THE ABCS OF DNA AND RNA
DNA—deoxyribonucleic acid—is a molecule made up of two chains (a.k.a. polynucleotides) that carry the genetic instructions for growth, development, functioning, and reproduction of living organisms and many viruses.
RNA—ribonucleic acid—is a large molecule essential to the coding, decoding, regulation, and expression of genes.
Nucleotides are the building blocks of nucleic acids.
Nucleic acids are the small molecules essential to all forms of life.
Gene expression is the process by which the instructions of the DNA are translated to a protein through “messenger” RNA (mRNA).
The DNA alphabet consists of four letters, each of which represents a type of nucleotide:
A
Adenine
C
Cytosine
G
Guanine
T
Thymine
* * *
Studying SuperAgers, people who are still living independently by age ninety-five, based on their DNA and other biological factors, is central to understanding the blueprint for how we all can age more slowly and maintain our good health. By discovering what makes these people so special, we’re discovering the real secrets of aging for the first time. SuperAgers largely sidestep the diseases that plague their peers—diabetes, cognitive decline, cardiovascular disease, Alzheimer’s, and cancer—maintaining vibrant lives that may slow down but don’t dim. They’re successful business leaders, musicians, and artists living independently into their late nineties and older. They help to raise their grandchildren, travel the world, learn new skills, and live full lives far longer than the rest of us. When they do contract debilitating diseases, it happens much later in life—sometimes two to three decades later than for most people and for a very compressed period of time.
We might theorize that these people derive all these benefits because they have healthier lifestyles than the rest of us, but that’s not the case. Instead, many of them break the health rules that the rest of us need to follow. Nearly 50 percent of the centenarians in our study are overweight or obese, nearly 50 percent smoke, and fewer than 50 percent do even moderate exercise. Remember the Kahns? When I asked Helen, who lived to 110 and smoked for more than ninety years, “Didn’t any of your doctors tell you to stop smoking?” she said, “Sure, but all four of those doctors died.”
Demographers estimate that for most people, genetics are responsible for about 20–25 percent of aging and the environment is responsible for the rest. But the statistics are vastly different for centenarians, whose genes are about 75–80 percent responsible for how they age and the environment accounts for only about 20 percent. That’s why we’re so determined to unlock their secrets. Doing so can give us insight into providing everyone with the same protections from aging that they enjoy.
Besides being medical marvels, these amazing people have made the most of their “extra years” by remaining engaged with life and dwelling on the positive. Every SuperAger I’ve met has interesting stories to tell and pearls of wisdom to share, no matter how humble they might be about sharing them. They make me look forward to the day when all our elders can be engaged members of society well into their nineties and beyond. At Einstein, we are determined to make that happen sooner rather than later.
Studying Centenarians
The idea to look for the secrets of longevity in centenarians was exciting and promising, but figuring out how to design and conduct the study was devilishly complicated. How could we study a population that had no living control group? And what should we be looking for?
When we started the Longevity Genes Project in 1998, we had three distinct hypotheses about what made centenarians so special genetically. One was that the centenarians had a perfect genome, one without any variants or other errors or imperfections in the sequence of the genetic code of DNA, allowing them to grow and age in the most optimal way. The second hypothesis was that centenarians had very healthy lifestyles and environments. Our third hypothesis was that centenarians had all the same variants in their DNA as the rest of us but were being protected from their negative effects by other variants in the sequence of their DNA. If that was the case, though, how could we discover those protective variants?
* * *
MUTATIONS AND VARIANTS
A mutation is a natural and permanent change in the sequence of the chromosomal DNA. Mutations are rare. Only about one person in one million has a mutation that causes a phenotype of sickness, or for centenarians, extended health.
A variant is a mutation that has spread into the population and therefore has become more common.
Geroscientists are looking at rare and common variants associated with exceptional longevity in our centenarian population.
* * *
Common changes that occur across the DNA in individuals are known as variants, some of which are associated with and may cause diseases. If the variants are rare, they’re known as mutations. Each variant or mutation gets a single nucleotide polymorphic (SNP) number that identifies it in the sequence of the genome.
As for finding answers, strong data suggests that exceptional longevity runs in families—people with a centenarian parent are about ten to twenty times likelier to become a centenarian or have a sibling who will make it to one hundred than people who don’t have centenarian parents. For that reason, it made sense for us to study exceptional longevity genetically. And because it’s rare, it’s easier to find genetic differences in a group of centenarians than in a group of people with common illnesses like diabetes or hypertension. When the human genome was sequenced, we looked for common variant differences between people with diseases and people without diseases, but we were disappointed by how little we found. Despite the great expense of the technology at the time, the genetic information we got usually explained less than 5 percent of the contribution that these common variants made to each of the common diseases. This happened because most of the DNA we have is not coding for the genes that make up the less than 30,000 proteins that make up our biology. So about 90 percent of the variants are overrepresented in noncoding areas and underrepresented in the regions that code the exact sequence of a protein. In other words, there are more variants near the genes, between the genes, and between the coding sequences of the genes than in the coding sequences of the genes themselves. We were more interested in finding genetic variants in the coding regions of the genes, but at that time, we knew there was no chance of getting funded because the genetic testing was extremely expensive and had major quality-control issues. Furthermore, to study this in an unbiased way, we needed to design a scientific study that was solid enough to get funding. In particular, we needed to figure out how to isolate what made centenarians genetically different without being able to compare them with their peers who had died decades earlier.
I should point out that by no means was I the first scientist to be interested in centenarians. But in the quest for genuine secrets for health span and longevity, I put together the first group to study centenarians’ biology and genetics, and we launched the Longevity Genes Project the year after Madame Jeanne Calment died at the age of 122. Madame Calment, who became a celebrity of sorts, stirred a lot of interest in centenarian studies because she was known for being “young” well into her later years. Calment was born in 1875 in Arles, France, and lived there for her entire life. Arles is known for inspiring Vincent van Gogh’s paintings, and Calment met Van Gogh when she was twelve. When she was twenty-one, she married a second cousin and went on to enjoy a prosperous life filled with physical activity, including fencing, swimming, tennis, cycling, and mountaineering. Her husband died in 1942 when she was sixty-seven, but that didn’t slow her down. She continued to participate in all the activities she’d enjoyed with her husband for decades, including riding her bike around Arles until she was one hundred. She reportedly ate two pounds of chocolate every day and credited her olive oil–rich diet for her calm disposition and her long life. “That’s why they call me Calment,” she used to say. (Calm in French is calme.)