In an Amish community in Indiana, those with one copy of the mutant SERPINE1 gene live up to seven years longer. How valuable is this finding?by / November 21, 2017 / Leave a comment
If this was a news column, I might tell you that scientists have found a Methuselah gene: one that conveys longer-than-average life. But that’s the kind of half-truth this column is here to pick apart.
Unravelling the genetics of ageing is complicated but illuminating. People who live to an unusually ripe age—100 or so—often have a particular genetic profile, yet average life expectancy has rather little to do with genes.
Confused? The rather steady rise in average life expectancy since ancient times doesn’t reflect any change in human genetics, but is due to social transformation: better medicines and medical treatments, better diets and so on. A slight decline in US life expectancy in 2016 was attributed to lifestyle factors: more heart disease through obesity, more accidents, spread of drug addiction and suchlike. As with so much else involving human traits and behaviour, environmental effects tend to swamp genetic influences.
But genes do matter, especially for particularly long-lived people: many have been dealt a strong genetic hand. The trouble is, that fact is more obscured than explained by talk of “Methuselah genes” associated with long life (and it’s not just lazy reporters who do it). That several genes have been associated with longevity reflects the complexity of the ageing process itself. It’s not a single process, but a concatenation of many things, and some of them are still poorly understood. So-called “anti-ageing genes” haven’t arisen in human evolution to make us live longer: they serve a variety of (sometimes rather obscure) biochemical roles, which might happen to disrupt one or more of the processes that cause ageing.
All this provides the backdrop against which to consider the latest report of a gene that can stave off ageing. Cardiologist Douglas Vaughan of the Northwestern University School of Medicine in Chicago and his coworkers have found that a particular genetic mutation, found among people in an Amish community in Berne, Indiana, can increase life expectancy by up to seven years.
“Environmental effects tend to swamp genetic influences”
There’s quite a lot to unpack there. This gene has been commonly reported as an anti-ageing gene, but the fact is that everyone has it. You need it. It’s called SERPINE1, and like most genes it encodes a particular protein molecule that does a job in our cells. The protein is called PAI-1, and it is involved in the process of blood clotting.
However, some of the Berne Amish community have a mutant form of SERPINE1, meaning that it can’t produce the fully functioning protein PAI-1. Our DNA contains all genes in duplicate, because we inherit copies from both birth parents. A person who has the mutant form of SERPINE-1 in both of their copies of this gene can’t make working PAI-1, and they suffer from a bleeding disorder. It was this condition that alerted Vaughan to the presence of the SERPINE1 mutation in the Amish people—it has not yet been identified outside that community, and Vaughan says it “generally does not exist in the world at large.” The mutation stayed within the community because of its closed nature—and what’s more, it was relatively easy to identify the genetic cause of the disorder because the Amish people otherwise have such uniform lifestyles.
But here’s the thing. Plenty of individuals in the community have only inherited one copy of the mutant SERPINE1 gene. Their other copy of the gene makes PAI-1 just fine. And so they are healthy—and the researchers discovered that this subpopulation with one SERPINE1 mutation lived longer, on average, than other people from the community with the regular SERPINE1 gene in both copies. Crudely put: one mutant good, two mutants bad. It is analogous to the way in which some people (those of sub-Saharan African descent are particularly prone) carry a mutant form of a gene involved in making hemoglobin, the molecule that carries oxygen through the bloodstream. A double dose of the mutation is harmful: it leads to the form of anaemia called sickle-cell disease. But a single dose is good, because it confers some protection against malaria.
Why, though, does reduced production of PAI-1 in individuals with one SERPINE1 mutation lead to longer average lifespan? That’s where it gets truly complicated. Vaughan says that many people in the developed world carry too much PAI-1—it increases with body mass index, and is also raised by inflammation and exposure to chemical “oxidants.” “Isn’t it interesting that many factors that are known to promote aging—obesity, inflammation, oxidative stress—all converge on increasing PAI-1?” he says. But what’s it doing to cause problems? Well, if PAI-1 affects blood clotting then it can lead to problems of arterial blockage and high blood pressure (hypertension).
