Secrets of the Centenarians

Those who were lucky enough to be born with genetically determined lower IGF-1 levels are more likely to live past 90. After 90, low IGF-1 values and physical activity are an indicator of continued survival. Interestingly, among Ashkenazi Jews—whom I descend from—there are two mutations associated with reaching 100 years that lead to elevated IGF-1 levels, but the mutations are in the IGF-1 receptor, so the elevated levels are probably due to the body unsuccessfully trying to overcome the weakened receptor. Either way, dialing down IGF-1 appears to be a mechanism of human longevity.

So is it just luck whether we are born with good genes? No matter where our genetically determined baseline level of IGF-1 activity lies, we can raise or lower it depending on what we eat.

The big ones live shorter

Dog lovers know that smaller breeds usually live longer than larger ones. Tiny toy poodles live almost twice as long on average as the largest Great Danes. That makes sense when you know that an important determining factor in the size differences among breeds is IGF-1. The same phenomenon is observed in other animal species. Indian elephants are smaller than their African relatives and usually live longer, and smaller horses, rodents, and cattle also tend to outlive the larger ones. What about humans?

In the past, bigger was considered better. Height was a sign of socioeconomic status and more favorable living conditions in childhood, which translated into a higher life expectancy. But since living conditions today are generally better and relatively few children still suffer from malnutrition, innate factors come more to the fore. Nowadays, smaller stature means higher life expectancy. That could even explain differences in life expectancy between the sexes. Men are, on average, about 8 percent taller than women and have a life span that is about 8 percent shorter.

The relationship between greater stature and a shorter life is mainly driven by higher cancer rates. Men may generally have more than a 50 percent higher cancer risk than women. Each additional inch of height (2.54 cm) is associated with a 6 percent higher risk of dying of cancer. That could simply be because larger people have more cells that can become malignant. After all, people with more skin are more likely to get skin cancer. But the link between height and cancer could also be due to cancer-promoting growth hormones such as IGF-1.

The 100-year-old Ashkenazim with the IGF-1 mutation were, on average, about an inch shorter, but the height difference was not statistically significant. This shows that we may all be able to enjoy the longevity benefits of turning down IGF-1 and still have a shot at the basketball league.

Cancer drivers

We are reborn each year. Each year we destroy and create cells in an amount that is almost equivalent to our entire body weight. About 50 billion of them die each day, but about 50 billion new ones arise. Of course, there are also times when you grow, for example in childhood and puberty, but the cells don’t get bigger—they become more numerous. As an adult you have about 40 trillion cells, four times more than in childhood.

During growth periods such as puberty, you need net cell growth—more must be created than die—but in older age that no longer applies. Cells still have to be created and divide, but excess cell growth in adulthood can mean that tumors develop.

How does the body keep the balance? It sends hormones—chemical signals—to all cells. One of the key signals for cell growth is IGF-1. Children have more growth hormones that drive their development, but in adults there are fewer, and they signal the body not to produce more cells than it retires.

If IGF-1 levels are still elevated when you are old enough to vote, cells continue to receive the command to grow and divide. As expected, the amount of IGF-1 in the blood is directly related to the risk for certain forms of cancer such as breast, colorectal, and prostate cancer. (This does not appear to apply to lung, ovarian, or pancreatic cancer.) In the Harvard Nurses’ Health Study, premenopausal women under 50 whose IGF-1 values were in the top third had almost a fivefold higher risk of developing breast cancer than those in the bottom third. When there was not yet successful chemotherapy, surgeons treated advanced breast cancer by removing patients’ ovaries and then performing brain surgery to remove the pituitary gland, which controls the production of growth hormones in the body.

Those with lower IGF-1 values have only a low cancer risk, and those who survive cancer and have lower values are likely to stay alive longer. Most of the time it is not the original tumor that kills you but the metastases. As a growth factor, IGF-1 not only promotes tumor growth; it helps cancer cells break away from the primary tumor, infiltrate the surrounding tissue, and enter the bloodstream. Through IGF-1, breast cancer invades the bones, liver, lung, brain, and lymph nodes. IGF-1 is involved in every step: from the very beginning, it enables the transformation of normal cells into cancer cells and nourishes them so they can survive, spread, renew themselves, grow, migrate, invade other parts of the body, and ultimately stabilize into new tumors. It even helps the new tumors connect to the blood supply.

Centenarians, however, seem to be endowed with a special resistance to cancer. With age, the risk of getting cancer and dying from it rises year by year—until you are 85 or 90. After that, the cancer risk interestingly declines. Getting a tumor at 65 is 100 times more likely than at 35, but if you have no cancer up to a certain age, you probably won’t get it anymore. Centenarians are ten times less likely to die of malignant tumors than people in their 50s and 60s (4 to 40 percent). What is, at least in part, responsible for this relative cancer resistance among centenarians? Less IGF-1. So if you reduce IGF-1 activity, you could benefit twice: You lower cancer risk and increase your life expectancy.

A mutation that protects against cancer

The primacy of IGF-1 in tumor biology is shown in a natural experiment involving Laron syndrome, a genetic defect that triggers a severe, lifelong deficiency of IGF-1. The first case of this syndrome was reported in the Israel Journal of Medical Sciences, but the largest affected population lives in a remote region in Ecuador. In the 15th century, Jews fled the Spanish Inquisition to South America and brought the gene mutation with them, creating this isolated geographic distribution.