Survival of the Sickest: The Surprising Connections Between Disease and Longevity. Jonathan Prince

a potentially deadly liability, it shouldn’t be surprising that we have iron-related defense mechanisms as well.

      We’re most vulnerable to infection where infection has a gateway to our bodies. In an adult without wounds or broken skin, that means our mouths, eyes, noses, ears, and genitals. And because infectious agents need iron to survive, all those openings have been declared iron no-fly-zones by our bodies. On top of that, those openings are patrolled by chelators – proteins that lock up iron molecules and prevent them from being used. Everything from tears to saliva to mucus – all the fluids found in those bodily entry points – are rich with chelators.

      There’s more to our iron defense system. When we’re first beset by illness, our immune system kicks into high gear and fights back with what is called the acute phase response. The bloodstream is flooded with illness-fighting proteins, and, at the same time, iron is locked away to prevent biological invaders from using it against us. It’s the biological equivalent of a prison lockdown – flood the halls with guards and secure the guns.

      A similar response appears to occur when cells become cancerous and begin to spread without control. Cancer cells require iron to grow, so the body attempts to limit its availability. New pharmaceutical research is exploring ways to mimic this response by developing drugs to treat cancer and infections by limiting their access to iron.

      Even some folk cures have regained respect as our understanding of bacteria’s reliance on iron has grown. People used to cover wounds with egg-white-soaked straw to protect them from infection. It turns out that wasn’t such a bad idea – preventing infection is what egg whites are made for. Egg shells are porous so that the chick embryo inside can “breathe.” The problem with a porous shell, of course, is that air isn’t the only thing that can get through it – so can all sorts of nasty microbes. The egg white’s there to stop them. Egg whites are chock-full of chelators (those iron locking proteins that patrol our bodies’ entry points) like ovoferrin in order to protect the developing chicken embryo – the yolk – from infection.

      The relationship between iron and infection also explains one of the ways breast-feeding helps to prevent infections in newborns. Mother’s milk contains lactoferrin – a chelating protein that binds with iron and prevents bacteria from feeding on it.

      Before we return to Aran Gordon and hemochromatosis, we need to take a side trip, this time to Europe in the middle of the fourteenth century – not the best time to visit.

      From 1347 through the next few years, the bubonic plague swept across Europe, leaving death, death, and more death in its wake. Somewhere between one-third and one-half of the population was killed – more than 25 million people. No recorded pandemic, before or since, has come close to touching the plague’s record. We hope none ever will.

      It was a gruesome disease. In its most common form the bacterium that’s thought to have caused the plague (Yersinia pestis, named after Alexander Yersin, one of the bacteriologists who first isolated it in 1894) finds a home in the body’s lymphatic system, painfully swelling the lymph nodes in the armpits and groin until those swollen lymph nodes literally burst through the skin. Untreated, the survival rate is about one in three. (And that’s just the bubonic form, which infects the lymphatic system; when Y. pestis makes it into the lungs and becomes airborne, it kills nine out of ten – and not only is it more lethal when it’s airborne, it’s more contagious!)

      The most likely origin of the European outbreak is thought to be a fleet of Genoese trading ships that docked in Messina, Italy, in the fall of 1347. By the time the ships reached port, most of the crews were already dead or dying. Some of the ships never even made it to port, running aground along the coast after the last of their crew became too sick to steer the ship. Looters preyed on the wrecks and got a lot more than they bargained for – and so did just about everyone they encountered as they carried the plague to land.

      In 1348 a Sicilian notary named Gabriele de’Mussi tells of how the disease spread from ships to the coastal populations and then inward across the continent:

      Alas! Our ships enter the port, but of a thousand sailors hardly ten are spared. We reach our homes; our kindred … come from all parts to visit us. Woe to us for we cast at them the darts of death! … Going back to their homes, they in turn soon infected their whole families, who in three days succumbed, and were buried in one common grave.

      Panic rose as the disease spread from town to town. Prayer vigils were held, bonfires were lighted, churches were filled with throngs. Inevitably, people looked for someone to blame. First it was Jews, and then it was witches. But rounding them up and burning them alive did nothing to stop the plague’s deadly march.

      Interestingly, it’s possible that practices related to the observance of Passover helped to protect Jewish neighborhoods from the plague. Passover is a week-long holiday commemorating Jews’ escape from slavery in Egypt. As part of its observance, Jews do not eat leavened bread and remove all traces of it from their homes. In many parts of the world, especially Europe, wheat, grain, and even legumes are also forbidden during Passover. Dr. Martin J. Blaser, a professor of internal medicine at New York University Medical Center, thinks this “spring cleaning” of grain stores may have helped to protect Jews from the plague, by decreasing their exposure to rats hunting for food – rats that carried the plague.

      Victims and physicians alike had little idea what was causing the disease. Communities were overwhelmed simply by the volume of bodies that needed burying. And that, of course, contributed to the spread of the disease as rats fed on infected corpses, fleas fed on infected rats, and additional humans caught the disease from infected fleas. In 1348 a Sienese man named Agnolo di Tura wrote:

      Father abandoned child, wife husband, one brother another, for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices … great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night. … And as soon as those ditches were filled more were dug. … And I, Agnolo di Tura, called the Fat, buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world.

      As it turned out, it wasn’t the end of the world, and it didn’t kill everyone on earth or even in Europe. It didn’t even kill everyone it infected. Why? Why did some people die and others survive?

      The emerging answer may be found in the same place Aran Gordon finally found the answer to his health problem – iron. New research indicates that the more iron in a given population, the more vulnerable that population is to the plague. In the past, healthy adult men were at greater risk than anybody else – children and the elderly tended to be malnourished, with corresponding iron deficiencies, and adult women are regularly iron depleted by menstruation, pregnancy, and breast-feeding. It might be that, as Stephen Ell, a professor at the University of Iowa, wrote, “Iron status mirror[ed] mortality. Adult males were at highest risk on this basis, with women [who lose iron through menstruation], children, and the elderly relatively spared.”

      There aren’t any highly reliable mortality records from the fourteenth century, but many scholars believe that men in their prime were the most vulnerable. More recent – but still long ago – outbreaks of bubonic plague, for which there are reliable mortality records, demonstrate that the perception of heightened vulnerability in healthy adult men is very real. A study of plague in St. Botolph’s Parish in 1625 indicates that men between fifteen and forty-four killed by the disease outnumbered women of the same age by a factor of two to one. So let’s get back to hemochromatosis. With all this iron in their systems, people with hemochromatosis should be magnets for infection in general and the plague in particular, right?

      Wrong.

      Remember the iron-locking response of the body at the onset of illness? It turns out that people who have hemochromatosis have a form of iron locking going on as a permanent condition. The excess iron that the body takes