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Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.
Before delving into the genetic aspects of longevity, let’s briefly review two of the most well-studied biological pathways in aging research, which will emphasize the immense value of understanding the underlying genetics.
Insulin and Insulin-like Growth Factor-1 (IGF-1) are both hormones crucial for regulating metabolism and growth in the body. Insulin controls blood glucose levels by helping cells absorb sugar from the bloodstream. IGF-1 promotes cell growth and development – mainly in the bones and muscles. While they have distinct functions, insulin and IGF-1 share signaling pathways and can influence similar processes. These processes include cell proliferation, nutrient uptake, and aging. Studies of model organisms show that reducing insulin/IGF-1 signaling has been linked to extended lifespan.
A 2022 study examined the link between ginger extract and lifespan in the roundworm (C.elegans). The main active compounds (gingerol and shogaol) helped improve movement and reduce the buildup of the aging pigment lipofuscin, indicating healthier aging. Genetic testing confirmed that these effects played out using the insulin/IGF-1 pathway
In a 2024 experiment, again, on the roundworm, researchers focussed on lin-35, the worm version of RBL1/RBL2 genes in humans that are thought to confer protection against tumors.
Throughout history, humans have been fascinated by the prospects of increasing lifespan and maintaining good health as they age. Today, modern science seeks to discover both genetic and environmental factors that influence healthy aging, aiming to improve not only how long people live but also the quality of their later years.
Research indicates that aging is a complex and multifactorial process, involving genetic predispositions, the cellular accumulation of damage, and lifestyle determinants such as nutrition, physical activity, and stress management.
Promoting longevity is not solely about living to older ages; it is about ensuring that the years lived are healthy, functional, and meaningful. Scientists and healthcare professionals increasingly recognize the concept of “healthspan” the portion of life spent in good health as a more comprehensive measure of aging than lifespan alone.
Continued research into the mechanisms of aging, coupled with public health initiatives and individual lifestyle choices, holds promise for delaying the onset of many age-related conditions, thereby improving quality of life and potentially enabling people to remain active and independent well into advanced age.
Longevity is a very broad topic. In this article, we will unravel the link between longevity and a gene dubbed the “longevity gene” in the scientific community – FOXO3.
Before delving into the genetic aspects of longevity, let’s briefly review two of the most well-studied biological pathways in aging research, which will emphasize the immense value of understanding the underlying genetics.
Insulin and Insulin-like Growth Factor-1 (IGF-1) are both hormones crucial for regulating metabolism and growth in the body. Insulin controls blood glucose levels by helping cells absorb sugar from the bloodstream. IGF-1 promotes cell growth and development – mainly in the bones and muscles. While they have distinct functions, insulin and IGF-1 share signaling pathways and can influence similar processes. These processes include cell proliferation, nutrient uptake, and aging. Studies of model organisms show that reducing insulin/IGF-1 signaling has been linked to extended lifespan.
A 2022 study examined the link between ginger extract and lifespan in the roundworm (C.elegans). The main active compounds (gingerol and shogaol) helped improve movement and reduce the buildup of the aging pigment lipofuscin, indicating healthier aging. Genetic testing confirmed that these effects played out using the insulin/IGF-1 pathway
In a 2024 experiment, again, on the roundworm, researchers focussed on lin-35, the worm version of RBL1/RBL2 genes in humans that are thought to confer protection against tumors.
mTOR stands for mammalian (mechanistic) Target of Rapamycin. It is a protein switch in the cell that helps it grow and respond to nutrients. When food is plentiful, mTOR triggers the production of proteins and other materials, driving cell growth and division.
If nutrients are low, mTOR activity drops, allowing the cell to focus on repair and maintenance rather than growth. mTOR is the pathway cited when improving longevity using methods like caloric restriction or the rapamycin drug. Caloric restriction is considered the most robust way to downregulate mTOR signaling.
In a 2023 study, researchers analyzed 72 genes from the mTOR network in 48 different mammals. They discovered 20 genes showing distinct evolutionary signals in long-lived species. Many of these genes relate to autophagy (PRKCB, WDR24, NPRL3, and LAMTOR2), aging-related diseases, and cancer, suggesting that long-lived mammals might have developed specialized ways to regulate autophagy and prevent tumor growth.
