Can This Gene Influence A Person’s Lifespan? (PARP1)

The PARP1 gene codes for an enzyme called poly-ADP-ribose polymerase 1. This enzyme plays two major roles in the body: DNA repair and regulating inflammation.

As we will see, these two processes are actually closely inter-related, and need to be held in a careful state of balance to ensure optimal overall health!

PARP1 and DNA Repair

The cells that make up your body are constantly dividing and making new copies of themselves; and in order to reproduce properly, each of these cells needs to be able to read and copy the DNA they contain as accurately and reliably as possible.

While this process usually goes off without a hitch, occasional errors are made in the DNA-copying process. These “copying mistakes” are what biologists are often referring to when they talk about “mutations” — and these mistakes can sometimes lead to negative consequences, such as changing the functioning of cells in a way that causes them to grow uncontrollably (a situation that most people know of as cancer).

Additionally, a large number of different environmental and lifestyle factors can also contribute to DNA damage, which further increases the risk of harmful genetic mutations. Some of the most common causes of DNA damage include:

• Reactive oxygen species (ROS), which build up to cause oxidative stress that can damage DNA [R]
• Radiation, such as UVA and UVB from excessive sun exposure [R, R]
• Alcohol use, smoking, air pollution, and other environmental toxins [R, R, R, R]

Fortunately, your body has developed a number of important defence mechanisms that it uses to counteract and repair DNA damage. One of these defences is the PARP1 gene, and the enzyme it produces.

First, the PARP1 enzyme becomes activated whenever your cells detect DNA damage. This enzyme then comes into the cell and “attaches” (binds) itself to the location of the damage, which then serves as a signal to a number of other cellular mechanisms to come in and “repair” the genetic code before any further harm can be caused [R, R, R].

The PARP1 gene protects the DNA in your cells from being damaged by toxins, oxidative stress. UV radiation, and other potential dangers.

PARP1 and Inflammation Control

While the ability of cells to repair their own DNA is clearly a good thing, there is unfortunately a catch: whenever PARP1 is activated, many of the repair mechanisms that kick into gear also cause an inflammatory response [R, R, R].

Although this might sound counter-intuitive, it actually makes a lot of sense: after all, inflammation is in fact a critical part of how the body protects and repairs itself from damage and disease. In other words, inflammation is not always “bad” — it’s primarily just when it becomes chronic or excessive that it can start to pose a major problem for a person’s overall health [R, R].

When the PARP1 enzyme is activated, the DNA repair mechanisms it stimulates also cause an inflammatory response.

The Trade-Offs of PARP1 Activity

So what does all this mean for the PARP1 gene? Well, in short it means that a person’s level of PARP1 gene activity has to be held in a careful balance to maintain optimal overall health.

Too little of it, and the body’s cells will be less able to repair themselves. This can potentially make them more vulnerable to damage from oxidative stress, increase the rate of cellular aging, and even increase the long-term risk of developing cancer.

However, too much PARP1 activity can also be bad, as this could lead to a persistent stimulation of the inflammation response — even when it’s not needed! Therefore, it wouldn’t be good to simply increase PARP1 gene activity as much as possible, because the (short-term) negatives could start to outweigh the (long-term) benefits (i.e. by causing chronic inflammation).

Because PARP1 is necessary to repair DNA damage, but also stimulates the inflammatory response, a person’s levels of PARP1 need to be held in a careful balance to ensure optimal health.

Given the complex roles that the PARP1 gene and its enzyme play in the body, it can theoretically affect overall lifespan in multiple ways.

One way is by influencing a person’s long-term risk of cancer, which stems from its role in DNA repair. The better-able one’s cells are to resist damage from factors such as oxidative stress, and the better they are at repairing this damage when it occurs, the less likely cells will be to develop the sorts of mutations that can turn into cancer and other serious health issues [R, R, R, R].

In other words, one of the reasons that PARP1 has been associated with differences in longevity is likely because on average, people with relatively lower PARP1 activity will be at a greater lifetime risk of dying from cancer. Therefore, when scientists look at large numbers of people, variants in this gene can stand out as one possible genetic factor that affects how long people tend to live [R, R, R, R].

