Among cell biologists, these mechanisms remain to this day the most accepted ways of explaining what’s happening to that face reflecting back at us in our bathroom mirror. But telomere science has opened up the possibility of drilling even deeper into the molecular bedrock of aging. The fledgling field was energized in 1984, when biochemist Elizabeth Blackburn of the University of California at Berkeley and her then-grad student Carol Greider discovered the telomerase enzyme in a pond-scum protozoan, an achievement that won them a Nobel Prize. Since then, our picture of human telomeres and telomerase has sharpened considerably.
Telomeres are made of repeating sequences of six DNA bases—two thymine, one adenine, three guanine (TTAGGG)—that serve to “cap” chromosomes, preventing potentially cancerous breaks; the analogy usually trotted out is the plastic aglet that prevents a shoelace from fraying at the ends. Telomeres also assist cell division. Every time a cell splits, the ends of its chromosomes fail to get fully copied in the two new daughter cells, and a bit of telomeric DNA gets lost. No harm is done to the rest of the chromosome, but in cells that divide frequently, the telomeres shorten with each replication. Telomerase’s job is to synthesize new DNA to add to the shrinking telomeres, slowing down the decline.
Human life, it turns out, is a losing effort to hang on to our telomeres. At conception, telomeres have roughly 15,000 DNA base pairs. Because telomerase can’t keep up with rapid cell division in utero, they shrink to about 10,000 base pairs at birth. At that point, the telomerase gene is mostly turned off. Without the enzyme, we continue to lose telomeric DNA—once we’re out of our teens, usually at a rate of 50 base pairs a year. By the time some of our telomeres drop below about 5,000 base pairs, typically well into our “golden” years, our cells may have lost the ability to divide. They become senescent, bad at doing the work they were designed to do but good at doing things like releasing inflammatory chemicals that harm their neighbors. Or they may be targeted for cell death.
Andrews sounds almost giddy when he describes the “aha” moment 20 years ago when he first heard his soon-to-be boss at Geron, pioneering telomere biologist Calvin Harley, lecture about telomeres as a “mitotic clock,” in which the steady shortening of the telomeres serves as the tick-tock of the aging cell. “I was floored,” Andrews says. He found the lockstep precision suggested by the metaphor irresistible.
Cultured in the lab, cells can divide just 50 to 70 times before packing it in (this is known as the Hayflick Limit, after longevity-research eminence Leonard Hayflick, who discovered the phenomenon). The human body is significantly more complex than a petri dish, but some similar limit must be enforced there, Andrews says, to account for the fact that the maximum human life span is so tightly regulated, with the longest-lived humans making it to 100 and, to the best of our knowledge, nobody surviving past 125. If free-radical damage were really the primary driver of aging, he says, people’s rate of bodily decline would vary widely based on the amount of environmental damage they had absorbed, a major contributor to the free-radical load, and therefore so would their maximum life span. “But you can look at a person and have a 95 percent chance of guessing their age within five years,” he says. “There has to be some kind of internal clock ticking inside of us.”
Biologists continue to debate the extent to which aging at the cell level determines the aging of the whole organism. Most have argued that short or damaged telomeres aren’t as big a deal as Andrews, or even the more measured Harley, make them out to be. Tissues and organ systems that depend on cell division have a fair amount of reserve capacity, and the cells that seem to play the biggest role in our decline, neurons and heart-muscle cells, hardly replicate at all.single page
Five amazing, clean technologies that will set us free, in this month's energy-focused issue. Also: how to build a better bomb detector, the robotic toys that are raising your children, a human catapult, the world's smallest arcade, and much more.