The Maasai people of East Africa, villagers from a small Cretan Mountain, and the Old Amish from Lancaster come from three very disparate and isolated groups far removed from each other. Yet they share a distinct commonality; a much higher tolerance for fat in their diet than the rest of the world!
Obesity and poor health tolerance to excess fat is a pandemic of global proportions1. It now affects a third of the world’s population2, impacting both developed and developing nations and affecting people across socioeconomic strata1,3. Changes in diet & physical activity precipitated by changing lifestyle, demographics, and societal factors appear to be primarily responsible2 for this pandemic. And despite extensive efforts by doctors, public health services and educational campaigns the problem continues to grow.
In the face of this problem, we need to find alternate strategies that may be more successful; and, reducing the consequences of excess fat in humans could be a potential approach. The most efficient way to do so is to identify groups of individuals or populations who show a higher than normal resilience to fat. Studying their characteristics and genomic makeup will give us a peek into the results of mother nature’s evolutionary “trial and error” adaptation to high fat diets, ready to be found and emulated. The article examines three such promising populations that have been identified around the world.
The first population, namely the Maasai, is one that has been studied by scientists for a very long time because of their distinct appearance and lifestyle. They are a Nilotic tribal group living in Tanzania and northern Kenya. The Maasai tend towards a tall thin ectomorphic body habitus, follow a pastoral lifestyle, and consume a diet rich in dairy, meat, and blood. This results in a high intake of lactose, fat, and cholesterol and despite a much higher daily intake, their cholesterol levels are significantly lower than Europeans and Americans. Older Maasai men also have a lower incidence of atherosclerotic coronary artery disease, despite the men having a relatively sedentary life upon completion of their warrior role by their mid-twenties. While environmental factors were also considered, they did not satisfactorily explain the significant differences, thus researchers turned to genetics for further insights. Genome Wide Association Studies (GWAS), that look for genetic variants at a population level have identified several candidate gene variants enriched in the Maasai that are involved in fat and cholesterol metabolism. While these are still under investigation, one variant of note is found in the gene that codes for FABP1, a fatty acid binding protein present in liver cells. The same variant has been reported in a study on French-Canadian men who were noted to have reduced levels of a very specific fat, associated with predisposition to metabolic syndrome, which predisposes people to diabetes and cardiovascular disease. While this does not fully explain the Maasai tolerance to fats and cholesterol, it has yielded a significant target for drug intervention4-6.
Very different from the Maasai are the Lancaster Amish, a population group that arose in Switzerland in the 16th century and migrated to Pennsylvania in the 18th century7. The Lancaster Amish are a close knit, highly endogamous community. They share a common lifestyle and environmental exposures and, as a result of their endogamy, have much less genetic diversity than the surrounding Non-Amish US population. When tested for the effect of a fat challenge they appeared to tolerate it much better than is typical for the country. GWAS studies identified the difference having genetic component8 and subsequently, a mutation was found in the APOC3 gene. The protein product due to this gene, ApoC-III, is primarily involved in lipid metabolism and is found mainly in the liver and intestine. Carriers for this mutation were found to have a better lipid profile with lower triglycerides and favorable cholesterol ratios. Furthermore, atherosclerosis, the commonest reason for heart disease, was found to be less common in these individuals9 and these findings too may be clinically relevant and important for future treatments and remedies.
Serendipitously, evidence confirming the above findings came from another insular population, the 4000 residents of Anogia and Zoniana, a couple of ancient, isolated mountain villages on the island of Crete. The citizens of these two villages have anecdotally been known in Greece for their long lifespan and the rarity of cardiovascular diseases despite a diet rich in meat and cheese. Genomic studies found the population had a very high carrier rate for the same APOC3 variant and, like the Amish, demonstrated a favorable cholesterol profile and low triglycerides10.
These findings have led to development of drugs that target the ApoC-III protein produced by the APOC3 gene. One such drug, Volanesorsen, has recently received initial approval for use for a targeted disorder of fat metabolism in Europe and a second one is in the drug development pipeline11,12. It is anticipated that this and other related drugs will help many more people dealing with abnormal levels of fats and cholesterol and the consequent complications.
The insights from the studies above show that human adaptations, both genetic or otherwise, may be shared or quite different in distinct and isolated populations, and BOTH have value in research. The three populations highlighted above are all endogamous resulting in genetic mutations that become enriched and shared within the population group over time. This is an important component in what makes them distinct from other populations and studying these genetic & phenotypic distinctions allows researchers to better relate potentially significant genetic changes to their characteristics.
Meanwhile, we still need to better understand the genes that are protecting the Maasai, as well as other isolated populations around the world. Some have known traits that could help others, but many remain unstudied with a wealth of insights and data waiting to be uncovered. Finding these adaptive clinically relevant gene changes provides the knowledge needed to scientifically and very precisely create drugs that target problems at their roots.
These findings are important for our understanding of how the body works and what keeps people healthy and what does not. However, ultimately it is our ability to take this information and use it to help people that matters.
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