Cellular Housekeeping May Help Prevent Alzheimer’s Disease, Aging
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Copy of Good Housekeeping magazine from 1928. Research suggests that 'good' cellular housekeeping could help prevent Alzheimer's Disease and aging.
Following Japan’s surrender in World War II, millions of Japanese experienced famineas the Allies scrambled to re-establish order to Japan. Dr. Yoshinori Ohusmi, this year’s recipient of the prestigious Kyoto Prize in Basic Science, was born the year that Japan surrendered. Dr. Ohsumi later overcame an impressive number of professional obstacles in order to discover a unique process that occurs in individuals experiencing famine. Dr. Ohsumi discovered that under conditions of famine, our body cells break down old proteins so that new proteins can be created. The scientific name for this process is “autophagy,” and Dr. Ohsumi’s insights into autophagy may help prevent Alzheimer’s disease and aging.
In Greek, “auto” stands for “self” and “phage” stands for “eating.” “Autophagy” therefore literally translates as “self eating.” Autophagy entails breaking down body proteins into constituent amino acids (the building blocks of proteins) and recycling these amino acids to create new proteins. Just as periods of famine force communities to become increasingly resourceful, nutrient deprivation forces our body cells to recycle their proteins.
One of Dr. Ohsumi’s earliest epiphanies came while observing microscopic vessels within yeast cells. Dr. Ohsumi noted that after 30 minutes of “starving” yeast cells, a significant amount of material began collecting in microscopic vessels within the yeast. This material, it turns out, was proteins that were being degraded into amino acids via the process of autophagy. Dr. Ohsumi then identified “mutant” yeast cells that did not undergo this process, and eventually identified genes responsible for autophagy (genes named “ATG” for “AuTophagy Genes”). Because yeast and human cells share an impressive number of genes, Dr. Ohsumi’s research also led to a much better understanding of autophagy in humans.
More recently scientists analyzed organisms lacking critical ATG genes and surmised that autophagy also plays an important role in “cellular housekeeping,” or the breaking down and removal of harmful proteins from body cells. Japanese Drs. Komatsu and Waguri presented convincing evidence that organisms missing “ATG 7,” one the autophagy genes discovered in Dr. Ohsuni’s lab, experience neurodegeneration and shortened lifespans. Drs. Komatsu and Waguri bred mice that lacked ATG 7 and found that these mice showed neurological dysfunction, died prematurely, and demonstrated diminished levels of autophagy.
This research suggests that cellular housekeeping is critical for preventing excessive accumulations of toxic proteins in brain cells, accumulations that contribute to neurodegenerative diseases like Parkinson’s, Huntington’s, and Alzheimer’s disease.
Alzheimer’s disease is the most prevalent neurodegenerative disorder is the U.S. and is associated with accumulations of protein “plaques” and “tangles” in the brain. These plaques and tangles are believed to precipitate the death of nerve cells resulting in the loss of brain functions. Many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease, are characterized by an accumulation of misfolded proteins. Therefore, abnormal autophagy may contribute to the deposition of toxic proteins in individuals experiencing many forms of neurodegeneration.
However, researchers recently made a surprising discovery- an early sign of Alzheimer’s disease is the creation of autophagy vessels where toxic proteins appear to actually assemble instead of degrade. Scientists are developing a more nuanced understanding of autophagy in order to resolve this perplexity. Our cellular housekeeping can be described as two general steps: the formation of a vessel around a harmful protein and the degradation (or break-down) of the protein within the vessel. Failure of this second step, the break-down of harmful proteins, could at least partially account for the increased deposition of toxic proteins in individuals experiencing Alzheimer’s disease.
The cellular housekeeping observed in individuals with Alzheimer’s disease can be compared to literal housekeeping. Imagine someone placing garbage in a garbage bag but forgetting to remove the garbage from the house. Over time, the garbage will fester. In both the cellular and literal housekeeping examples, housekeeping itself is not necessarily problematic, but a failure to breakdown or remove the “garbage” brings about a wreaking (or reeking). Therefore, future treatments for Alzheimer’s disease might activate or enhance this stage of breaking down and removing harmful proteins.
Interestingly, a few compounds found to alleviate neurodegenerative diseases appear to also optimize autophagy. For example, chronic treatment of lithium (a mood-stabilizing drug) enhanced autophagy in one study and slowed the development of Alzheimer’s disease in another study.
Neurodegenerative diseases become more prevalent with age, and recent investigations suggest that aging may also be associated with abnormal autophagy. Potential methods for enhancing one’s lifespan, such as drastically restricting the number of calories one eats (while avoiding malnutrition), appear to enhance autophagy. Also, the compound “resveratrol” (found in the skin of grapes and other fruits) may increase longevity in animals while also enhancing autophagy. (Interestingly, a clinical trial is currently studying resveratrol to prevent the onset of Alzheimer’s disease.) Similarly, the compound “spermadine” (yes, it’s found in human sperm) enhances autophagy and prolongs lifespan in animals.
To summarize, dysfunction of cellular housekeeping likely contributes to neurodegenerative diseases like Alzheimer’s disease and perhaps also aging. As scientists build upon Dr. Ohsumi’s pioneering work and gain a more nuanced understanding of autophagy, their insights could yield methods for warding off Alzheimer’s disease and aging.
