This story is one of many exploring recent advances in the science of longevity and aging. The following few articles in the series, including this one, will focus on the relationship between genetics and longevity; Which genes are involved in aging and longevity? How are they involved? What are the therapeutic implications?
Why do some people age more quickly than others? Why is it that one person develops heart disease and another, of the same age, doesn’t? Although aging is a complex process, with hundreds of different variables, one thing is becoming increasingly clear: the sum of your genetic information —known as the genome— matters. In the largest genetic study of aging to date, researchers at the National Institutes of Health (NIH) have uncovered multiple new genetic “regions” that influence lifespan and healthy aging. Their work, published in the journal Nature, has important therapeutic implications and opens up new avenues for future research.
Crash Course: Genome-Wide Association Studies
Integral to the team’s findings is a research approach called genome-wide association studies, or GWAS for short. This is a relatively new technique that first burst onto the scene in 2002. Since then, the number of genome-wide association studies has soared to almost 60,000, based on a catalog maintained by the National Human Genome Research Institute (NHGRI).
So, what exactly is this research approach, and how does it work? Pick any two people in the world and they’ll share roughly 99.6% of their genome. The remaining 0.4% may seem like a tiny, almost insignificant number but it is precisely that 0.4% that determines whether a person has blue or brown eyes, whether they have curly hair or straight hair, and a host of other traits. It is also these small differences across genomes that can affect a person’s likelihood of developing various diseases, including those that impact longevity.
In brief, genome-wide association studies allow scientists to pinpoint genetic variations that are correlated with a particular trait or with increased risk for a certain disease. This is done by analyzing the genomes of thousands, if not millions, of people. Indeed, many countries have set up “biobanks” precisely for this purpose — databases made up of the genetic information of a portion of their population.
During genome-wide association studies, researchers will focus on a particular trait or disease and check to see if people with the trait or disease are more likely to carry a specific genomic variant than those without it. They look for changes at the level of nucleotides —the building blocks of DNA (deoxyribonucleic acid)— known as single-nucleotide polymorphism (SNPs). If a statistically significant number of people with the trait or disease carry a certain genetic variation, or allele, as such variations are known, then it can be considered a key player.
The More the Merrier: Multivariate GWAS
Traditional genome-wide association studies focus on one single genetic variant. Although effective, this may also be limiting. Healthy aging, for example, is made up of multiple factors: “healthspan” (the portion of one’s life spent in good health), parental lifespan, extreme longevity, epigenetic aging, and frailty. Focusing on any one of these may offer insight into the aging process, but why not focus on all at once to get a better picture of the underlying genetic architecture of aging?
This is exactly what the researchers of the latest study did. Rather than focusing exclusively on one variable, they performed a “multivariate” genome-wide association study. This means they looked at the above five variables simultaneously, to get a deeper understanding of how they relate to each other. Their multivariate analysis, which they dubbed “mvAge”, was based on data gathered from 1.9 million participants from diverse biobanks. The analysis yielded 52 genetic variants associated with healthy aging, twenty of which had not previously been linked to aging. This included one genetic variant, rs2863761, not previously identified in any genome-wide association study. Many of the variants are known to influence cardiometabolic risk factors, heart and circulatory diseases, and brain health.
Along with discovering new gene variants linked to healthy aging, the group of researchers also helped validate prior findings that suggested metformin, a drug that is used to treat type 2 diabetes, may also support healthy aging, even in those without the illness. Two trials are currently ongoing to test the age-busting effects of metformin: MILES (Metformin in Longevity Study) and TAME (Targeting Aging with Metformin).
But, since trials often take many years to complete, the researchers decided to “test” the drug against their genetic model. Metformin works by targeting genes linked to blood sugar and regulating how active they are. Mimicking this effect, the researchers artificially targeted the same genes in their model and checked the impact these changes had on aging. Across the board, genes targeted by metformin were associated with positive effects on healthspan, lifespan, and the aging process at the genetic level.
Of course, genetic evidence of this type is not a stand-in for human trials, but it does provide an early peek at what may be to come: if all goes well, the findings of the human trials will reflect those of the genetic models.
This genetic study on aging represents the largest such study to date. Its findings help us deepen our understanding of the intricate ways different genes and genetic “regions” are interconnected and come together to impact healthy aging. Although there doesn’t seem to be a single “aging” gene, it is becoming clear that there is an expansive and complex web of genes that contributes to health, longevity, and age-related disease. This latest research helps us fill in gaps and brings us one step closer to a full-fledged map of the genes involved in aging. The work also helps forefront potential genetic targets for drug development and points to already-available drugs that might be repurposed for the sake of healthy aging.