Hannah K. Lee
Genetic mutation changes from adaptive to dangerous after reproductive age.
Martin read everything he could on aging. He took particular interest in observations showing how organisms ranging from clonal yeast to human twins had wildly different lifespans. One of the more dramatic examples were reports of tiny worms, Caenorhabditis elegans, that varied in lifespan by up to five-fold even when the worms were genetically identical and lived in identical laboratory surroundings.
Biologists know how chance events in the environment (such as getting hit by a bus) impact lifespan. And they understand the role of chance in genetics (such as inheriting genes for Huntington’s disease and certain cancers). But it now seems a third realm of uncertainty emerges as animals grow older, causing them to age in different ways. Researchers are only beginning to figure out the basis of biological fluctuations that build up over time. Some result from mutations that slip into the genomes within cells as they replicate. Others occur because of changes in molecules that either shut off or activate genes.
The location of random variations within a cell’s nucleus matters, and that too may be determined by chance. It’s as if they were small tears forming on a blueprint that is sloppily folded, unfolded, and refolded over time. Depending on where the wrinkles occur, the building the blueprint encodes either remains intact or is rendered vulnerable to collapse.
Like a gust of wind into a glass shop, chance dictates the extent of the damage.
Why would evolution have allowed such instability to persist in our biological makeup over the eons? Martin, now an 89-year-old researcher who studies the genetic basis of aging at the University of Washington, and a handful of other researchers who study aging, speculate that a limited amount of internal uncertainty is beneficial because it helps animals adapt to changing environments.
This notion fits with a broader picture of the vital role of diversity in evolution: Variation among individuals in a population provides options for natural selection to choose from. After all, natural selection cannot weed out excessive variations if they occur after an animal has passed on its genes, since survival in the evolutionary sense only means survival of that lineage in the next generation.
As Martin puts it, “Nature doesn’t give a damn about us after we make our babies. Natural selection is pretty much gone around age 40—and that’s where aging begins.”
While mutations and fluctuations in gene expression within organisms can provide an adaptive boon, they become problematic late in life as mutations accumulate and the breadth of swings in gene expression grows wider. In turn, Martin says, these chance swings may lead to “geriatric disorders,” including cancer and degenerative brain diseases.
Throughout our lives, chance slips into our bodies through tiny, accidental mutations. Somatic mutations occur in cells as they divide over time. During every division, mistakes are made in the new strand of DNA. Genes involved with DNA repair normally fix those mutations—but if enough time passes, a mistake will inevitably occur within one of those repair genes, too. When, exactly, is a matter of chance—although the risk increases over time. But once that error occurs, additional mutations will be sustained rather than fixed. Again, chance determines how much more time passes until one of the mutations randomly affects a cancer-causing gene.
“Imagine that you are throwing darts at DNA,” Martin explains. “It might hit at some places where you’re lucky—and like me, you live until 89. Or you could be unlucky like my late wife who died of an aggressive form of cancer beginning in the brain. Even though she was in great physical shape, she got a hit in a dominant oncogene.”
Not all cancer is caused by chance. In January, 2015, a biostatistician and a cancer geneticist estimated that about a third of cancer cases can be attributed to inherited defects and assaults from environmental factors ranging from sun rays to cigarettes. The rest, they wrote in Science, may be due to random internal events like chance mutations…