Longevity and Genetics: FOXO3, CETP, IGF1, and more

We all know the beginning signs of aging: the graying hair, changes in your skin, and odd creaking noises from joints that shouldn’t creak. Beyond those initial signs, there is a lot of research going on right now to determine exactly why and how we age — and why some people naturally live longer. Several identified longevity genes show links to a statistical increase in lifespan. Most importantly, these particular genetic variants show links to a longer ‘healthspan’.

Investigating the genes linked to a longer lifespan can help us understand at a cellular level the important pathways in the body for a long, healthy life. Whether you carry the specific variants linked to longevity or not, figuring out those pathways can be important. The Lifehacks section includes research-backed ways to mimic the effect of ‘good longevity genes’.

Longevity:

The average lifespan in the US is around 80. It is something that we generally accept as ‘just the way it is’.

But… some people live to 100+ and are still relatively healthy. A few people live to 110 or 120.

When you look to the animal kingdom, most lab mice and rats live for 2 to 3 years. This is in line with other small mammals — with the exception of the naked mole-rat which live over 30 years in captivity without any age-related declines.[ref]

What is the difference? Why do some people live 20 or 30 years longer without dying of the chronic diseases of aging (heart disease, diabetes, cancer, Alzheimer’s)?

You may immediately assume that everyone who lives longer did everything right- exercised, meditated, ate the very best diet, etc – but that isn’t necessarily the case. In fact, researchers estimate that about 25% of the variation in lifespan is due to genetics.[ref]

What does it take to live a long, healthy life? Avoiding smoking, not drinking too much alcohol, and not getting cancer are all important for the first 80 years. Beyond that, genetics becomes really important.

Looking at the genetic variants in long-lived humans as well as investigating long-lived animals, like the naked mole-rat, helps us understand what is important for extending healthspan and (perhaps) lifespan.

What can genetics tell us about longevity?

There are several ways to approach health problems:

  • mitigate the symptoms (e.g. take a pill that causes the symptom to go away),
  • figure out what causes the symptoms on a population-wide level (example: epidemiological studies that show excessive soda consumption linked to metabolic syndrome)
  • try to determine the ‘root cause’ by looking at various metabolic pathways (for example: a deficiency in vitamin B12 as one cause of peripheral neuropathy)
  • study the genetic variants in people with the condition – or without the condition – to see which genetic variants actually are at the heart of an issue:
    • focus on known genetic variants that researchers suspect should cause the condition
    • investigate the interaction between specific genetic variants and environmental conditions
    • look at the whole genome of a large population group to see if people with a certain condition have statistically different levels of a genetic variant

The outliers, those centenarians come from all types of backgrounds – different lifestyles, different ways of eating, different environmental factors.

These outliers, though, have common genetic variants that can be determined (with a whole lot of computing power) when you look at genome-wide association studies.

Putting longevity statistics into perspective:

Before we get into the genetic variants that cause a statistical increase in the likelihood of living longer, let’s take a quick look at the baseline numbers.

Someone born a hundred years ago has less than a 1% chance of being alive today. In contrast, if you are female and born in 1973 (46 years old), your odds of living to 100 are 20%. (Here is a nice chart of your odds of living to 100 based on your birth year.)

Keep in mind, though, that these statistics are about the population in general rather than you as an individual. While genetics does play a role in how long you live, there are lots of other health and lifestyle factors that are also important.

Causes of mortality:

Understanding what causes the majority of deaths can also guide us, to some extent, in our understanding of longevity.

In 2018, there were a total of 2.8 million deaths in the US. The 10 leading causes of death in the US are heart disease, cancer, unintentional injuries, lower respiratory diseases, stroke, Alzheimer’s, diabetes, influenza and pneumonia, kidney disease, and suicide.[ref]

What needs to go on at a cellular level for healthy aging?

Studies of centenarians show that their offspring also tend to live longer than their peers – and also have fewer of the diseases of aging. These studies also show that there isn’t just one thing, or a couple of things, that are different for centenarians. Instead, there is a lot of heterogeneity – small differences that affect many different aspects of health.[ref]

Let’s take a look at some of the causes of aging:

Cells in the body accumulate damage and get replaced all the time, at all ages. This is just part of the way that the body works. The cells in your intestines turn over fairly quickly, with a cellular turnover rate of 2-6 days. Fat cells turnover every 8 years. In contrast, most brain cells are never replaced.[ref][ref]

Cells dying, getting cleared out, and replaced need to all work in concert. You don’t want too much cell death, nor out of control growth.

