membrane known as an autophagosome around the organelle marked for destruction. Then, the autophagosome fuses with the lysozyme where the acidic lysosomal hydrolases cause degradation of the contents of autophagosome.
2. Micro-autophagy: In this pathway lysosome itself directly takes up the cytosolic components via lysosomal membrane invagination.
3. Chaperone-mediated autophagy (CMA): It is a very complex and specific pathway. A receptor on the lysosomal membrane, lysosomalassociated membrane protein 2 A (LAMP-2 A), recognizes chaperone proteins (such as Hsc-70) bound to misfolded proteins. This leads to the translocation of the target protein across the lysosomal membrane and subsequent unfolding and degradation. CMA plays an important role in diverse pathophysiological conditions, including aging.
The term “autophagy” usually refers to macroautophagy, which is the most prevalent form. The macroautophagy machinery is highly conserved from the unicellular yeast Saccharomyces cerevisiae, nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and upto mammals. During aging, the autophagic ability of cell declines in most organisms and as a result of this intracellular waste products accumulate. Conversely, genetic and pharmacological interventions that stimulate autophagy do promote longevity.
FASTING OR CALORIE RESTRICTION
Autophagy can be induced by a variety of stress stimuli, such as nutrient and energy stress, endoplasmic reticulum (ER) stress, pathogenassociated and danger- associated molecular patterns, hypoxia, redox stress, and mitochondrial damage.
Fasting and Calorie restriction (CR) is considered as an optimal intervention for improving health, increasing resistance to stress, slowing aging and increasing longevity without the undesirable side effects associated with alternative interventions. CR is generally defined as a 10– 40% reduction in calorie intake without a reduction in dietary nutritional content. Researchers have suggested that intermittent fasting may have a positive effect on longevity and it exerts preventive effects on conditions such as cancer, hypertension, diabetes, and other age-related diseases. The restriction of calorie intake from intermittent fasting can lead to benefits including improved insulin sensitivity, increased sirtuin levels, and increased DNA repair. These changes lead to improved stem cell function, mitochondrial function, and tissue repair, all of which are crucial for improvements in longevity.
Dietary restriction (DR) in a broad sense includes calorie restriction (CR) and is defined as a reduction of particular or total nutrient intake without causing malnutrition. Dietary restriction can lead to numerous biological changes like improved organ function, and improved resistance to stress, which ultimately improves longevity. Beneficial effects on various physiological processes that are known to deteriorate with age have been attributed to CR which appears to increase longevity through various mechanisms like changes in energy production and utilization, oxidative stress, insulin sensitivity, inflammatory responses, and alterations in communication between cells and organs.
CONCLUSION
The old time tradition of fasting once in a week and on certain festivals in India indicates that the ancient Indians might knew the beneficial effects of fasting on the body. The studies overwhelmingly suggest that both fasting and CR have a main role in the upregulation of autophagy markers and autophagy activation. Modulated autophagy plays a crucial role in normal function and homeostasis of cells, leading to an improvement in the health and function of various organs and tissues, including muscle, liver, kidney, heart, pancreatic and the nervous system. The consequences of accumulating old junky proteins all over the place can be seen in two main conditions namely Alzheimer’s Disease (AD) and cancer.
‘Any error in this manuscript is silent testimony of the fact that it was a human effort’ |
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