Digging Into DNA to See Why Some People Live Until 110

The Betterhumans project is making DNA from supercentenarians available to researchers so they can study the genes of people who live well past 100 years.

Eating healthy, exercising regularly, avoiding smoking, limiting stress.

They can all help you live a long time.

But making it to an age like 110?

That takes a special superpower, one encoded in your genes.

“To live beyond 102 or 103 and make it to the rarefied status of a supercentenarian (110 and older) you need to have ‘the right stuff’ — genetic variations in your DNA that protect you from disease,” James Clement, one of the leaders of the Betterhumans project, told ishonest.

“Supercentenarians can smoke and drink, for example, without suffering, whereas the rest of us get debilitating diseases from doing such. Many of us non- supercentenarians get debilitating diseases early in life. … Supercentenarians sail through that time of their life as strong and active as ever and never seem to suffer with similar diseases. We believe that it’s because of protective gene variants, which the rest of us don’t have.”

Clement is leading an effort to learn what it is about the DNA of supercentenarians that allows them to live so long.

It’s one of several projects turning to genetics in the search for the secrets of longevity — and how those secrets might help the rest of us.

Looking for patterns

The Betterhumans project has made the genomes of 35 supercentenarians available for researchers to study.

As that sample size grows, the hope is patterns will emerge.

Those patterns might pinpoint the genetic mutations that are shielding the long- lived from ailments such as Alzheimer’s, cancer, diabetes, heart disease, and stroke.

That, in turn, could lead to drugs that can reduce disease risk in the general population.

Those genomes were sequenced by Veritas Genetics, a gene sequencing company founded by Harvard geneticist George Church.

Clement said Betterhumans has 10 or so geneticists and bioinformaticians analyzing the DNA in-house.

That’s in addition to work done by outside researchers who want to study the genomes.

Other projects are taking similar approaches.

At the Albert Einstein College of Medicine in New York City, Nir Barzilai’s team has been looking for genetic mutations tied to longevity in the DNA of 213 Ashkenazi Jews with an average age of almost 98 years.

At Boston University, Thomas Perls has been studying the DNA of people with an average age of 101 years.

So far, Perls’ team, according to their website, has found that longevity runs in families.

They’ve also concluded that disability and disease is most common in long-living people only after they’ve reached their early 90s.

Genetics, they add, seems to plays a stronger role than lifestyle or environment in survival the older they get after their 90s.

Variants may be key

However, the researchers concluded that it’s likely not specific genetic variants that are key.

Instead, it’s many variants combined.

Clement said earlier work by Betterhumans found some “2,500 rare variants that were overexpressed” in the supercentenarians they were studying at the time, although some of them were surely erroneous.

Perls’ team has only discovered that centenarians usually have just as many genetic variants associated with diseases as the general populations.

So, it’s not that they don’t have “bad” genes but that they likely have other variants that slow or decrease the risk of actually getting those diseases.

Clement agreed with that conclusion.

“My best guess,” Clement told ishonest, “is that these protective genes are mostly ‘loss of function’ mutations that limit some of the negative effects that are related to the insulin, growth hormone, cardiovascular, and other pathways.”

Other studies have found the exceptionally long-lived are typically smaller in stature than average and stay active and socially engaged despite their age.

Clement, however, noted this may be a chicken-and-egg problem.

“We don’t know whether this helps them live longer and healthier, or whether they’re more active because they’re healthier and aren’t wracked with chronic pain, dementia, or other illnesses that the less fortunate suffer from,” he said.

Working with others

Outside researchers are interested in working with the Betterhumans genomes, though they caution that there are limits to what can be learned from a few dozen supercentenarians.

“We have not worked directly with these genomes, but they are complementary to the genomes from our healthy aging cohort, and we are definitely interested in working with these data,” said Ali Torkamani, genomics director at the Scripps Translational Science Institute in California who has been studying the genomes of people 80 to 100 years old.

However, Torkamani told ishonest he has concerns over the limited number of supercentenarian genomes.

“This is not a problem with the design of the study. Centenarians are simply rare,” he said. But, “if it turns out that the genetics of longevity are as complex as the genetics for other common diseases, unraveling the genetic components of healthy aging, especially for the discovery of protective genetic variants, will be a difficult task.”

William Mair, a professor of genetics and complex diseases at Harvard’s T.H. Chan School of Public Health who is also not involved in the Betterhumans initiative, told ishonest, “I think it’s cool that they released this data and could give people in lots of different areas opportunities to study genomes” that wouldn’t normally be so easily available.

Centenarians, he said, live a long time but generally don’t suffer from prolonged periods of poor health— even those that don’t have the healthiest lifestyles.

Instead, there’s a “compressed period of health concerns right at the end.”

Like the other research projects, his lab is trying to understand why.

But Mair is focused on studying how factors like nutrition affect the degree to which age is a risk factor for different diseases.

To do that, his team tests the effects of different nutritional and environmental factors on animals in the lab.

But now, with tools like CRISPR gene editing, they can also test whether different genetic changes make a difference.

Having more genomes from long-lived humans available and being able to find patterns between them might make the search for longevity-related mutations even more precise.

“If we have enough centenarian genomes, you could find two or three processes that tend to have mutations that you don’t see in the general population,” Mair told ishonest. “So you can go in and modulate those in the lab and test what sort of effect they have using CRISPR systems. So having access to these genomes can help with that.”

He expects this sort of line of research to become more common in the future.

Searching for solutions

Ultimately, all the genomic research is aimed at developing targeted drug therapies to help people avoid age-associated diseases and live longer and healthier.

“The Holy Grail of these studies would be the identification of genetic variants that either slow aging in general or are protective against major causes of morbidity and mortality,” said Torkamani.

He noted that some drugs already mimic the effect of protective genetic variants, such as PCSK9 inhibitors used to treat high cholesterol.

“One could certainly imagine that similar drugs could be developed to slow aging if the appropriate drug targets were identified,” he added. “I think that as the cohorts continue to grow and our knowledge of the genetic components of major diseases increases, we will slowly gain the power to inspect these genomes in a more directed fashion to uncover interesting protective variants.”

Clement said Betterhumans is currently conducting human clinical trials on compounds “that have shown promise in slowing aging.”

It will be publishing results as the trials progress.

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