Avoiding cancer: When cells divide, the DNA needs to be copied correctly for the newly created cells. Errors in the DNA copy mechanism occur, and if the errors aren’t corrected, that cell may need to go through apoptosis (cell death).  DNA errors that occur in specific genes are what causes cancer…  Avoiding cancer is important for longevity.  As we age, the odds of DNA errors occurring increase due to various insults such as toxins that cause oxidative stress in the cell.

Telomeres: When DNA is replicated, the end very end of the DNA strand ends up not included in the new cell. To compensate for this, at the end of each chromosome is a region of repeated nucleotides called the telomere which protects the genes from getting cut off during replication. As cells replicate multiple times, the telomeres shorten, eventually getting too short and halting cell division. At this point, the cell goes into senescence and eventually cell death.

Telomere shortening isn’t as straightforward, though, as ‘replicate x number of times and stop’. Telomeres can be lengthened again with an enzyme called telomerase, which is coded for by the TERT gene. Both internal and external stress (toxin exposure) can decrease telomerase.

While it sounds like telomerase is the key to immortality (and it is for some cancer cell lines), telomerase is almost non-existent in certain tissues of the body including the kidneys, blood vessels, liver, skin, and peripheral leukocytes. Genetic variants in the TERT gene (not covered in 23andMe or Ancestry) were recently linked to human longevity.[ref] (Note how well these tissues correspond well to the causes of mortality – cardiovascular disease, kidney disease, immune function).

Metabolism: One way to increase lifespan in lab animals is to decrease calories. Restricting calories works great for short-lived animals, but it doesn’t seem to be effective for humans and other long-lived mammals. But, this does point to metabolism as being intertwined with longevity in some ways.  A couple of the theoretical reasons for why calorie restriction increases lifespan include the changes to IGF1 (insulin-like growth factor 1) and autophagy.[ref]

Longevity and lifespan are often about tradeoffs — those things that are beneficial for initial growth and development can become problematic later in life. IGF1 epitomizes this concept of tradeoffs, at least to some degree.

IGF1 (insulin-like growth factor 1) is synthesized in the liver. The level of growth hormone in the body is one of the main regulators, causing the liver to increase or decrease IGF1 production. IGF1 binds to its receptor on cell membranes throughout different tissues in the body, and this binding activates a bunch of different actions to happen inside of a cell that are mostly related to being pro-growth. Lower levels of IGF1 are linked with extended lifespan in a lot of species, but there is a big tradeoff, at least in humans…IGF1 is really important for cognitive function and brain plasticity.[ref]

Autophagy is the cellular process of cleaning up damaged organelles and recycling cellular waste. It is also important for targeting intracellular microbes and misfolded proteins.[ref]

Alzheimer’s: The genetic variants in the APOE gene increasing the risk of Alzheimer’s have a link to decreased longevity due to death from Alzheimer’s.

Inflammatory response:  Inflammation is important for fighting off a bacterial infection when you get a cut. But the flip side of the inflammatory response is that increased inflammation is also linked with cardiovascular disease, diabetes, and bone fragility. Elevated levels of inflammatory cytokines such as IL-6 are linked with decreased longevity.[ref]

Response to toxins: Genetic variants influence the level by which environmental toxins impact a person. Some of us are more resilient and can metabolize and get rid of various toxicants rather easily. Others may have a variant negatively impacting a detoxification pathway for a certain toxicant — which only matters if the person becomes exposed to that substance.

Genetics research shows links between CYP2B6 variants and longevity. The CYP2B6 enzyme is important in the metabolism of many drugs (including statins) as well as pesticides and insecticides (pyrethroids and DEET). Interestingly, women have higher CYP2B6 levels than men. It could also be that people with altered drug metabolism are statistically more likely to survive cancer and thus influencing longevity statistics.[ref][ref]

Overall, genetics research shows that the following pathways are important for longevity:

  • apoptosis and autophagy
  • nutrient sensing and metabolism
  • tumor suppression
  • regulating growth
  • heart health
  • metabolism of xenobiotics

Next, let’s get into the variants that you can check for with your genetic data.


Genetic variants associated with longevity:

Members: See your data below

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Let’s get more specific here on the genes that have been identified as being important for longevity.

