Can this Gene Affect Your Lifespan? (NOS2)

The NOS2 gene codes for a protein also called NOS2, short for nitric oxide synthase 2. NOS2 produces the messenger molecule nitric oxide (NO) from the amino acid arginine, just like its two other close relatives (NOS1 and NOS3) [R].

However, NOS2 is different from the other two in three main aspects [R, R]:

• NOS2 is found in more cell types, including immune, liver, muscle, and lining tissue cells.
• While NOS1 and NOS3 production is permanently activated, NOS2 expression needs to be triggered (hence its alternative name of inducible nitric oxide synthase, or “iNOS”).
• NOS2 produces higher amounts of NO, and for longer periods.

Dual Role in Inflammation and Cancer

NOS2 is expressed in white blood cells, and is activated by pro-inflammatory messengers (such as TNF-alpha, IL-1beta, and IFN-gamma), infectious microbes, and free radicals. At moderate levels, NOS2-derived NO acts as a messenger that promotes inflammation and the development of immune cells. NO also kills invading microbes and cancer cells [R, R, R].

However, excessive or uncontrolled release of NO by NOS2 can have several harmful effects that may trigger or worsen diseases and even reduce lifespan!

For instance, sustained NO production can cause chronic inflammation, and may contribute to the progression of inflammatory conditions such as allergies, asthma, arthritis, and COPD (chronic obstructive pulmonary disease) [R, R].

Furthermore, excessive NO can lead to the build-up of free radicals (such as peroxynitrite and superoxide) that damage the DNA and proteins of cells and tissues. This kills cells and impairs the function of several important enzymes, which can in turn speed up the aging process and may even contribute to the development of age-related conditions such as Alzheimer’s, multiple sclerosis, and liver failure [R, R].

Finally, both chronic inflammation and DNA damage by free radicals may stimulate the development and progression of several cancer types [R, R].

NOS2 encodes a protein that produces nitric oxide (NO). While NO protects from infections and cancer at moderate levels, having too much of it may speed up aging as well as contribute to the progression of cancer and age-related diseases.

The most widely-studied NOS2 polymorphism is rs2297518. Its minor ‘A’ allele causes the gene to produce a version of the NOS2 protein that is significantly more active. This variant also reduces the expression of arginase, which competes with NOS proteins for the essential amino acid arginine [R, R].

As a result, the ‘A’ allele increases NO production in several different ways, which may be why it has been associated with the negative effects of NO excess discussed above.

Indeed, one study in Italian populations found that this NOS2 variant was significantly less common among people living to 90 years of age or older. Although the association was not very strong, this study nonetheless provides some suggestive evidence linking the ‘A’ allele to reduced longevity [R].

The minor ‘A’ allele of rs2297518 encodes a version of the NOS2 protein that leads to significantly increased NO production. This variant has been associated with reduced longevity in at least one study.

Associations with Blood Pressure

Although Nitric Oxide (NO) helps lower blood pressure by relaxing the blood vessels (vasodilation), the free radicals formed when NO levels are too high can damage the inner lining of the blood vessels. This reduces their ability to widen, which may lead to an increase in the risk of heart disease and other chronic cardiovascular problems (such as elevated blood pressure, or hypertension) [R, R].

Two studies in Chinese and Brazilian populations found that the ‘A’ allele of rs2297518 was significantly more common among people diagnosed with high blood pressure. The ‘A’ allele was also associated with high blood pressure during pregnancy (pre-eclampsia) in Brazilian women [R, R, R].

However, not all research on this SNP has found these associations. For example, a study in Finnish middle-aged people found no association between this polymorphism and blood pressure [R].

The ‘A’ allele of rs2297518 has been associated with high blood pressure in many — but not all — studies.

Associations with Cancer

A few studies associated the ‘A’ allele of rs2297518 with an increased frequency and severity of the following types of cancer:

• Stomach [R, R]
• Bladder [R]
• Colorectal [R] 
• Lymph nodes (non-Hodgkin and B cell lymphoma) [R, R]

Although these cancer types may differ in their underlying mechanisms, the authors of the studies have speculated that increased NO production could be involved — for example, by causing chronic inflammation and free radical damage in carriers of this allele.

Nevertheless, remember that the studies only associated this NOS2 variant with some cancer types. Since an association doesn’t imply causality, it doesn’t necessarily mean that having the rs2297518 allele will make you more likely to develop these forms of cancer! More work is needed before we can establish what role (if any) this variant may play in actually causing cancer.

A few studies have associated the ‘A’ allele of rs2297518 with several types of cancer. However, more research will still be needed to know whether these associations imply a causal link.

Associations with Septic Shock Complications

Septic shock is a severe reaction to infections that may damage the organs, and which can even lead to death if untreated. One of its main features is NO overproduction, which leads to a widespread widening of blood vessels throughout the entire body. As a result, blood pressure drops significantly, making it much harder for the heart to pump blood to supply oxygen to the body’s tissues [R].

The NO-overproducing ‘A’ allele of rs2297518 was associated with complications derived from septic shock in two different Chinese populations [R].

However, keep in mind that septic shock is a relatively rare condition that only occurs in response to very severe infections. The risk of septic shock and its complications can be greatly reduced by seeking medical attention immediately.

One study in a Chinese population associated the ‘A’ allele of rs2297518 with an increased susceptibility to medical complications during septic shock.

Primary SNP: NOS2 rs2297518:

• ‘G’ = More common among longer-lived people.
• ‘A’ = Less common among longer-lived people. This allele has been associated with high blood pressure, some cancer types, and septic shock complications.

Population Frequency:

• Almost 70% of the world population has the ‘GG’ (homozygous major) genotype.
• The ‘AA’ (homozygous minor) genotype is relatively rare across all major ethnic groups, with a prevalence of ~1.5% to 3%, depending on the specific group.
• African-descended populations are slightly less likely to carry any ‘A’ alleles.