Do Genes Hold The Secret to Longevity?

Since the launch of the Human Genome Project, there’s been a lot of discussion and analysis on the extent to which our genes and heritability influence our lives.  Nature versus nurture… Just do a Google or AI search, and you’ll see what we mean.

Longevity, Genes and Scientific Discovery

The launch in 1990 of the Human Genome Project initially provided a strong viewpoint that our genes can have a significant influence over most aspects of our lives. This had a powerful impact on the world of behavioral and health sciences. Over time, views, and outcomes have been moderated as scientists gained more knowledge, and additional information has become available.

Once upon a time, the role of genetics was pretty much unknown to the average person. Today, you don’t have to have a master’s degree in genetics to be able to dabble in the world of genealogy. Indeed, anyone with a credit card and access to the internet can go online and pick up a gene test, which will offer a lot of information previously unknown.

Gene tests will tell you where you come from, connect you with long-lost relatives in far-flung parts of the world, and even provide you with a health-risk profile and suggested lifestyle modifications.

Aside from the obvious reasons of getting a better grip on how genes influence your life, at a very basic level, knowing your gene profile and your heritability when it comes to health outcomes may be life-saving.

But what about the concept of a particular longevity gene, or set of genes, that will only give those who have it a superpower for aging? 

The longevity gene

In the last few years, we’ve seen more scientific papers published and a plethora of references available discussing the FOX03 gene and the possibility of a longevity advantage.

The FOXO3 gene

The FOXO3 gene (Forkhead Box O3) is a crucial transcription factor linked to longevity, cell survival, stress resistance and metabolism.

• Function: FOXO proteins are a family of transcription factors that act as key regulators of longevity in various organisms, from worms to mammals, downstream of the insulin and insulin-like growth factor signaling pathways. In humans, there are four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6.
• Role in Aging: The FOXO3 gene is a major gene associated with human longevity. It’s involved in crucial cellular processes such as DNA repair, metabolism, cell cycle arrest, and resistance to oxidative stress.
• Gene Variant: Everyone has the FOXO3 gene, but only about one-third of the population has the specific “longevity version” (polymorphism) associated with living a longer, healthier life and reduced risk of age-related diseases. 

A master regulator

The FOXO3  acts as a master regulator for genes involved in oxidative stress, DNA repair, and autophagy. Its variants are strongly associated with exceptional human lifespan, and it plays key roles in aging-related diseases by managing cellular stress responses, making it a significant target for anti-aging research and medicine. 

Luigi Ferrucci, scientific director at the US National Institute on Aging, explains how the children of centenarians typically live healthier, longer lives than their peers. “It’s probably not one single gene, but a profile, a combination of genes,” 

Age Later

Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City, has studied the lives of hundreds of centenarians, the people they’ve married, and their children.  He says the children of centenarians are “about 10 years healthier” than their peers.

Dr. Barzilai  is a pioneer in the study of centenarians and the author of the book Age Later. Through the Longevity Genes Project, his team has studied the genetic makeup of over 500 healthy elderly people (ages 95 to 112) and their offspring to understand the genetic factors contributing to exceptional longevity and protection against age-related diseases. 

Key Findings

Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine

Barzilai and his colleagues are launching a platform where individuals can upload information from a genetic-testing service to discover whether they have genes linked to “exceptional longevity”. Those with a particular mutation on their growth hormone, for example, are likely to live longer, since their cells focus increased energy on maintaining existing cells, instead of growing new ones. 

Barzilai’s group aims to enroll 10,000 centenarians and their children against a control group from the general population in identifying the specific genes that play a role in living longer.

“We really want to find all the longevity genes,” Barzilai says.

The power of a FOXO3 gene

Then there’s Professor Bradley Willcox and his co-researcher, Professor Richard Allsop, who’ve been working on the FOX03 gene impact on longevity out of their center in Hawaii. Willcox is a professor and director of research in the Department of Geriatric Medicine at the John A Burns School of Medicine at the University of Hawaii. He’s also a principal investigator of the NIH-funded Kuakini Hawaii Lifespan and Healthspan Studies and co-principal investigator of the Okinawa Centenarian Study. Allsop is his longstanding co-contributor on many of the scientific papers published. 

