Genetic Lottery? Some Versions Of FOXO3 Help Extend Lifespan

This story is one of many exploring recent advances in the science of longevity and aging. The following few articles in the series, including this one, will focus on the relationship between genetics and longevity: Which genes are involved in aging and longevity? How are they involved? What are the therapeutic implications?

What does it take to reach your 100th birthday? Surely a whole array of factors: a healthy diet, frequent exercise, a caring community, and financial stability, to name a few. But there’s also something we have little-to-no control over, our genome. That is, the complete set of genetic material that we carry within us. Up to 50% of all variation in lifespan may boil down to sheer luck — whether or not you won the genetic lottery. One of the genes most closely associated with longevity encodes a protein called Forkhead box O3, more commonly known as FOXO3. What follows is an introduction to this gene and an overview of its implications for the science of aging.

What is FOXO3?

FOXO3 is one member of a larger family of Forkhead Box (FOX) proteins. These proteins, although different from one another in subtle ways, share a common feature: they are all “transcription factors”. This means they bind to specific parts of the DNA (deoxyribonucleic acid) present in cells to help regulate which genes are expressed. In brief, by binding to a certain region of DNA, they turn the genes in that area “on” or “off”, like a light switch. DNA regulation is a vital process of cellular function; it helps make sure that the right genes are expressed in the right amounts at the right time.

The FOX proteins are especially well-suited to this task. In fact, the ‘forkhead’ in the name refers to a particular region of the proteins, the fork head domain, specifically designed to recognize and bind DNA, like an open hand ready to grasp.

What Does It Do? 

So, what cellular processes does FOXO3 help regulate? Well, many. But the three most relevant to aging and longevity are apoptosis, autophagy, and metabolism.

Apoptosis is a form of controlled cell death. When cells are damaged beyond the possibility of repair, they need to be broken down, removed, and finally, replaced. This programmed or intentional destruction of damaged cells is called apoptosis. It is also used as an immune strategy during viral challenge, where infected cells will self-destruct in an effort to prevent viral replication and spread. If apoptosis begins to dysfunction, as it does in many cell types with age, damaged cells start to pile up, leading to inflammation and other issues. FOXO3 helps trigger apoptosis by “switching on” genes required for cell death —PUMA and Bim, for example— and “switching off” genes that produce anti-apoptopic proteins, such as FLIP.

Autophagy is closely related to apoptosis — both act as a kind of cellular quality control. Where apoptosis is the controlled breakdown of an entire cell, autophagy is the controlled breakdown of cellular components. A cell that is only somewhat damaged, just the mitochondria, for example, may not need to be replaced entirely; instead, only the components causing trouble need to be removed. Dysfunctional components and misfolded clumps of protein are ferried to special organelles called lysosomes. These subcompartments are highly acidic and contain many different enzymes allowing them to “eat” and “digest” cellular debris and harmful pathogens. FOXO3, and other members of the protein family, is integral to the smooth functioning of autophagy. As before, it achieves this by binding to DNA and regulating genes involved in the process. In one situation, this may require upregulation of autophagy, in another, it may require downregulation. Either way, FOXO3 helps keep the balance.

Finally, FOXO3 also helps modulate metabolic pathways, including those in charge of insulin. At its broadest, metabolism is simply the process through which our body converts food into energy. This energy can then be used by all of our cells to fuel their usual activities and functions. The same goes for our organs and muscles, which are just collections of specific cells. Old age significantly increases the risk of various metabolic disorders such as type 2 diabetes, high blood pressure, and vascular disease. Certain variants of the FOXO3 gene, those most closely associated with longevity, have been shown to improve insulin sensitivity. This means individuals with the gene variant require less insulin to move the same amount of sugar out of their blood than those without the variant, decreasing their risk of developing diabetes. The FOXO3 gene is also intimately linked with vascular homeostasis, and dysregulation of FOXO3 is implicated in numerous vascular disorders.

FOXO3 and Longevity

The discovery of the longevity properties of FOXO3 has its origins in an entirely different part of the animal kingdom: Caenorhabditis elegans (C. elegans), a roundworm often used in the study of aging. In 1988, two scientists uncovered a gene variant in some of the roundworms they were studying that extended lifespan anywhere from 40% to 65% compared to the control group. The gene variant was dubbed age-1. Spurred on by these findings, other researchers began to search for potential mechanisms and pathways by which to explain the increase in lifespan. They soon homed in on the insulin/IGF-1 pathway, which became the first age-related genetic pathway to be discovered.

Fast forward to 2008, a group of researchers at the Pacific Health Research Institute in Hawaii are studying long-lived Japanese-American and Okinawan-American men. They notice that all of the oldest and healthiest individuals carry the human versions —known as homologs— of the longevity genes discovered in model animals like the roundworm. In particular, the long-lived men were far more likely to share similar variants of the FOXO3 gene.

Their findings have since been replicated the world over: from Japan to France to Germany, men and women aged 90 and above, and especially those older than 100, all carry particular longevity-associated variants of the FOXO3 gene.

Boosting FOXO3 Expression? 

Given the intimate link between FOXO3 gene expression and longevity, is there any way of artificially boosting the expression of the gene?

Studies across various organisms like yeast, worms, and mice have provided evidence indicating that restricting calorie intake, a practice known as caloric restriction, possesses the ability to activate FOXO3 and potentially extend lifespan. Caloric restriction induces a metabolic state characterized by enhanced efficiency in utilizing energy and heightened stress resistance, mechanisms speculated to contribute significantly to the observed extension in lifespan.

Similarly, physical activity, particularly endurance training, has been identified as another factor capable of activating FOXO3. Exercise instigates oxidative stress and cellular damage, triggering FOXO3-mediated repair processes. This adaptation to stress through exercise is thought to be a key contributor to the multitude of health benefits associated with regular physical activity.

Researchers are also actively investigating the development of drugs specifically designed to activate FOXO3 directly or indirectly. These pharmaceutical compounds, aiming to mimic the effects of FOXO3 activation, hold potential in therapeutically extending a healthy lifespan and possibly preventing age-related diseases by leveraging the mechanisms associated with FOXO3. Of course, the challenge lies in developing interventions that specifically target FOXO3 without causing adverse effects. Fine-tuning the regulation of FOXO3 activity is crucial, as excessive activation could lead to unintended consequences.


FOXO3 stands out as a key player in the intricate network of genes and cellular processes influencing longevity. While our understanding of FOXO3’s role has advanced significantly, continued research is essential to unravel the full complexity of its interactions and potential applications in promoting healthy aging.

If you’re not one of the lucky few blessed with the longevity-associated variants of the gene, don’t fret. Stimulating FOXO3 expression may provide a similar boost in longevity, and this can be done through means available to almost everyone: exercise and intermittent caloric restriction. And as scientists learn more about FOXO3 and the many pathways it is involved in, pharmaceutical options that mimic the protein may become available.

© William A. Haseltine, PhD. All Rights Reserved.