Is Long Life Without Disease Possible? A Rare Genetic Syndrome May Point The Way

(Posted on Sunday, May 19, 2024)

We hear the words “genetic mutation” and tense up: if it’s a mutation, it has to be a bad thing, right? Not always. In some cases, a mutation can offer protective or beneficial effects. These types of gene variants are a hotspot of research since they carry the promise of new treatments — if we understand how the mutation works, we may be able to mimic its protective effects artificially. 

Laron syndrome, known technically as growth hormone receptor deficiency (GHRD), falls into this category. Individuals with the syndrome are much less likely to suffer from age-related diseases like cancer and diabetes. A new study suggests they may also be more resilient against heart attacks and other cardiovascular issues. 

What is Laron Syndrome?

Laron syndrome is an extremely rare disorder —there are less than 500 confirmed cases in the world— caused by mutations to the growth hormone receptor gene (GHR). As with any gene, the strand of DNA that comprises the growth hormone receptor is made up of thousands of “base pairs” — the chemicals that form the foundation of DNA. Just a single change to any of these base pairs may be enough to cause a difference in the function of the protein that the gene encodes. 

These changes to the growth hormone receptor gene interfere with the production of important proteins involved in childhood growth. As a result, people with the syndrome are almost never taller than four and a half feet (1.5 meters). They are also prone to developing obesity and tend to have higher levels of low-density lipoprotein (LDL), or “bad cholesterol.” 

Despite this, people with Laron syndrome are long-lived compared to unaffected relatives. Back in 2011, a group of researchers suggested that this may be due to almost nonexistent levels of cancer and type two diabetes, lucky protective byproducts of the genetic mutation that causes the syndrome. Individuals with Laron syndrome tend to produce less of a growth hormone called insulin-like growth factor 1 (IGF-1), which although crucial for growth during childhood, has also been linked to the kind of haywire cellular proliferation that leads to cancerous tumors. 

The same longevity boost has been observed in mice with Laron syndrome, who, compared to their peers, tend to live 40% longer. They also develop fewer tumors and exhibit the same smaller stature. 

Another potential explanation for the increased lifespan of those with Laron syndrome is the fact that their cells are significantly more likely to self-destruct after suffering damage than those of unaffected individuals. This prevents the cells from accruing mutations or DNA damage over repeated generations, which is considered one of the hallmarks —and potential causes— of aging. 

The same group of researchers, led by Dr. Jaime Guevara-Aguirre at the San Francisco de Quito University and Dr. Valter D. Longo at the University of Southern California, followed up these initial findings with a second study in 2017. This time, their research indicated that the protective effects of the syndrome were not restricted to the body alone: cognitive performance also remained high with age, and there were barely any cases of dementia. All in all, the brain function of older adults with Laron syndrome was closer to that of younger adults in the general population. 

What About Heart Health? 

But one big question mark remained. Many researchers speculated that since those with the syndrome were more likely to develop obesity, they would also be more likely to develop heart issues. These issues could possibly outweigh the protective factors. To answer this question, Dr. Guevara-Aguirre and colleagues returned to the Ecuadorian families they had worked with in the past. They recruited 24 individuals with the syndrome and compared them to their unaffected relatives. 

The results suggest that those with the growth-factor deficiency are no likelier to suffer from heart issues than their unaffected counterparts. If anything, the syndrome seems to be slightly protective against cardiovascular diseases. Affected individuals had lower blood pressure and glucose levels. They also had fewer issues with atherosclerosis, which is when plaque builds up in the arteries and begins to restrict blood flow. If left untreated, which is not uncommon since it is hard to notice, the plaque buildup can lead to heart attacks and strokes. 

Same But Different: Not All Individuals With Laron Syndrome Share Protective Benefits

Something worth noting is that not all individuals with Laron syndrome enjoy the same protective effects. Zvi Laron, professor emeritus at Tel Aviv University, was the first to recognize and define the syndrome in 1966 — that is why it carries his last name. But in the population that he studied, made up of consanguineous Jewish families from Yemen, a portion of the patients did develop an insulin intolerance and diabetes. Also, only a handful of individuals displayed the usual resilience against cancer seen in the Ecuadorian families with Laron syndrome.

How should we make sense of these discrepancies? Laron syndrome is caused by mutations to the growth hormone receptor gene, but these mutations can take many different forms. More or less of the gene may be affected, and in different areas. So even though all of the individuals in question suffer from the same syndrome, it may be brought on by subtly different mutations. Indeed, to date we know of 17 different genetic mutations that cause the disease. Based on the research of Zvi Laron, it seems that the protective benefits against cancer are only present when both parents share the same mutation in the same place and pass it on to their child, known as homozygosity. 

The Ecuadorian community, whose roots can be traced back to Sephardic Jews who fled Spain during the Inquisition, all share the same mutation. It may just be that this particular mutation is the one that happens to grant longevity benefits. In which case, focusing on this community may prove most useful when it comes to the development of treatments that mimic the life-lengthening and disease-busting qualities of the syndrome. 

Implications

Although Laron syndrome comes with clear challenges, it also seems to provide certain benefits. Those with the disorder, at least the Ecuadorian contingent, live longer and struggle with fewer age-related diseases than their unaffected counterparts. Most of these benefits can be traced back to lowered levels of insulin-like growth factor 1. 

By studying the syndrome and learning more about its effects at the molecular level, we may discover ways of transferring the protective effects to the general population. The point here is not necessarily to grant longevity so much as to increase “healthspan,” the number of years of your life you spend in good health. Indeed, Dr. Valter D. Longo —the senior author of the study— has experimented with different fasting-like diets that can reduce the levels of insulin-like growth factor 1 circulating in the body and along with it, various risk factors for disease. There are also molecules that block the protein, slowing down cancerous growths in the process. By fine-tuning these approaches, the protective effects of the syndrome might soon be available to everyone.