September 2008 - Research led by Stanford University School of Medicine published in Cell
has identified specific genetic pathways driving the aging process in worms. Researchers explain that these surprising
findings challenge the commonly-held theory that aging results from an inevitable accumulation of tissue damage and
suggest there may be implications for eventually being able to stop or reverse the process.
The study focused on aging regulation mechanisms in C. elegans, described as a millimeter-long
nematode worm with a simple structure, small number of genes and maximum lifespan of about two weeks making it a
useful research model. Researchers found age-related changes in the levels of three transcription factors
( molecular switches that turn genes on and off) triggering pathways that resulted in aging.
The researchers explain that the predominant theory about the causes of aging argues that it is an
inevitable consequence of accumulated wear and tear: "toxins, free-radical molecules, DNA-damaging radiation,
disease and stress ravage the body to the point it can't rebound".
Alternatively, it is suggested that inborn genetic programs may be responsible implying an
evolutionary process favoring younger organisms. After reproduction ceases natural selection cannot influence
problems developing later in the lifespan so genetic pathways for aging become entrenched, a process referred
to the researchers as "developmental drift."
Lead author Stuart Kim, professor of developmental biology and genetics said:
"Our data just didn't fit the current model of damage accumulation, and so we had to consider the
alternative model of developmental drift."
Researchers used microarrays (silicon chips that detect changes in gene expression) to try to identify
genes that responded differently in worms at either end of their lifespan. They found hundreds of age-regulated
genes switched on and off by elt-3, a transcription factor which increases with age. Two other transcription factors
that regulate elt-3 also changed with age. Researchers tested whether these signal molecules were part of a
wear-and-tear aging mechanism by exposing worms to stressors (such as heat, free-radical oxidation, radiation and
disease) none of which affected the relevant genes.
Stuart Kim commented:
"We found a normal developmental program that works in young animals, but becomes unbalanced as the
worm gets older. It accounts for the lion's share of molecular differences between young and old worms."
At this stage, researchers are unsure whether the same process applies to humans, but argue that
developmental drift offers a coherent hypothesis to explain why creatures age.
Stuart Kim said:
"Everyone has assumed we age by rust. But then how do you explain animals that don't age?"
Researchers point out that the wear-and tear theory is difficult to reconcile with the fact that
different species have significantly different lifespans; tortoises can lay eggs at 100, whales can live to 200,
and clams to more than 400 years. All species use the same building blocks, thus the chemistry of the wear-and-tear
process should be the same in all cells including those of humans and worms.
Stuart Kim said:
"A free radical doesn't care if it's in a human cell or a worm cell."
Researchers conclude that if the aging process is driven by changes in regulatory genes it may not
be inevitable and it may be theoretically possible to slow down or stop developmental drift.
Marc Tatar, a professor of biology and medicine at Brown University not part of the research
"The take-home message is that aging can be slowed and managed by manipulating signaling circuits
within cells. This is a new and potentially powerful circuit that has just been discovered for doing that."
Stuart Kim concluded:
"It's a new way to think about how to slow the aging process."