But the full story is very complex and far from understood. The job of PAI-1 is a recherché, indirect one: it ramps down the activity of another protein, called tissue-type plasminogen activator or t-PA. It’s actually t-PA that does the blood-clotting work—but it also influences a number of other proteins that act as hormones involved in ageing. What’s more, PAI-1 does other stuff: it affects how cells move around and how they are released from bone marrow, where some are produced. And PAI-1 is involved in another aspect of ageing, called cell senescence. After cells have divided a certain number of times, they stop dividing further and in fact stop doing much at all: they become “senescent.” Quite how PAI-1 influences senescence isn’t known yet.
It is known that this senescence has something to do with ageing, but it’s not quite clear what. It is connected to changes in the end regions of the chromosomes on which genes reside: these regions are called telomeres, and they get steadily eroded when chromosomes are copied before a cell divides (so that both progeny cells have copies). Telomere shortening has long been linked to ageing.
What’s more, PAI-1 also gets involved in metabolic processes, and Vaughan thinks that the known effect of restricting caloric intake in slowing ageing might actually be operating via a suppression of PAI-1 levels.
I know: this is all more than you needed to know. Except that what you do need to know—to appreciate why it’s not terribly helpful to think of SERPINE1 (remember? The gene that makes PAI-1?) as a potential “anti-ageing gene”—is that this label says pretty much nothing about what the gene actually does in the body, which is a complicated, poorly understood story.
“There is good reason, if you extrapolate all the interventions in ageing, to suppose that there’s an upper limit beyond which we cannot progress”
It’s also important to recognise that individuals with a single SERPINE1 mutation don’t necessarily live longer. They just have a higher chance of doing so. The variation in lifespan among individuals is large, and the influence of SERPINE1 only becomes apparent in averages. That’s how it generally is with genes: having a gene variant associated with some health problem—or indeed with a health benefit—doesn’t mean you’ll develop that condition, but only that you have a greater likelihood of doing so. In many cases, lifestyle and environment may dominate over genetic effects. A heroin user or a morbidly obese person with a single SERPINE1 mutant would be far less likely to feel its advantage.
And perhaps most important of all: above age 95 or so, any advantage to having one copy of the SERPINE1 mutation vanishes. The life expectancy graphs for those with and those without converge. In other words, other aspects of ageing dominate by that stage. Vaughan says that what his team might be seeing is not so much offset as “compressed” morbidity: you hold off some ageing-related biochemical changes for a few years, but age catches up in the end. And it seems that it always does. There is good reason, if you extrapolate all the interventions in ageing seen for humans, to suppose that there’s an upper limit beyond which we have absolutely no reason to think we can progress: above about 100, no interventions seem to make much difference.
Despite all this complication, knowing that the SERPINE1 has an effect on ageing is valuable. It’s a surprisingly big effect: for a single gene mutation to enhance average life expectancy by seven years is rather striking. Vaughan thinks that this makes the protein PAI-1 a potential target for drugs aimed at arresting age-related illness. “We are not trying to develop “snake oil” for ageing,” he says. “We are more concerned about helping the millions of individuals with medical problems that make them age rapidly, like chronic kidney disease, chronic HIV infections, obesity and insulin resistance.” It’s not about inhibiting the protein completely, but finding that sweet spot apparent in people with one SERPINE1 mutation: not too much, not too little. Vaughan says that some such drugs already exist: one called metformin (or Glucophage), used to treat type 2 diabetes, has been identified as having anti-ageing effects and reduces PAI-1 levels.
It’s worth recognising, then, that the Amish SERPINE1 mutation is only an “anti-ageing” gene in much the same sense as David Davis is the UK’s Minister for Withdrawal of Businesses from Britain. That is not what they are there for, but happens to be a consequence of what they do.