To pursue his hypothesis, Longo started out by emailing Zvi Laron himself in 2002. Could Laron please comment on the lifespan and longevity of those with the disease?
Laron pointed him to a paper he wrote on hereditary dwarfism on a remote island in Croatia. In the paper were two data points of immense interest to Longo: A couple of the subjects lived to their mid-90s. Then a colleague told Longo about Guevara-Aguirre’s work. Longo immediately looked up the Ecuadorian endocrinologist and invited him to USC to give a talk.
In April 2006, Guevara-Aguirre flew to Los Angeles and gave his presentation. People with Laron syndrome seemed to live to a ripe old age, he reported—not to age 110, but well into their 70s and 80s. He also said he didn’t recall seeing a case of cancer or hearing of anyone who had died of the disease. “That was exactly what I was hoping to hear,” Longo says. “Although obviously it was just an observation, he was their doctor, their endocrinologist.”
Longo and Guevara-Aguirre decided to work together on a survey that could confirm both their suspicions—for Longo, that the mutation revealed the secrets of longer life, and for Guevara-Aguirre, that his Laron patients had something that indeed kept cancer at bay.
“Jaime and I had to find out how much of this was true,” Longo says. He secured a small grant to do a rigorous investigation comparing cancer rates in the Laron syndrome patients with those of their relatives of normal height. After five years of fieldwork, laboratory experiments, and analysis, they reported in February 2011 that of 99 Laron syndrome cases, only one case of cancer existed on record, and that patient had survived.
By comparison, of more than 1,000 relatives of Laron patients who died during the study, one in five succumbed to cancer. The study came a couple of weeks after Laron and his colleagues published a survey of cases in the Middle East and Europe that also revealed a near-complete absence of cancer. “It seems that I was right,” Guevara-Aguirre says.
Guevara-Aguirre and Laron have differing views when it comes to connecting Laron syndrome with another deadly disease: diabetes. Although Laron has diagnosed diabetes in a handful of his patients, Guevara-Aguirre says he has never seen a case of diabetes among Laron patients in Ecuador, even though their weight should put them at high risk. In their 2011 paper, he and Longo reported that of the 99 Laron patients they studied, none had diabetes despite the prevalence of obesity in the group. In contrast, among the patients’ relatives, 5 percent of deaths were from diabetes.
Normally, people who are overweight face a greater risk for insulin resistance, a condition in which the body does not use insulin effectively to shuttle glucose into liver, fat, and muscle cells. To compensate, the pancreas secretes more insulin. In some cases, the amount of glucose in the bloodstream overwhelms the pancreas’s ability to keep up; in these cases, insulin resistance progresses to pre-diabetes or full-blown diabetes.
For people with Laron syndrome, a different set of rules seems to apply. Instead of being insulin resistant, Guevara-Aguirre’s patients seem to be especially sensitive to insulin, which may protect them against diabetes. He and Longo have recently conducted glucose-tolerance and insulin tests to explore how patients’ sensitivity to insulin affects their diabetes risk. They expect results later this year.
If the genetic mutation that gives people with Laron syndrome their short stature also protects them against two of the most pernicious diseases of aging, diabetes and cancer, then it prompts two obvious questions: What other diseases might the mutation protect against, and do people who carry the mutation in fact live longer than their unaffected peers?
The second question is more difficult to answer than it might seem because the low prevalence of cancer and diabetes in Laron patients is counterbalanced by an abnormally high risk of death from other causes, especially accidents, alcohol, and convulsive disorders.
To help untangle the question, Longo and Guevara-Aguirre are comparing mortality rates of people with Laron syndrome with their siblings to look for a noticeable difference in life expectancy. They have also begun examining whether these individuals are resistant to other aging-related killers, including cardiovascular disease and Alzheimer’s disease—both linked to dysfunctional production or metabolism of insulin and IGF-1.
Longo has also taken the first step in turning the lessons of Laron syndrome into anticancer and antiaging drugs. In 2008 he founded DSR Pharmaceuticals, where he is consulting with Kopchick to develop a pill that blocks the growth hormone receptor. They hope the drug will do artificially what the genetic defect in Laron syndrome does naturally: protect against DNA damage that fuels cancer growth.
A more expensive injection form of the drug was discovered by Kopchick a decade ago, and it has since been approved by the FDA to treat individuals with acromegaly, a condition in which there is too much growth hormone in adults, resulting in abnormal growth of body tissues, especially hands, feet, and face. Longo believes that it might be useful in the treatment of cancer and, perhaps eventually, as an antiaging supplement.
In any race to defeat cancer with a new drug, it is always wise to bet on the tumor rather than the drug. Pharmaceutical victories over cancer have been few and far between over the years. But the absence of cancer in individuals with Laron syndrome, combined with the new research on the importance of hormones such as insulin and IGF-1, suggests that the odds may soon change.
During his initial trip to Ecuador more than 24 years ago, Rosenbloom never imagined an outcome like this. “It was a phenomenal aligning of the stars,” he says. “I came to Ecuador in 1988 for another reason. Jaime had just opened his institute, and he had the road-building company to go exploring and find these people. My colleagues are very envious of my having fallen into this.”