As we learn more about the human genome, there will be an increasing recognition that general diet recommendations are going to give way to diet recommendations that more closely track the genotype of individuals. For those interested in healthy life extension an important question concerns the relationship between ApoE status and diet. In Why We Age : What Science Is Discovering About the Body’s Journey Through Life (1997) Steven N. Austad writes:

.. piles of evidence suggest that certain genes have a major impact on the development of atherosclerosis, probably the major disease of aging in the Western world. One of those genes is the Apolipoprotein E, usually abbreviated ApoE, which is involved in processing dietary fat. People with one form of the gene, called e4, have higher blood cholesterol (as well as higher LDL, or ”bad” cholesterol) levels than people with other forms of the gene. Finns have the highest rate of atherosclerosis in the world and also have one of the world’s highest frequencies of e4. The Japanese have the world’s lowest national rate of atherosclerosis and also among the world’s lowest frequency of e4. So you could call e4 an atherosclerosis gene. But this would be misleading, because the world’s highest frequency of e4 is found in a country, Papua New Guinea, where until recently atherosclerosis was virtually unknown.

People living in the bush in Papua New Guinea eat a low-fat diet (less than 5 percent fat, compared with 30 to 40 percent fat in an American diet) from necessity rather than choice. Their daily life also involves exercise at levels that would cripple or kill most Americans, even the athletically inclined….So genes operate not in a vacuum but in a specific environment. This is something to bear in mind when reading of the discovery of new “longevity” genes. For instance, there is another form of the ApoE gene, e2, which appears to lower blood cholesterol and therefore probably protects against developing atherosclerosis. Is this a longevity gene? It depends on the environment. Where people eat a lot of fat and don’t exercise, it may well be a longevity gene. In fact, French centenarians are about twice as likely to have this gene as the French population as a whole. But in other environments, the gene may well have little or no effect.

What these examples suggest, besides the difficulty in defining genes with respect to longevity, is that unless we understand how a particular gene is influenced by a particular environment, it will be difficult to translate the effects of genes from animals to humans. This is why most gerontologists are hesitant to claim too much about the relevance to humans of genes now being found with increasing frequency in simple organisms such as fungi and worms that seem to slow aging dramatically. It is difficult to draw parallels between human and worm and fungal environments. (p-41-43)

It is important to keep this point in mind when one considers the pro- and cons of a popular diet. For example, the Paleo Diet has become increasingly popular in the life extension & transhumanist communities. But if the observations of Austad are correct, a diet high in (saturated) fat could have adverse consequences for carriers of one or two copies of the ApoE4 gene. In fact, in her book The Perfect Gene Diet Pamela McDonald steers ApoE4 carriers in the direction of a vegetarian / vegan diet. As we learn more about the ideal diet for carriers of the ApoE4 gene, further refinements may be expected.

Another interesting emerging finding about ApoE4 is that its effect on having a higher probability of developing late-onset Alzheimer’s disease may be dependent on gender. A number of preliminary studies have found that the risk for developing Alzheimer’s disease for males with just one copy of the ApoE4 gene may not be much different from that of individuals who carry the more common ApoE3 gene:

Together with the previous meta-analysis, the data support the idea that a man with one E4 allele may not have much more risk of AD than an E3 homozygote, Greicius said, but added, “If you have two copies of the E4 allele, whether you are a man or a woman, there is no question that your risk leaps tremendously.” He is analyzing older datasets to see if the interaction between gender and ApoE genotype holds, and is also looking for genes that act synergistically with ApoE in women but not men.

If there is anything that is becoming clear from such studies it is that it will be increasingly inadequate to make sweeping statements about lifestyle, diet, and longevity without taking into account ethnicity, gender, age, genotype, and environment of a person. This does not mean that all general recommendations should be discarded. For example, there could be good reasons to believe that a low calorie diet and (moderate) exercise benefit most people. But when it is comes to the nitty gritty of what to eat and how to exercise a more personalized approach is warranted.