The continual and inevitable shortening of telomeres, the protective "caps" at the end of all 46 human chromosomes, has been linked to aging and physical decline. Once they are gone, so are we. But there are more ways than one to grow old.
Researchers at Salk Institute for Biological Studies demonstrate for the first time that the roundworm Caenorhabditis elegans succumbs to the trials of old age although its telomeres are still long, and moves with a youthful spring in its crawl despite short telomeres, they report in PLoS Genetics, available online now.
In the past, preventing telomere shortening has often been portrayed as the key to preventing aging and living longer. In their study, Salk scientists Jan Karlseder, an assistant professor in the Regulatory Biology Laboratory, and Andrew Dillin, an assistant professor in the Molecular and Cell Biology Laboratory, provide a much more nuanced view of telomeres and the process of cellular and organismal aging.
"Some long-lived species like humans have telomeres that are much shorter than the telomeres in species like mice, which live only a few years. Nobody yet knows why. But now we have conclusive evidence that telomeres alone do not dictate aging and lifespan," says Karlseder.
Each time a cell divides, its telomeres get shorter, a process called replicative or cellular aging. Some have likened this progressive erosion of telomeres to a genetic biological clock that winds down over time, leading to a gradual decline in our mental and physical prowess. Yet, C. elegans, a tiny creature, which spends the better part of its adult life without a single dividing cell in its body, still shows signs of old age and eventually dies, raising intriguing questions.
Are telomeres in non-dividing cells eroding slowly over time? If so, will worms with longer telomeres live longer? If not, how do worm cells and by extension non-dividing human cells, such as nerve cells, keep track of their biological age? To answer these vexing questions, Karlseder, who is interested in telomeres, teamed up with Dillin, who studies lifespan and aging in C. elegans.
Researchers use this 1 millimeter-long soil roundworm that feeds on bacteria mainly because it is simple, easy to grow in bulk populations, and is quite convenient for genetic analysis.
When these scientists began their work almost nothing was known about worm telomeres. "We had to start at the very beginning. But now we know that C. elegans is the perfect model organism to study telomere biology since their regulation is similar to human telomeres," says first author Marcela Raices, a post-doctoral researcher in Karlseder's lab.
Many cells in our body keep dividing throughout life (e.g., those that line our digestive tract, blood, and immune cells) because they must be replaced over time. When these cells' telomeres reach a critically short length, however, they can no longer replicate. The cell's structure and function begin to fail as it enters this state of growth arrest, called replicative senescence.
"But even in very old people, blood cells, which divide continuously, don't have critically short telomeres. In humans and, as we know now, in worms, telomere length is certainly not a limiting factor for lifespan," says Karlseder.
The Salk team, which also included graduate student Hugo Maruyama, found that despite the close correlation of telomere length and cellular senescence in mammalian cells, worms with long telomeres were neither long lived, nor did worm populations with short telomeres exhibit a shorter life span. On the other hand, long-lived and short-lived mutant worms could have them either way without any effect on their lifespan. When Raices monitored telomere length over the full lifespan of worms and under stress, a situation reported recently at another laboratory to shorten telomeres in humans, she found absolutely no change.
"For successful aging you have to control both, aging in your dividing cells, which hinges on telomere maintenance, but also aging in your non-dividing cells. We thought that telomeres might play a role in the later but that's clearly not the case," says Dillin. "What is probably playing a role in the other half of aging is the insulin signaling pathway, proper mitochondrial function and dietary restriction," he reasons.
Several types of cells in our body, such as mature nerve cells in the brain, oocytes, skeletal and heart muscle cells don't actively divide but stay put just like the cells in adult worms.
"That makes our findings relevant for age-related decline in mental function and neurodegenerative diseases, such as Alzheimer's," says Karlseder. "Making people live longer is not enough, we want them to grow old healthy," he adds.
"To prevent accelerated aging in an organism, you need to have both proper telomere maintenance and those other genetic pathways intact," says Dillin. "If you wanted to develop a drug to combat aging it wouldn't be enough to target telomeres, you would also have to target these other genetic pathways."
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, founded the Institute in 1960 on land donated by the City of San Diego and with the financial support of the March of Dimes.
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