Healthy Aging and Longevity
Longevity Genes and Phenotypes
This is one of three articles on healthy aging and longevity. Companion articles include:
If you happened to stumble on a random TV interview with a cheery, lucid one hundred-year-old woman, my guess is that you would have probably thought, “wow, she must have good genes!” This turns out to be (mostly) wrong. Longevity can certainly be genetically inherited, but across large populations, it turns out to be less important than how one lives one’s life, the attitudes one cultivates, and one’s life circumstances (unless, of course, you’re someone who inherits lucky genetic mutations yourself). Let’s look at the evidence supporting this claim.
Twins Studies: A Window into the Heritability of Human Longevity
Victorian scientist Francis Galton, a half-cousin of Charles Darwin, wrote a paper in 1875 that recognized the value of twins for studying the heritability of traits, while coining the term nature versus nurture. Regrettably, this ushered in the dark and racist practice of eugenics based on the belief that intelligence could be inherited. Regardless, to this day, twin studies remain instrumental in exploring the heritability of diseases, as well as more complex traits such as longevity.
Observational twin studies like this one cannot prove genetic influence — only suggest it. Take Thomas Bouchard’s seminal 1979 “Twins Reared Apart” study — in which he found that genetically-identical siblings who were reared apart often shared similar personalities, interests, and attitudes. Kelly Klump, co-director of the Michigan State University Twin Registry, explained that this study only shows that “there is a dynamic interplay between [genetics and environment].”
Nonetheless, when scientists study of large numbers of identical twins, compare them to non-twins, and perform some nifty statistical analyses, they can tease out traits that are more likely than not to be genetically inherited, including longevity. Consider this: having a twin who survives to old age increases your chance of reaching old age, too, and this chance is more than twice as great when your twin is identical rather than fraternal.
Through twin studies, researchers estimate that about one-fifth to one-quarter of lifespan variability results from lucky genes. However, if you manage to survive to extreme old age, the odds that you are, in fact, protected by lucky genes increase. (This is because, as people who are genetically unlucky start dying off, the proportion of survivors who are protected by longevity genes rises.) Take the oldest fifth percentile of aged individuals. For a 98-year-old woman, on average, lucky genes explain about one-third of the variability in lifespan. For a 95-year-old man, lucky genes explain about one-half of the variability. This genetic influence is the reason that extreme longevity is often clustered in families.
While lifestyle is more influential than genetics, there is no doubt that the oldest-old are biologically (and often genetically) different. Without getting too deeply into the biology of aging, here are arguments for why this is the case.
Longevity Genetics
Genetic sequencing is so fast and inexpensive these days that roughly 30 million Americans have already completed partial DNA profiles for ancestry or health reasons. If you so choose, today you can even procure a readout of all 6.4 billion letters of your genome by mail-order. In spite how easy this all seems, scientists have struggled to identify specific longevity genes. So far, only two genes are widely accepted as directly influencing longevity, and neither exert a strong or reliable effect across study populations (of course, at an individual level, if you inherit a lucky mutation in one of these genes you are off to the races, and should life a long and healthy life).
One longevity gene (called APOE) provides instructions for how to make proteins which combine with fats to remove cholesterol from the bloodstream, and mutations in this gene are associated with Alzheimer’s and cardiovascular disease. The other (called FOXO3) regulates many processes involving energy metabolism, cell growth, and inflammation. Several others have recently been described as “significantly associated with exceptional longevity.”
Beyond these few, scientists have clues that many other genes are involved, with each contributing a small influence, or maybe only affecting a subset of people. Researchers are now working to identify groups of these genes, but this is painstaking, time-consuming work.
A couple of high-quality studies are worth looking at. Consider this one — not based on a twin study, but instead a large, random sampling of almost 315,000 individuals from over 20,000 geographically-dispersed families, spread over three generations. After crunching the numbers, investigators saw strong evidence that longevity is a transmitted genetic trait. For instance, the greater the number of long-lived parents or siblings, the greater the likelihood that a subject will live long enough to reach the top ten percent of the longest-lived survivors.