One the other hand, another way that PARP1 can impact longevity stems from its role in inflammation. In addition to the many short-term negative effects of inflammation, over the long term it also generally increases the risk of developing other chronic health problems, such as cardiovascular issues [R, R].

Therefore, it is possible that people with certain PARP1 variants that stimulate inflammation too much will tend to accumulate more health issues as they get older, which in turn could make them less comparatively less likely to live quite as long [R].

Genetic variants in PARP1 affect longevity in two main ways: by reducing cells’ ability to recover from DNA damage, or by contributing to chronic inflammation. Each of these different mechanisms can contribute to the long-term development of certain health issues, such as cancer or cardiovascular problems, which can in turn influence overall lifespan.

You can see your genotypes for a few noteworthy PARP1 SNPs in the table below. However, before we dive into the details, there are some important limitations to keep in mind as we continue.

Firstly, when it comes to the genetic aspects of longevity, studies suggest that there are many genes associated with lifespan. However, any single one of these genes generally plays only a very modest and limited role in the overall picture — and PARP1 is one such gene.

Secondly, there are many different factors that may influence how well someone ages, and how long they can live. In fact, according to some researchers, genes may only have a relatively small effect on overall longevity. For example, some have estimated that less than 10% of the variation in human lifespan may be determined by genetics — and which genes, and exactly how they contribute to longevity, are not yet well-understood [R, R].

The ultimate takeaway here is that lifestyle, dietary, and other non-genetic factors are probably much more important when it comes to longevity than any individual gene — so at the end of the day, your best bet for living a longer life is to focus on the factors that you can control!

With those caveats in mind, let’s see what your PARP1 variants may have to say about one specific genetic factor associated with longevity:

PARP1 rs1805415:

When it comes to the SNP rs1805415, some evidence suggests that it is probably better to have the heterozygous major ‘CC’ genotype, which approximately 65-72% of the general population carries.

For example, one targeted gene study with over >5,000 participants reported that the minor ‘T’ allele was associated with relatively reduced overall lifespan in several large samples of European-American, African-American, and Ashkenazi Jewish populations [R].

Furthermore, the authors concluded that this effect was likely due to elevated inflammation, as each additional copy of the minor ‘T’ allele was correlated with a 15-20% increase in a person’s baseline levels of interleukin 6 (IL-6), an inflammation-related cytokine [R].

A person’s genotype for the SNP rs1805415 may play a role in longevity by determining how susceptible their body is to chronic inflammation.

PARP1 rs3219090:

When it comes to the SNP rs3219090, evidence suggests that it is likely better to carry the minor ‘C’ allele. Just under half (48%) of the general population carries this allele, although it is significantly more prevalent in European populations in particular (where ~68% of people of European descent carry it).

For example, multiple gene-targeted studies — each with several thousands of participants from diverse populations — have associated this allele with reduced incidence of several types of cancer [R, R, R]. This slightly lower cancer rate means that the average lifespan for large groups of people with this allele tend to be longer overall.

Although the exact mechanisms involved in this SNP’s effects are complex and not yet fully understood, several researchers have concluded that this allele causes a change in the PARP1 gene that effectively increases its activity, which may protect against cancer by enhancing the ability of cells to repair their DNA [R, R, R].

Certain genotypes for the SNP rs3219090 have been associated with increased PARP1 gene activity, which may impact longevity by enhancing the ability of cells to repair their DNA.

Limitations & Caveats:

However, while these studies have each associated certain PARP1 variants with longevity, it is important to note that these effects are still considerably smaller than many common lifestyle factors.

For example, in one particular study (on rs1805415), the effect of a person’s PARP1 genotype on their longevity was many times smaller than the effects of other common health-related factors, such as their fitness / body weight (BMI), or whether they were a smoker [R].

This is significant because it underscores how many of the most important factors that determine your longevity are actually under your control! So, while genetics can still be important, at the end of the day the most important thing is to ensure that you’re living a generally healthy lifestyle.

While many studies have associated certain PARP1 variants with longevity, these effects still generally pale in comparison to other common-sense health-related factors, such as fitness, obesity, and refraining from smoking. Therefore, it’s always best to focus on these basic factors before worrying too much about your genetics!