Is Longevity Genetic?

Today, we feature some of the research on the influence genetics has on longevity. And, we start with a study of thousands of twin pairs.

It has long been said that the best hope for a long life is to choose your parents wisely. After all, doesn’t longevity just run in the family? Centenarians are people who live to be at least 100, and their siblings are certainly more likely to become centenarians themselves, and the parents of centenarians have been found to be more likely to have lived to at least 90 years old. On the other hand, the lifespans of spouses sometimes correlate as much—or even more than—those of genetic relatives. Your partner may have as much of an impact as your parent. After all, genes aren’t the only things that get passed down. Perhaps Grandma’s healthy recipes, or even a lifelong love of running, runs in the family too. To tease out the role of genetics, researchers turn to twin studies, comparing differences between identical twins and fraternal twins.

For example, imagine you’re trying to determine the role of genetics in cancer—the role played by genes versus other factors that we may have control over. Since identical twins share 100 percent of their genes, whereas, on average, regular twins only share 50 percent, if genes play a large role, then you’d expect that identical twins would be more likely to share the same fate than fraternal twins, right? If there was no difference in the chances that both sets of twins got the same disease, then it would appear there’s no genetic contribution.

It turns out that the overwhelming contributor to the causation of cancer is not genetics, but rather what we’re exposed to. Primary genetic factors may only account for 5 to 10 percent of all cancers. The BRCA genes, popularized by Angelina Jolie, for example, may account for as little as 2 percent of breast cancers. If one identical twin gets breast cancer, the likelihood the other will too is only 13 percent, despite having essentially identical DNA. Now, that’s higher than shared rates among nonidentical twin women. So, there is a genetic component, but genes only appear to make a minor contribution to cancer risk. This is consistent with the rates of common cancers profoundly differing by as much as 200-fold around the world.

What do twin studies have to say about the heritability of lifespan? Based on a study of thousands of twin pairs, the heritability of longevity was 26 percent for men, and 23 percent for women. Subsequent twin studies have arrived at a similar estimate. Approximately 25 percent of our lifespan is determined by our genetic differences, which means how we live our lives may determine the bulk of our destiny. Estimates using other methods tend to fall in the 15 to 30 percent range. For example, an analysis of millions of family trees from 86 million public profiles in an online genealogy database led to an estimate of 16 percent, though due to so-called “assortative mating,” meaning the fact that we tend to pair up with mates similar to ourselves (rather than at random), that may actually be an overestimate. Chosen partners often have similar lifestyles; so, some of that 16 percent estimate may have been influenced by families sharing similar diets and healthy habits, and not exclusively their genes. Taking that into account, the actual heritability of lifespan may even be well below 10 percent.

To leverage the lifespan leeway we have beyond the relatively small genetic component, we must first understand the aging pathways that account for the nine hallmarks of aging. The term “anti-aging” has been much abused in popular culture, attached to all manner of unproven products and procedures. The term should probably be reserved for things that can delay or reverse aging through the targeting of one or more of the established aging mechanisms. In a landmark paper cited nearly 7,000 times in the biomedical literature, “The Hallmarks of Aging” delineates nine common denominators of the aging process. They are Genomic Instability, the accumulation of DNA damage; Telomere Attrition, the loss of the protective caps at the end of our DNA strands; Epigenetic Alterations, changes in the way our genes are expressed; Loss of Proteostasis, the buildup of misfolded proteins; Deregulated Nutrient Sensing, metabolic alterations particularly sensitive to diet; Mitochondrial Dysfunction, the declining efficiency of our cellular powerplants; Cellular Senescence, the arrest of cell replication; Stem Cell Exhaustion, the loss of the potential of our tissues to regenerate; and Altered Intercellular Communication, the rise in proinflammatory signals. I’m going to be covering each of them, and what we can do to slow, stop, or reverse each one, in my book, How Not to Age.

In our next story, we look at how the so-called Alzheimer’s gene, ApoE, is the single most important gene for longevity because of its role as a cholesterol carrrier throughout the body.