Evidence from New England Centenarian Study confirms this familial clustering. For example, just about half of these centenarians have siblings or close relatives who also reach very old age. And male siblings of centenarians have 17 times greater odds of reaching one hundred themselves compared to other men born around the same time. Also, many of the children of centenarians (ranging between 65 to 82 years old) appear to be following in their parents’ footsteps, with marked delays in cardiovascular disease, diabetes, and overall mortality. The same goes for cognitive impairment. After adjusting for confounding factors, children of centenarians were only half as likely to suffer this affliction, and were about one third less likely to become cognitively impaired during an eight-year follow-up period.
While these familial longevity clusters could result from common sociocultural or environmental influences, longevity genes probably play a role. Scientists suggest that complex traits such as longevity or the age of onset of a chronic disease are affected by a large number of small genetic effects, as well as other factors — such as the composition of our gut microbiota and even errors and faults in the way that our genes are switched on and off through epigenetic processes. Scientists describe this blurry heritability picture as “the missing heritability problem.”
It seems reasonable to accept the conventional wisdom that one-fifth to one-quarter of lifespan variability results from lucky genes. That it, until this unheralded, recent study was published.
“Assortative Mating” May Explain Away the Missing Heritability Problem
In 2018, a group of investigators at Google’s Calico Labs might have figured out why geneticists have had such a difficult time identifying longevity genes. These researchers concluded that the genetic heritability of longevity is not nearly as high as previous estimates — implying that the missing heritability problem might have less to do with inheriting lucky genes and more to do with other factors which influence longevity.
These Calico scientists first assembled a singularly massive genealogical dataset that could not have been constructed until very recently. They did this by teaming with the online genealogy company Ancestry to aggregate a set of subscriber-generated family trees comprising over 400 million individuals born from 1800 to 1920 whose year-of-death was also available, contributed by an astounding 54 million families.
Using this unprecedently large dataset, Calico researchers got to work performing some slick statistical analysis. Comfortingly, through this work, they found the heritability of longevity among related siblings and first cousins to be about in line with previous studies (around twenty to thirty percent).
Then they discovered something quite unexpected.
They saw that, within families, lifespans were correlated between (genetically unrelated) spouses — as well as remote in-law relatives, such as siblings-in-law, and first-cousins-in-law. Since these people do not share genetic backgrounds and the in-laws do not live together, the investigators had to dig deeper to understand the basis of this correlation. They determined that it is the result of “assortative mating,” whereby individuals choose spouses who are similar to themselves in observable characteristics. It turns out that assortative mating amplifies the heritability of longevity, but not through inherited genes. Rather, assortative mating doubles down on longevity-promoting traits having to do with non-genetic factors. For example, people who choose to have children together are more similar than not in sociocultural characteristics that confer longevity advantages, such as educational attainment, occupation, and personality (in Chapter 5, we will see how these traits are associated biological aging).
When assortative mating is taken into account in the statistical analysis, the genetic heritability of longevity plummets to well below ten percent. This is much lower than the twin studies we looked at earlier. Calico researchers explain this discrepancy by pointing out that most twin studies rely on socioeconomically homogeneous populations where assortative mating is prevalent (these populations include Danish twins, Swedish twins, Amish twins, and Utah twins). For instance, within these populations, spouse lifespans correlated as much or more than those of genetic relatives. This suggests that assortative mating plays a big role, and that these twin studies inflated the genetic influence on longevity because they did not take it into account.
This Calico study is a big deal for longevity science, as it suggests that factors such as environment, life circumstances and choices, and personality are vastly more influential than genetics in determining healthy lifespan. When coupled with emerging research showing that a mother’s gut microbiota influences her offspring’s metabolic health, to me, the likelihood that lucky genes confer longevity advantages looks lower and lower.
Longevity Phenotypes and Biology
In spite of how difficult it is to identify specific longevity genes, scientists are making progress unraveling biological clues about why longevity tends to cluster within families. For instance, a very large study of 12,000 elderly Swedish twins identified familial patterns for blood markers involving heart health, risk of diabetes, and inflammation levels. When markers such as these array themselves in a characteristic pattern, biologists call this a “phenotype” that arises from the interplay of genetics and environment. It just so happens that the biology of people with long, healthy lifespans is defined by characteristic longevity phenotypes. This graphic depicts the distinguishing characteristics of the healthy ager phenotype.
