In a previous post, “How is Your Biologic Clock Ticking?,” we discussed the two types of biological clocks that govern our daily lives. There are the ones that are present in most cells, whose periodicity is about 12.2 hours. And, there is the one located in the brain that rides herd over them, forcing them to conform to a 12-hour period of wake/sleep, through the action of the hormone melatonin.
Scientists have long suspected that there must be another clock—one that determines not our daily life, but our overall longevity. Where would be a likely location for such a clock? The “obvious” answer would be in our DNA. After all, it is common knowledge that if you selected your parents wisely, you are almost guaranteed to live to the same ripe old age that they did. And, if you maintained a healthier lifestyle than they had, you may even be able to exceed it.
The boomer generation, the post-war wave of kids who grew up having it all (and demanding even more), expect to live the good life as long as biology would allow—and perhaps even more. Scientists, many of them boomers themselves, have been eager to oblige.
Telomeres – the chromosome stabilizers
TTAGGG. No, this is not a stuttering finger trying to print TAG nor is it a typo. This is a sequence of the nucleotides thymine, adenine, and guanine (or T, A, G, respectively). At both ends of each chromosome, this sequence repeats itself about 2500 times, forming caps that keep the structure of the chromosome stable. You can think of it as analogous to the metal cap at the end of a shoelace.
When cells divide, their chromosomes undergo duplication so that each daughter cell gets the full complement of genes of its mother cell. The only one catch? The telomeres don’t duplicate. This results in the telomeres getting shorter with each cell division. Eventually, when they get short to the point that the stability of the chromosome is compromised, cell division stops. This occurs in order to protect the organism from the metabolic and genetic chaos of unraveled chromosomes.
This explains why every cell can undergo only a certain number of divisions before entering a phase of senescence. With time, senescent cells accumulate mutations and lose most of its normal functions, eventually dying.
Since we are basically the sum of our cells, you can see how the process of telomere shortening translates into life-shortening. Stated differently, telomeres determine our longevity.
Indeed, certain diseases characteristic of aging, such as autoimmune diseases, are associated with truncated telomeres. Cancer incidence also rises with age. But here, the opposite thing happens. The telomeres don’t truncate; they actually elongate due to the activity of an enzyme called telomerase, thus keeping the cancer cell essentially immortal, which is the very essence of cancer.
The longevity clock
It appears almost inevitable that telomere length and its rate of shortening would predict longevity, right? Indeed, many studies looked into this tantalizing possibility. Just imagine. If we could control the enzyme that lengthens it, telomerase, we could prolong life, or, at the very least, avoid the diseases that make aging an unappealing prospect.
Like everything in nature, nothing is as it seems. There are always ‘confounding factors’, or as Donald Rumsfeld of Iraq war infamy might say, “the unknown unknowns.”
The evidence suggesting telomere length as a biomarker of aging in humans is equivocal
The evidence suggesting telomere length as a biomarker of aging in humans is equivocal. Indeed, the correlation between age and the length of telomeres is less than 0.5. More and more, researchers in the field developed a consensus that a single biomarker of aging doesn’t exist. If a biomarker exists at all, it must be multifactorial. That’s where things have stood since the discovery of the telomeres in 1978. [Historical note: Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.]
The Gilgamesh project
An unusual article appeared in the April 8, 2014 issue of the usually dry, “just the facts, ma’am” journal Nature. It describes, in entertaining personal detail, the discovery of a marker of aging that really works. Here’s the story:
Three German teenagers, Steve Horvath, his identical twin Markus, and their friend Jörg Zimmermann formed ‘the Gilgamesh project’, which involved regular meetings where the three discussed mathematics, physics, and philosophy. The inspiration for the name, Horvath says, was the ancient Sumerian epic in which a king of Uruk searches for a plant that can restore youth. Fittingly, talks at their meetings often turned to ideas for how science might extend lifespan. Now, how more nerdy can you get?
The only one who remained faithful to the Gilgamesh project was Horvath. He supplemented his Ph.D in mathematics with a doctorate in biostatistics. In 2000, this led to a position in the genetics department at UCLA.
Now, an untenured assistant professor cannot undertake such a risky project as discovering a longevity clock, since failure rarely leads to tenure. But in 2006, after working and publishing on other projects, Horvath received tenure. It was now safe for him to embark on the Gilgamesh project again.