FOXO3 gene: The FOXO3A gene (forkhead box O3 or FOXO3) has links to longevity in several different studies. This gene is believed to regulate apoptosis (cell death) and function as a tumor suppressor. Also, it is involved in nutrient sensing, regulation of IGF1, and the response to oxidative stress.[ref][ref]

Check your genetic data for rs2802292 (23andMe v4, v5; AncestryDNA):

  • G/G: increased odds of living longer (1.5 to 2.75-fold increased odds)[ref][ref] lower blood glucose levels in women[ref]; increased FOXO3[ref]
  • G/T: increased odds of living longer
  • T/T:  typical

Members: Your genotype for rs2802292 is .

Check your genetic data for rs1935949 (23andMe v4, v5; AncestryDNA):

  • A/A: increased longevity for women[ref]
  • A/G: increased longevity for women
  • G/G: typical

Members: Your genotype for rs1935949 is .

Check your genetic data for rs479744 (AncestryDNA only):

  • T/T: somewhat higher probability of increased longevity[ref]
  • G/T: somewhat higher probability of increased longevity
  • G/G: typical

Members: Your genotype for rs479744 is .

IGF1R gene: The IGF1R gene codes for the insulin-like growth factor 1 receptor. IGF1 is a hormone that signals growth and anabolic activities. Growth hormone levels generally fall as we age.

Check your genetic data for rs2229765 (23andMe v4, v5; AncestryDNA):

  • A/A: lower IGF levels, increased longevity[ref][ref]
  • A/G: typical longevity
  • G/G: typical

Members: Your genotype for rs2229765 is .

 

CETP Gene:  Another gene related to longevity is the CETP gene (cholesteryl ester transfer protein) which involves the exchanging of triglycerides with cholesteryl esters. One polymorphism related to longevity is rs5882 (also referred to as I405V). The G allele associates with a somewhat longer lifespan, lower odds of dementia (including Alzheimer’s), and higher HDL levels.[ref]

Check your genetic data for rs5882 (23andMe v4, v5; AncestryDNA):

  • G/G: longer lifespan, higher HDL cholesterol, significantly decreased risk of dementia and Alzheimer’s[ref][ref]
  • A/G:  longer lifespan, higher HDL cholesterol
  • A/A:  typical

Members: Your genotype for rs5882 is .

IMPK gene: The IPMK gene provides the instructions for the inositol polyphosphate multikinase (IMPK) enzyme. IMPK converts inositol triphosphate (IP3) to IP4 and IP4 to IP5, which act as signaling molecules that increase intracellular calcium ions (Ca2+ ). This impacts cell proliferation and mTOR, among other functions. It is also important in the brain in neural plasticity as well as in regulating Toll-like receptors in the immune system. (Note that other variants in this gene not included in 23andMe or AncestryDNA data also have links to longevity.)[ref]

Check your genetic data for rs6481383 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: most common genotype
  • T/T: increased longevity (women only)[ref]

Members: Your genotype for rs6481383 is .

 

TP53 gene: This gene encodes a tumor suppressor protein. With cancer being one of the top causes of death, it is obvious that not getting cancer gives a longevity benefit.

Check your genetic data for rs1042522 (23andMe v4, v5):

  • G/G: increased longevity (possibly due to increased cancer survival)[ref]
  • C/G: slightly increased longevity
  • C/C: typical

Members: Your genotype for rs1042522 is .

 

IL-6 Gene:  Interleukin-6 is an inflammatory cytokine. While inflammation is good when you need to fight off a pathogen, an excessive inflammatory response is detrimental, especially in regards to chronic inflammation.

Check your genetic data for rs2069837 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: increased IL-6 response
  • G/G: increased IL-6 response to inflammatory stimuli; fewer centenarians carry this genotype.[ref][ref]

Members: Your genotype for rs2069837 is .

 

CYP2B6 gene: This gene codes for a phase I detoxification enzyme that is important for the metabolism of various drugs (including cancer drugs) as well as being active in cholesterol synthesis.[ref]

Check your genetic data for rs3745274 (23andMe v4; AncestryDNA):

  • G/G: typical
  • G/T: typical
  • T/T: decreased CYP2B6 enzyme, genotype less likely to be found in elderly, possible longevity disadvantage due to cancer risk or toxicant exposure[ref]

Members: Your genotype for rs3745274 is .

 

COMT gene: The COMT gene codes for a phase II enzyme involved in the metabolism of estrogen, catecholamine neurotransmitters, and more.

Check your genetic data for rs4680 (23andMe v4, v5; AncestryDNA):

  • A/A: genotype more likely to be found in the elderly, possible longevity advantage[ref]
  • A/G: typical longevity
  • G/G: typical longevity

Members: Your genotype for rs4680 is .