These scientists are firm proponents of the role of the FOX03 gene in longevity. They say the longevity version of the FOXO3 gene is fundamental to a robust response to cellular stress that occurs throughout life. And that the effect of the FOXO3 gene on cell resilience likely explains the protection provided to at-risk older individuals. They’ve published several papers in peer-reviewed publications.

Living Beyond 100

Studies of humans who live to be 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3).

Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine in New York, and her colleagues were led by these findings and used them to investigate how this gene contributes to brain health during aging. The investigators revealed that FOX03 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment supports the new cells’ arrival. 

There are also some whole-genome sequencing studies of super-centenarians that have identified the same gene variants that increase disease risk in people with average life spans. The super-centenarians, however, also had many other newly identified gene variants that possibly promote longevity. 

Genes matter as you get older

Scientists speculate that, for the first seven or eight decades, lifestyle was a stronger determinant of health and lifespan than genetics. Eating well, not drinking too much alcohol, avoiding tobacco, and staying physically active enable some individuals to attain a healthy old age. Genetics then appears to play a progressively more important role in keeping individuals healthy as they age into their 80s and beyond. Many nonagenarians and centenarians can live independently and avoid age-related diseases until the very last years of their life.

Lessons from the super-centenarians

Ferrucci says researchers have found that healthy older adults tend to remain physically active, spend time outside, and have strong connections with their friends and family.

And, Justice adds, a good public-health system “can’t be undersold”. If you have a better healthcare system, you’re going to have a higher life expectancy, she says.

Still, Ferrucci suggests centenarians, and especially super-centenarians, are often “unique”. Some people have this “biological resilience” to live a long life, despite everything going against them.

“There’s a curve of mortality that characterizes the general population, and then there are these individuals that are unique singularities,” Ferrucci says. “We don’t know how, and that is the great secret.”

In closing

For the rest of us, the concept of a longevity gene, or set of genes, may not be of too much interest right now. Maybe a Netflix documentary will change that. But until it does, the longevity gene theory will remain confined to the laboratories of esteemed universities and the scientific congresses.

As Willcox stated in his PubMed report, “The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FOXO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FOXO3, its gene, and proteins in the pathway(s) FOXO3 regulates should be encouraged and supported.”

The future will be gene mapped for us

It’s not inconceivable that, one day, in the not-too-distant future, we may well wake up to a world where we can buy the test over the internet. Find out whether we have that silver bullet for aging or not… Imagine that.

In the meantime there are ways you can support your genes for longevity

• Many compounds, including resveratrol, metformin, quercetin, and omega-3 fatty acids, are known to activate FOXO3.
• Activating FOXO3 is a strategy for promoting healthy aging and treating age-related conditions by boosting the body’s internal defense mechanisms. 

Can you change your longevity even if you haven’t won the gene lottery?

Many researchers believe we can materially change our longevity outcomes by making better lifestyle  choices. According to Jamie Justice, an assistant professor of gerontology at Wake Forest University in the US, research indicates that genetics accounts for around just 25% of longevity. The other 75% is down to your environment: where you grew up and spend your life, your diet and exercise routine, and your support system.

“The goal isn’t necessarily to live to 118 years. It’s to live well within those years,” Justice says. “What individual things can we do that we can really harness our health and live healthier within the years we’re given?”

Don’t just rely on going with the flow, no matter how healthy you think you are. Take charge of your healthspan. Create your own longevity plan, manage and update the plan and extend your health span no matter if you haven’t won the genetic lottery.

Create your own Longevity Toolkit

We have written a post which provides some easy to implement tools to achieve a better health span.

How to Create Your Own Longevity Toolkit

Editor’s note

This article first appeared in our themed annual printed magazine format issue, Living Beyond 100, also available in digital format for download.  This magazine edition is packed with content themed on Living Beyond 100, and one of the articles explores the idea of ‘longevity genes’ and whether being blessed with these genes will translate to a more successful career, marriage, and even a longer and better life.

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