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The role of dietary restrictions in delaying aging and increasing longevity in organisms, from worms to primates, is well known. Now, a multi-institutional team from India has unveiled one of the mechanisms by which worms (C. elegans) exposed to moderate stress early in life in the form of dietary restriction can cope with chronic stress related to aging.
Role of stress
The team led by Dr. Arnab Mukhopadhyay of the National Institute of Immunology (NII) in Delhi has also shown that some organelles of the cells (endoplasmic reticulum), stressed early, could do their job more efficiently later in life, thus delaying aging and increasing longevity. Moderate stress early in life essentially prepares the endoplasmic reticulum to cope with age-related stress later. It also delays the onset of age-related diseases, such as Huntington and Alzheimer's.
Instead of dietary restrictions, researchers used a small molecule early in life in small doses for 24 hours to produce the same kind of stress in children. C. elegans. They have been able to delay aging and increase longevity.
Protein folding
The endoplasmic reticulum is responsible for most of the need for folding cellular proteins and destroying misfolded proteins. Normally, the ability of the endoplasmic reticulum to bend and destroy proteins is compromised with aging. "The priming helps delay the deterioration of the endoplasmic reticulum during protein folding," says Dr. Latika Matai of the NII and co-author of an article published in the Proceedings of the National Academy of Sciences (PNAS).
"Worms undergoing dietary restriction early in life showed an increased longevity of 30-40% compared to C. elegans it was not a restricted diet, "says Dr. Mukhopadhyay. "We can bypass the dietary restriction to induce stress by using a small molecule." A small dose of the molecule, which is a form of glucose that can not be used by cells, administered 24 hours earlier in life, has been found to prime the endoplasmic. reticulum and improve the protein folding ability and degradation of aggregated proteins in adults.
The endoplasmic reticulum requires glucose for optimal protein folding. Thus, when the small molecule is used, glucose availability is limited and the organelle is stressed by the load of misfolded proteins. The defense mechanism to fight against stress becomes regulated and tries to fold the proteins correctly or to degrade them.
Priming helps the endoplasmic reticulum to manage stress as the worm ages. "We observed an increase of about 20% in worm lifespan when the small molecule was only used," says Dr. Matai.
"By using the small molecule, we were able to mimic the stress of mouse cell lines. We then induced the cells to produce aggregates of proteins and we could see the cells suppress and degrade the aggregates better than the controls. As a result, cells have survived better, "says Dr. Mukhopadhyay.
Delay the onset of the disease
In addition to delaying aging and increasing lifespan, priming the endoplasmic reticulum with a little stress can delay certain age-related diseases, such as Huntington and Alzheimer's.
With aging, the mechanism of protein folding is usually altered. Thus, proteins tend to be misfolded and aggregates tend to form. Protein aggregates are the cause of Huntington's and Alzheimer's causes. "In C. elegans under stress, we were able to observe a delay in the aggregation of proteins as well as a reduction in overall numbers. The delay in aggregation was greater (50%) than that seen in controls, "says Dr. Matai.
"It is now important to test it on mouse models for Huntington and Alzheimer's," says Dr. Mukhopadhyay.
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