Though the genetic contribution to lifespan may be relatively minor, are there specific genes that have been associated with longevity? The leading method for complex genetic mapping is called genome-wide association analysis, which is essentially a massive game of Go Fish, comparing a million or more letters of DNA between groups of similar people, looking for a match. So, for example, if you stretch out the DNA of hundreds of centenarians, and compare those sequences to that of non-centenarians, is there a DNA letter at a certain position that centenarians share disproportionately? The problem is that hundreds of centenarians are all researchers are typically able to find.

Extremely long-lived individuals, such as centenarians, comprise only a tiny fraction of the population, on the order of one in 10,000 or so. As you can imagine, the more people you have in a genome-wide association study, the more likely you’ll be able to find a needle in the DNA haystack. With so few people available to study for extreme longevity research, it becomes much more difficult to identify trends. Some researchers have tried solving this problem by lowering the age requirement to 85. Then, you can enroll thousands into your study, but making it to 90 is not the same as making it to 100. In fact, statistically, it’s as hard to get from 90 to 100 as it is to get to 90 in the first place. So, by using younger age brackets, we may miss out on discovering some secret centenarian sauce.

That brings us to the largest genome-wide association study of lifespan to date, based on data from a million people. How were researchers able to include so many subjects? By correlating the genetic fingerprints of half a million middle-aged individuals with the ages of both of their parents, they were able to find a dozen DNA regions linked to lifespan that appeared to account for up to five years difference between individuals. Twelve DNA markers is actually a surprisingly low number, compared to height, for example, which is determined by more than 400 different DNA spots. (Although, unlike lifespan, height is highly heritable.)

A review of all the genome-wide association studies for longevity put together only found one gene confirmed in multiple independent meta-analyses: the “Alzheimer’s gene” ApoE. Beyond just determining lower or higher dementia risk, ApoE is the single most important gene when it comes to longevity (though again, that’s not necessarily saying much). ApoE codes for a protein that is 299 amino acids long, called apolipoprotein E. Some people have ApoE genes that code for the protein with the amino acid cysteine at positions 112 and 158 (known as the ApoE2 variant), while others have an arginine in those spots (the ApoE4 variant of the protein). And ApoE3 is the third major type of variant, which has one of each. Having genes that code for the ApoE4 variant increases your risk of cognitive decline, full-blown Alzheimer’s disease, and premature death.

If you have one copy of the ApoE4 gene from your mother or father, your odds of becoming a centenarian are cut roughly in half, and if you have ApoE4 genes from both parents, your centenarian odds drop by more than 80 percent. What does this protein do to have such a powerful impact on our health and longevity?

ApoE is the primary cholesterol carrier in the brain, and plays a major role packaging and transporting LDL cholesterol throughout the body. The LDL cholesterol level in those with ApoE4 genes averages more than 40 points higher than those with ApoE2 genes, gunking up the arteries that feed both the heart and the brain. (LDL cholesterol is a risk factor not just for heart disease, but Alzheimer’s disease as well.) Switch people to a diet lower in animal fat and cholesterol though, and those LDL differences can disappear—nearly a 60-point drop in LDL. The difference in cholesterol level caused by the different ApoE genes can simply disappear if you eat a diet low enough in saturated fat and cholesterol. So, diet can trump genetics.

This may explain the so-called Nigerian paradox. If you inherit one ApoE4 gene, your risk of getting Alzheimer’s may triple, and if you get ApoE4 genes from both parents—which occurs in about one in 50 people in the U.S.—you might end up with nine times the risk. The highest frequency of the ApoE4 variant occurs in Nigerians, but they also have some of the lowest rates of Alzheimer’s disease. How can that be? The population with the highest rate of the “Alzheimer’s gene” has one of the lowest rates of Alzheimer’s disease! This contradiction may be explained by Nigerians’ extremely low blood-cholesterol levels, thanks to a diet low in animal fat and consisting mainly of grains and vegetables.

Humans may have evolved to maintain an LDL level of about 25 mg/dL, but the average in the Western world is approximately 120 mg/dL. It’s no wonder that heart disease is the leading cause of death in high income countries, and Alzheimer’s disease, according to the World Health Organization, is killer #2.

Too often, doctors and patients have a fatalistic approach to chronic degenerative diseases, and Alzheimer’s is no exception. “It’s all in your genes,” they say, “and what will happen will happen.” But research shows that although you might have been dealt some poor genetic cards, you may be able to reshuffle the deck with diet.