Starved to Life
Autophagy: a viable mechanism for prolonged life
Have you ever skipped a meal and been scolded for being unhealthy? Such
reprimands may no longer be warranted, as new discoveries suggest that
starving your cells for short, controlled periods of time may actually
have beneficial effects. Current research on autophagy, a process
activated during periods of cell stress and starvation, is providing
new information on this metabolic pathway that may increase longevity
and decrease risks for certain diseases. Recent studies demonstrate
that autophagy increases life expectancy and health in mice. This
suggests that controlled dieting and fasting, if done responsibly, may
have similar benefits for humans. When people age, their cells may be
too damaged to reproduce healthy copies. As a result, the cell may
either undergo apoptosis (programmed cell death), or autophagy-mediated
recovery wherein lysosomes degrade the damaged organelles. Alzheimer’s,
Parkinson’s, and many other neurodegenerative diseases can be
attributed to malfunctions of the autophagic pathway.
Autophagy is a nutrient-sensitive process in which lysosomes in a cell degrade unnecessary, dysfunctional cell parts and extracellular pathogens. Target of rapamyacin (TOR) kinase, a protein regulating the pathway that controls autophagy levels, and the downstream autophagy (ATG) genes, which encode proteins required for macroautophagy, are both activated when the body senses the presence of nutrient-deprived cells. When TOR kinase is activated, the main functional unit of autophagy, the autophagosome, is expressed, and basal levels of autophagy are increased both within a specific cell and throughout the body. The autophagosome will then fuse with a lysosome to degrade its contents.
Beth Levine, MD, and Guido Kroemer, MD, PhD, University of Texas, Southwestern Medical Center, published their research on the role of autophagy in different human diseases and how it functions in different organs in the body in the January 2008 issue of Cell. In their review, autophagy is shown to be actively involved in reducing or preventing neuromuscular diseases, neurodegenerative diseases, liver problems, and tumor formation, many of which augur serious health consequences for people who are genetically predisposed to such conditions. After undergoing the wear and tear of metabolic processes – regardless of the presence of pathogens – the body becomes immunocompromised and more prone to damage.
Autophagy functions to recycle old and damaged organelles, thereby redirecting energy for the cell and maintaining its condition. When an accumulation of potentially harmful aggregate proteins exists, autophagy also functions in clearing these complex masses through protein degradation via proteasomes, enzymes that break down proteins. Properly controlled fasting for certain periods of time can activate this metabolic pathway that will reduce, if not prevent altogether, the likelihood of the development of certain medical conditions that may be caused by such protein aggregates, thus increasing lifespan. However, the act of fasting can also result in side effects that may not make it a viable method to stimulate higher levels of autophagy within the body.
Qing Zhong, MD, PhD, University of California, Berkeley, researches autophagy and apoptosis, particularly in the tumor suppressor p53 gene. He argues that while fasting may increase basal levels of autophagy, other effects may outweigh its benefits. Nutrient deprivation can produce several negative side effects when conducted on any living organism. These effects were observed in humans through the Minnesota Starvation Experiment, conducted during World War II and published in The Biology of Human Starvation in 1950 by Ancel Keys et al., to measure the effects of famine and the recovery rate from starvation in Europe. Subjects of the experiment underwent 12 weeks of standardized calorie intake, followed by 24 weeks of reduced semi-starved calorie intake to emulate impoverished conditions in Europe at the time. Subsequent steps involved 12 weeks of restricted rehabilitation during which calorie intake was slightly increased, and finally eight weeks of unrestricted rehabilitation. The resultant psychological effects were disastrous, as several subjects were found to be withdrawn, emotionally distressed or depressed, while many of their metabolic processes such as heart rate and respiration were impaired.
In addressing this problem, Zhong makes an interesting proposition: while the act of fasting may initiate the autophagic pathway, it does so mainly through activation of the TOR kinase and ATG genes that lie downstream. Thus, pharmaceutical companies can possibly design drugs to stimulate this pathway while eliminating fasting as an autophagy sequence-initiator. Finding a drug or an external regulator able to stimulate this pathway would decrease the risk of several neurodegenerative diseases, as well as maintain cell health, bypassing the harmful physical and psychological side effects of starvation. The implications of these research findings are significant in an increasingly health-challenged nation. By preventing the accumulation of aggregated proteins and other potential dangers leading to pathogenesis in humans, it is possible to prevent diseases before they start. Eating healthy, or keeping a healthy level of calories that maintains the autophagic process could promote well-being, as well as an extended life span.
About the Author
Quang Nguyen is a first year majoring in Molecular and Cell Biology. He hopes to one day attend medical or graduate school.