Nematode May Hold Clues into Aging Elixir

The scientists looked at how treatments known to increase longevity in the 1-mm-long C. elegans (including calorie restriction and treatment with the drug rapamycin) affected the expression of genes that manufacture collagen and other proteins that make up the extra-cellular matrix (ECM), the framework of scaffolding that supports organs, tissues, and bones.

“Any longevity intervention that we looked at, whether genetic or nutritional or drugs, increased expression of collagen and other ECM genes, and enhanced ECM remodeling,” stated T. Keith Blackwell, MD, PhD, senior and co-corresponding author on the study. “If you interfere with this expression, you interfere with the lifespan extension. And if you over-express some of these genes, the worm actually lives a little bit longer.”

These findings indicate that production of collagen and other ECM components plays a key role in longevity for the worm. They also suggest that agents promoting this tissue remodeling might slow aging in humans, according to Dr. Blackwell. C elegans is a well-suited model for examining the aging process because of its short life and easily engineered genetics. “Essentially every other mechanism that people find in this tiny worm ends up applicable, in the most fundamental sense, to higher organisms,” he pointed out. “That’s a strong predictor that this mechanism is relevant to people as well.”

The major structural proteins in connective tissue, collagens comprise about one-third of the proteins in the human body. “Collagens are everywhere; they are like the scaffolding for our tissues, and they give us tissue elasticity and strength,” Dr. Blackwell noted. But these ECM structures deteriorate with age, and collagens have been implicated in human diseases ranging from diabetes complications to cardiovascular conditions to bone and kidney diseases. “The aging field really has been focusing on mechanisms that protect or regenerate the cell, but what we’re saying in this paper is that it’s all tied together with the ECM,” he said.

“This is a very important discovery, which may impact many areas of diabetes development and complications,” commented George King, MD, Joslin’s senior vice president and chief scientific officer, who was not involved in the study. “The ECM has been a key component for many studies in diabetic complications including the retina, the heart, the kidney and wound-healing. There’s also a great deal of interest in how the ECM is involved in insulin action as well as in the survival of insulin-producing beta cells.”

The investigators research required manipulating apart two molecular pathways in C. elegans, which live on a diet of rotten fruit that can create a feast-and-famine existence. Both pathways involve insulin and insulin-like growth factor 1 (IGF-1), a hormone with a molecular structure very similar to insulin. One pathway allows the worm to do a version of hibernation, so that it can better endure extremes of temperatures or lack of food or other stresses, and then resume normal life in better times. The second pathway, the main focus of the study, more closely parallels human mechanisms and requires activation of a gene known as SKN-1 in the worm. SKN-1 is a master gene regulator that controls many defenses against stress and is the C. elegans counterpart of a set of human regulators called Nrf1/2/3.

“Aging is a complex process in which maintenance of tissues declines over time,” said Collin Ewald, PhD, lead author on the article. “The ultimate goal of aging research is to find processes that promote healthy aging by ensuring the quality of youthfulness late in life. Other laboratories examining longevity treatments in the C. elegans worm had also detected higher expression of collagen genes, but those results were not followed up and people focused on processes that act within cells instead.”

The research has demonstrated that if mice are given a treatment that makes them live longer or are genetically predisposed to live longer, their muscle tendons are stronger and more elastic. In spite of these provocative clues, no one had previously examined the possibility that ECM remodeling might be a defense against aging.

This new findings will help to create up new opportunities for further research into longevity, and potentially could lead to improved antiaging drugs that would avert development or progression of chronic disease. “Additionally, it says that beauty is definitely not skin deep,” Dr. Blackwell remarked. In fact, the richest beauty is inner beauty, because if you want to look young you don’t start with the outside, you start with the inside. Cosmetic companies might even consider becoming more like pharmaceutical companies, and looking for drugs that enhance overall health.”

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