The continual and inevitable shortening of telomeres, the protective"caps" at the end of all 46 human chromosomes, has been linked to agingand physical decline. Once they are gone, so are we. But there are moreways than one to grow old.
Researchers at Salk Institute for Biological Studies demonstrate forthe first time that the roundworm Caenorhabditis elegans succumbs tothe trials of old age although its telomeres are still long, and moveswith a youthful spring in its crawl despite short telomeres, theyreport in PLoS Genetics, available online now.
In the past, preventing telomere shortening has often been portrayed asthe key to preventing aging and living longer. In their study, Salkscientists Jan Karlseder, an assistant professor in the RegulatoryBiology Laboratory, and Andrew Dillin, an assistant professor in theMolecular and Cell Biology Laboratory, provide a much more nuanced viewof telomeres and the process of cellular and organismal aging.
"Some long-lived species like humans have telomeres that aremuch shorter than the telomeres in species like mice, which live only afew years. Nobody yet knows why. But now we have conclusive evidencethat telomeres alone do not dictate aging and lifespan," saysKarlseder.
Each time a cell divides, its telomeres get shorter, a processcalled replicative or cellular aging. Some have likened thisprogressive erosion of telomeres to a genetic biological clock thatwinds down over time, leading to a gradual decline in our mental andphysical prowess. Yet, C. elegans, a tiny creature, which spends thebetter part of its adult life without a single dividing cell in itsbody, still shows signs of old age and eventually dies, raisingintriguing 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 cellsand by extension non-dividing human cells, such as nerve cells, keeptrack of their biological age? To answer these vexing questions,Karlseder, who is interested in telomeres, teamed up with Dillin, whostudies lifespan and aging in C. elegans.
Researchers use this 1 millimeter-long soil roundworm that feeds onbacteria 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 aboutworm telomeres. "We had to start at the very beginning. But now we knowthat C. elegans is the perfect model organism to study telomere biologysince their regulation is similar to human telomeres," says firstauthor Marcela Raices, a post-doctoral researcher in Karlseder's lab.
Many cells in our body keep dividing throughout life (e.g., those thatline our digestive tract, blood, and immune cells) because they must bereplaced over time. When these cells' telomeres reach a criticallyshort length, however, they can no longer replicate. The cell'sstructure and function begin to fail as it enters this state of growtharrest, 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 forlifespan," says Karlseder.
The Salk team, which also included graduate student Hugo Maruyama,found that despite the close correlation of telomere length andcellular senescence in mammalian cells, worms with long telomeres wereneither long lived, nor did worm populations with short telomeresexhibit a shorter life span. On the other hand, long-lived andshort-lived mutant worms could have them either way without any effecton their lifespan. When Raices monitored telomere length over the fulllifespan of worms and under stress, a situation reported recently atanother laboratory to shorten telomeres in humans, she found absolutelyno change.
"For successful aging you have to control both, aging in your dividingcells, which hinges on telomere maintenance, but also aging in yournon-dividing cells. We thought that telomeres might play a role in thelater but that's clearly not the case," says Dillin. "What is probablyplaying a role in the other half of aging is the insulin signalingpathway, proper mitochondrial function and dietary restriction," hereasons.
Several types of cells in our body, such as mature nerve cells in thebrain, oocytes, skeletal and heart muscle cells don't actively dividebut stay put just like the cells in adult worms.
"That makes our findings relevant for age-related decline in mentalfunction and neurodegenerative diseases, such as Alzheimer's," saysKarlseder. "Making people live longer is not enough, we want them togrow old healthy," he adds.
"To prevent accelerated aging in an organism, you need to have bothproper telomere maintenance and those other genetic pathways intact,"says Dillin. "If you wanted to develop a drug to combat aging itwouldn't be enough to target telomeres, you would also have to targetthese other genetic pathways."
The Salk Institute for Biological Studies in La Jolla, California, isan independent nonprofit organization dedicated to fundamentaldiscoveries in the life sciences, the improvement of human health andthe training of future generations of researchers. Jonas Salk, M.D.,whose polio vaccine all but eradicated the crippling diseasepoliomyelitis in 1955, founded the Institute in 1960 on land donated bythe City of San Diego and with the financial support of the March ofDimes.
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