Telomeres

Do you remember the "Hayflick limit" from the chapter on cellular senescence? Telomere shortening is the mechanism that prevents many cells from dividing more than 50 times. This cap on cellular immortality may limit our life expectancy, but it may also protect us from tumor formation. This could, for example, explain why people of European descent usually have shorter telomeres than people from sub-Saharan Africa. Europeans’ lighter skin color made them more susceptible to melanomas, so their cells likely had to adapt. This could be another example of antagonistic pleiotropy. What may have helped us reach reproductive age in order to pass on our genes (and not die of cancer as children) is not a good prerequisite for successful aging and a high life expectancy (the fact that our tissue is dotted with senescent zombie cells that arose from dangerous telomere shortening).

At birth, telomeres are as long as they can be, but then they are worn down year after year. That is why they are often considered a "clock of life." Depending on how much telomere length changes each year, you can estimate the pace of biological aging. Two people can be the same chronological age, but their cellular aging can proceed faster or slower. If you smoke a pack of cigarettes a day for ten years, for example, your cells can age about three years faster, and if you drink a quarter liter of sugary soda a day, you probably age almost two extra years.

Our telomeres can begin shortening as early as our birth, and when they’re done, so are we. That is a crude oversimplification, but they are something like the fuse of life. Accelerated telomere shortening has been identified as a central biomarker for accelerated aging, disease, and a reduced life expectancy, and shortened telomeres mean arthritis, diabetes, heart disease, kidney failure, liver failure, lung disease, osteoporosis, stroke, and vision loss. Telomere length is also associated with a reduction in muscle mass and performance (measured as grip strength), as well as with reduced immune function. If you drip a cold virus into people’s noses, those with shorter telomeres in key immune cells are considerably more likely to get sick. Alzheimer’s, though not necessarily cognitive decline in general, is among the age-related diseases most strongly associated with short telomeres. Shorter ends mean a sooner end.

Appearances can be deceiving

Large-scale studies found that participants with the shortest telomeres had a 17 to 66 percent higher risk of death than those with the longest telomeres. In other words, longer telomeres could mean a longer life. Studies of hundreds of twin pairs found, for example, that the twin with shorter telomeres is more likely to die earlier. And the twin with longer telomeres not only lived longer but also looked younger.

Looking "old for your age" is actually an indication of poor health and a sign of mortality risk, independent of physical and mental functional capacity. Geriatric nurses were able to tell from high-resolution photos of hundreds of twin pairs who would likely die first—based solely on which twin looked older. Subjective age is also linked to telomere length. Even people who are born with the genetic tendency toward longer telomeres develop fewer signs of facial aging as adults, which points to a causal relationship rather than to a third variable like smoking, which both makes you look older and shortens your telomeres.

As expected, women tend to have longer telomeres than men and presumably a slower erosion of telomeres, consistent with the fact that women usually live longer. Across all species, the rate of telomere shortening is a strong indicator of lifespan, and that also applies within a species. For example, telomere length is a strong predictor of average life expectancy in 15 different dog breeds, which unfortunately lose their telomeres about ten times faster than humans and live about ten times shorter.

Time is running out

Is telomere length a cause of aging or merely its consequence? Mice that were manipulated to be born with longer telomeres live longer and healthier. The argument for a causal connection in humans is supported by rare genetic disorders of telomere maintenance that manifest as accelerated aging, from premature graying of hair and skin pigmentation to early heart attacks. It is suspected that telomere shortening actively promotes aging through cellular senescence and the ensuing SASP inflammation (see the chapter on cellular senescence).

The idea of telomeres as a constantly ticking biological clock is not entirely correct. Forensic scientists can estimate a person’s age from the DNA in a bloodstain simply on the basis of telomere length in a blood cell, but the initial length and the rate of shrinkage vary greatly from individual to individual. In some people the fuse burns faster than in others. On average, in an adult population there appears to be a steady, inexorable annual loss of length, but the individual data are so widely scattered that it is not unusual to meet an 80-year-old whose telomeres are as long as a 30-year-old’s.

In addition, there is variability within the same person—and even within the same cell in the same person. In each cell there are 92 telomeres that cap our 46 chromosomes at both ends. It takes only a single dangerously short telomere to send the entire cell into a downward spiral of senescence or death. Most studies track individuals’ average telomere length, for practical reasons usually from blood cells, but the length of our shortest telomeres probably predicts more accurately how many healthy years of life we still have ahead of us. Fortunately, it is possible not only to slow the pace of telomere shrinkage, but also to rebuild the shortest telomeres.

Rebuild, but better

The solution lies in an enzyme from "Methuselah." That is what a bristlecone pine in California in the White Mountains was named. When the tree got its name, it was the oldest recorded living thing. Today it is nearing its 4800th birthday. To put that into perspective: When Egypt began building pyramids, "Methuselah" was already several hundred years old. An enzyme found in the roots of bristlecone pines appears to extend the tree’s life expectancy by a few thousand years and actually rebuilds telomeres. Science called this enzyme telomerase. Once researchers knew what to look for, they found that we, too, have this enzyme in our cells.

We need such an enzyme. If we had no telomere-maintenance mechanism in the testes and ovaries so that our egg and sperm cells could start out with fully intact telomeres, each generation would from the outset be missing at least the telomeres lost up to puberty. And how else would we explain cancer? The vast majority of cancer cells crank up telomerase activity to become practically immortal. In most cells, telomerase becomes relatively inactive after birth, so our telomeres normally lose ground year after year—but not every year and not in everyone.