It turns out that centenarians’ phenotypes are not entirely consistent across countries and cultures. For example, the prevalence of hypertension ranged from 19 percent in Finish centenarians to 65 percent in a Hong Kong centenarian study. Since there are so many factors that affect health status across cultures and regions (from educational attainment to air pollution levels, to dietary practices, to local climate), it might be a fool’s errand to try developing generalized longevity phenotypes.
So why spend time on this? Because longevity phenotypes offer important clues about healthy aging. So, without further fanfare, here is what we know about how healthy agers are different and better.
Much healthier cardiovascular systems. Especially in Blue Zones, centenarians have much younger cardiovascular systems. For example, in the Italian longevity hotspot of Acciaroli in southwest Italy, elderly residents had low levels of adrenomedullin — a hormone that widens blood vessels — equivalent to people in their 20s and 30s. Researchers suspect this is influenced not only by healthy diets and lifestyles, but also by longevity genes which protect blood vessels from the ravages of aging.
Healthier gut microbiota. The gut microbiota of centenarians is enriched by types of bacteria that confer health benefits such as lower rates of obesity, improved renal function, and healthier metabolism.
Healthier connective tissue. Centenarians have connective tissue that is different and better. This tissue is synthesized by fibroblasts, and the fibroblasts of centenarians produce less inflammation in response to injury and wear.
Lower levels of chronic inflammation. Chronic inflammation is lower in the children of centenarians compared to age-match controls. This points to the likelihood that families of super-agers are protected from age-related changes that cause such inflammation.
Stronger immune system. Supercentenarians over 110 years of age have a larger proportion of “killer” immune cells which supercharge their immune systems, and attack tumor cells, viruses and the like. “Normal” centenarians also have healthier immune systems and lower levels of chronic inflammation thanks to low levels of a pro-inflammatory immune cell called IL-6, and high levels of other anti-inflammatory immune cells such as IL-10.
Better glucose metabolism. Healthy centenarians have better glucose tolerance than younger elders. This means they are more likely to avoid diabetes and harmful, age-related metabolic changes.
Healthier kidney function. Measures of kidney function and diastolic blood pressure were superior on a large group of centenarians and their families compared to matched controls. Since chronic kidney disease is common in the elderly, this is a good thing. Investigators suggest genetic factors may contribute to these results.
Healthier blood lipid and cholesterol levels. Centenarians have low “bad” cholesterol and high “good” cholesterol levels compared to younger healthy elders (perhaps due to genetics). In fact, exceptional longevity is associated with widespread changes in the levels of 72 different lipids in the blood which make centenarians more resistant to inflammatory processes. Also, cholesterol particle sizes were significantly larger in near-centenarians than in control groups — a characteristic that also confers good heart health.
Takeaways
Through observational studies, in this article we saw how exceptionally long-lived people are different. From the genes they inherit, to their physiological phenotypes, their life choices and circumstances, personality traits, and the cultural contexts in which they live — these people have much to teach us about healthy aging.
Genes matter, but not as much as we think. While long life tends to run in families and genetic factors are at play, longevity is mostly influenced by factors such as environment, life circumstances and choices, personality, and even your parents’ spouse selection. It turns out that personality and the composition of our gut microbiota might also influence healthy lifespan.
Lucky genes. Lucky genes play a more significant role in influencing the lifespans of extremely old individuals, and are likely to be involved in producing longevity phenotypes.
Longevity biology. Healthy agers have distinct longevity phenotypes involving less inflammation, stronger immune response, better metabolism, good cardiovascular health, healthier gut microbiota and connective tissue, better kidney function, and optimal cholesterol levels and blood lipid profiles.
To learn more, click over to my companion articles, Genetics and Lifestyle: What Our Healthy Elders Teach Us and Deep Dive on Longevity Lifestyles.