What have I left out? 

It’s important to note that not all studies agree on longevity benefits, and other popular genetic reports may include genes that I have chosen to leave out.

For example, I’ve left out AKT1, which is included on other websites’ genetic reports. The minor allele of AKT1 rs3803304 (G allele) was initially linked to a shorter lifespan in some studies.[ref] Other studies, though, failed to replicate the initial studies.[ref]  Similarly, I’ve chosen not to include APOC3 (listed in other genetics reports) because the initial research could not be replicated.[ref]

Why do studies differ? It is likely that environmental factors play a role. For example, a genetic variant important in a Greek population eating a Mediterranean diet may not be important in an African population group eating a different indigenous diet. Likewise, other genetic factors that are common to a population’s heritage may also play a role.


Lifehacks:

Carrying the genes that increase my chance of living to 100 has changed my attitude and way of thinking about getting older.

Important here is not whether you carry the genetic variants linked to longevity, but instead, knowing which biological systems to target for healthspan.

While we can’t (yet) be like the naked-mole rats, there are ways of influencing the genetic pathways linked with longevity.

Diets that increase FOXO3 and/or decrease IGF1:

The Okinawan diet is thought to promote healthy longevity, in part, by affecting FOXO3. The diet focuses on fresh vegetables, fish, lean meats, omega-3 fats, and unrefined carbohydrates.[ref]

Ketosis is theorized to decrease IGF1 and enhance FOXO3. Therefore, it is theorized that a ketogenic diet or intermittent/periodic fasting will increase longevity.[ref][ref]

A study of women with BRCA mutations found that a Mediterranean diet with moderate protein restriction decreased serum IGF1. Researchers theorized that the reduced animal proteins caused the decreased serum IGF-1.[ref] Other studies also back up the fact that protein intake correlates with IGF-1 levels.[ref]

Supplements that increase FOXO3:

Green tea polyphenols (EGCG) have found to increase FOXO3 levels.[ref]

Astaxanthin, naturally found in shrimp, salmon, and red algae can increase FOXO3 levels.[ref] If you aren’t getting enough astaxanthin from your diet, you can get it as a supplement.

Berberine, a supplement, is often used for blood glucose regulation. Research shows that it may enhance FOXO3A.[ref]  You can get berberine as a supplement online or at your local health food store.

Lifestyle hacks for increasing FOXO3:

Heat-shock factor 1 (HSF1) activates due to stress from heat, and HSF, in turn, interconnects with FOXO3 – specifically through a difference in the FOXO3 formation in the rs2802292 G allele. While there aren’t specific human studies on this yet, people with the rs2802292 G allele may benefit more from heat stress such as using a sauna.[ref]

Avoiding toxicants:

We all differ in how well we metabolize and eliminate toxins. Since xenobiotic metabolism links with longevity, people not genetically gifted with getting rid of toxins should try to limit their exposure.

Inhibiting CETP:

The lifelong higher HDL levels in people with CETP variants have links to a statistical increase in lifespan and a decrease in coronary heart disease. This has lead to the idea that inhibiting CETP through drugs may be beneficial both for heart disease and longevity.

Targeting inflammation:

This is a huge topic, but the IL-6 variant linked to inflammation shows how important it is to keep chronic inflammatory cytokine levels low.  Read through the articles in the inflammation topic and check your genes in the inflammation topic summary report (member’s only).

 


Related Genes and Topics:

Telomere Length: How your genes affect telomeres and aging
Telomeres are the region of repeated nucleotides (the A, G, and T’s) that are found on the ends of all of your chromosomes.  They cap off the end of the chromosomes, protecting the nuclear DNA during replication before cell division. Each time a cell divides, it makes a copy of the nuclear DNA and a little bit of the telomere is lost. When DNA replicates, it can’t replicate the very end part of the chromosome, where the telomere is located.

Klotho Gene: Anti-aging superpowers?
I’ve been fascinated by the Klotho gene for a while now, partly because it has a cool name. It is named after one of the Three Fates in Greek mythology who spin the thread of Life. Klotho (or Clotho) was responsible for the thread of life for all mortals, when they were born and when they died. As you will see, this is an aptly named gene that is intertwined with lifespan.

Top 10 Genes to Check in Your Genetic Raw Data
Wondering what is actually important in your genetic data? These 10 genes have important variants with a big impact on health. Check your genes (free article).

 

Originally published: Mar 2015. Revised and updated: April 2020.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.