Sequencing the Genes
The study’s first five years have focused on analyzing the results obtained from sequencing all of the protein-coding genes of 450 healthy people ages 95 and older who are enrolled in Einstein’s ongoing Longevity Genes Project and donated blood samples for testing. For comparison, the genomes of 550 people (average age 70) with no family history of extreme longevity were also sequenced.
Sequencing reveals the order of the long strings of four nucleotides (abbreviated A, T, C and G) that comprise each gene and determines the shape and function of the protein that the gene codes for. For a particular stretch of a particular gene, differences in the nucleotide sequence of one person compared to another (for example, A-G-T-C-A versus A-A-T-C-A) are referred to as gene variants. As they look for gene variants that are enriched in the centenarians but rare or absent in the control individuals, the scientists confine their search to just a few genes.
“Gene variations among people are extremely common and only rarely have implications for human health, so pursuing all of them would be impractical,” said Dr. Vijg. “Instead, we decided to focus on variants of genes we knew were associated with aging, either in model organisms such as fruit flies or in humans. A key outcome of the project’s first five years is that this approach has already led to the discovery of quite a few variants associated with longevity.”
Finding How Variants Function
The saga of a gene called SIRT6 illustrates how Dr. Vijg and his colleagues—a multicenter scientific consortium conducting four different projects—are working collaboratively to translate gene sequencing data into drugs for combating age-related diseases.
Project one of the consortium, which is involved with studying gene sequences, paid special attention to the SIRT6 gene. Vera Gorbunova, PhD, Project Leader, University of Rochester, had earlier discovered that SIRT6 codes for an enzyme associated with DNA repair, and other research indicates it protects against aging and disease. For example, SIRT6 expression is reduced in the brains of Alzheimer’s patients, and overexpressing the gene in roundworms and mice significantly extended their lifespans. Yousin Suh, PhD, Adjunct Professor, Genetics, Medicine, Albert Einstein College of Medicine, and Project Member, Columbia University, then found that a variant of SIRT6, centSIRT6, occurred twice as often among the study’s centenarians compared with control-group participants.
The next step was to refer centSIRT6 to project two, which is led by Dr. Suh and evaluates promising gene variants. In one experiment, researchers manipulated human cells to express either the centSIRT6 gene variant or the “wild-type” (WT) SIRT6 variant that predominates in control participants. When they were exposed to DNA-damaging radiation, the cells expressing centSIRT6 repaired the damage faster than those expressing the WT SIRT6 variant, indicating that centSIRT6 improves DNA repair and bolsters cells’ resistance to DNA damage.
“Besides centSIRT6, we’ve identified several other longevity variants that are also involved in DNA repair,” said Dr. Vijg, “which tells you that resisting DNA damage is probably important for living a long life.”
Gene variants that perform well in cell studies “graduate” to project three, led by Laura Niedernhofer, MD, PhD, University of Minnesota, which tests whether longevity gene candidates can extend the lives of mice. In these experiments, prematurely aging mice (with lifespans of six months compared with the usual 30) are genetically manipulated to express the mouse version of a promising longevity gene variant. Several such variants have gone through mouse testing.
Genes as Models for Drugs
A variant that extends mouse lives became the focus of the fourth project, led by Paul Robbins, PhD, University of Minnesota. Project four is tasked with identifying an existing drug or designing a new drug that duplicates the variant’s activity and, ideally, will help extend human lifespans. Drugs mimicking several recently identified variants are now being developed, including for SIRT6. Dr. Vijg, however, cautions that longevity is more than a matter of “one and done.”
“You have to remember that centenarians undoubtedly possess a combination of rare gene variants,” Dr. Vijg said. “We’ll need to identify a sufficient number of such variants, and a sufficient number of drugs that mimic them, to have a real impact on warding off the major diseases associated with aging.”
In a major boost toward achieving that goal, the American Federation for Aging Research will soon contribute funds for enrolling 10,000 more centenarians and their family members in the study. “Since longevity gene variants are so rare, being able to test thousands of centenarians will give us much more statistical confidence that a particular longevity gene variant truly is enriched in the centenarian genome,” Dr. Vijg said. “And with thousands more centenarian genomes to analyze, we’ll be able to detect many more longevity gene variants, including those exerting subtle but still important effects.”
The NIH grant is titled “Genetic variant-based drug discovery targeting conserved pathways of aging” (2U19AG056278-07A1).