TOR inhibitors are compounds that reduce or block the activity of the Target of Rapamycin (TOR). Rapamycin is one of the most famous TOR inhibitors, and studies show that its use extends the lifespan in several model organisms.
The results of a new pre-print published very recently elaborated on a specialized yeast-based platform that is far more sensitive to compounds inhibiting the TOR/mTOR pathway. This system provides a cost-effective, rapid way to identify new TOR inhibitors, which could lead to promising treatments for aging and cancer.
Scientists have identified numerous genes involved in aging processes, from the insulin/IGF-1 signaling pathway to genes that regulate DNA repair, stress resistance, and metabolism. Variants in these genes can lengthen or shorten lifespans in organisms ranging from worms and flies to mice and humans.
Of these, the FOXO3 is one of the most well-researched. Numerous articles have studied and uncovered a direct genetic link between FOXO3 and different aspects of aging, like telomere length, vascular health, and response to oxidative stress. Let’s examine each of these effects through the lens of current research.
The FOXO3 gene is part of the forkhead box O (FOXO) family of transcription factors, which regulate the activity of other genes involved in cell repair, stress resistance, and metabolism. Transcription factors are special cellular proteins that help turn genes “on” or “off.” They do this by attaching themselves to specific parts of DNA and then either helping or blocking the machinery that reads those genes.
When activated, FOXO3 can switch on protective pathways that help cells cope with oxidative damage, support DNA repair, and encourage the cleanup of harmful proteins or organelles. Because these processes influence how cells age and respond to stress, variations in the FOXO3 gene have been repeatedly linked to extended lifespan in both animal studies and human populations. In humans, specific variants of FOXO3 have been found more frequently in individuals who live to very advanced ages, highlighting its importance in longevity research.
A 2020 paper detailed the effects of different FOXO3 polymorphisms on the FOXO3 gene expression and mortality risk in men with cardiometabolic conditions. Using a cell line assay with cells that have not been subjected to any stress, the authors have shown that the cells with the GT genotype of rs2802292 SNP produce more FOXO3 protein than cells with the TT genotype. Further, when the cells were exposed to oxidative stress, FOXO3 levels jumped in both genotypes, but rose three times higher in cells with the GT than TT genotype. This suggests that the rs2802292 GT version (often called the “longevity haplotype”) is better prepared to handle stress due to the presence of the G-allele.
Also read: The Genetics of Resilience
The same article also details an interesting connection between FOXO3 and vascular health. FOXO3 protein helps maintain healthy blood vessels. As we age, another regulatory protein called FOXA2 actively suppresses the effect of FOXO3, thereby weakening the blood vessels. However, individuals who have the beneficial variant of rs768023 (a SNP strongly linked to rs2802292) in their FOXO3 gene have a genetic loophole. In individuals carrying this particular variant of the FOXO3 gene, the suppressive FOXA2 protein cannot effectively bind to the resulting FOXO3 protein. As a result, FOXO3 expression remains elevated, providing enhanced protection against oxidative stress.
The rs2802292 SNP of the FOXO3 gene was also a significant factor in another longevity study conducted in the Indonesian population. The study, published in 2024, showed that among the Indonesian elderly, the G-allele frequency of rs2802292 was notably higher in those who had reached advanced ages.
Further, the rs2802292 G-allele showed protection against telomere shortening and increased telomerase activity in Japanese adults aged 55 years and older per a 2024 study. These G-allele carriers also demonstrated slightly higher FOXO3 mRNA expression.
In a 2022 gene–environment interaction study, researchers analyzed data from 3,085 older adults to see how genetic variations in the FOXO3 gene, and whether a person lives in an urban or rural setting, affect mortality. The results showed that participants carrying two copies of the “minor” allele in three FOXO3 SNPs (rs4946936, rs2802292, rs2253310) had lower mortality risks. The study thus highlights that genetic predisposition to longevity and the characteristics of one’s living environment both play a significant, interlinked role in how long people live.
Healthspan is the portion of a person’s life spent in good health and free from chronic diseases or disabilities, rather than just how long they live. Understanding FOXO3, a gene closely linked to longevity in a wide range of species, can shed light on how to extend healthspan and lifespan.
We saw from the preceding sections that when the amount of FOXO3 protein is increased, cells become more resilient to damage, which may help reduce the onset or severity of age-related diseases.
Insights into how FOXO3 operates, such as how genetic variants enhance its protective effects, can guide the development of interventions (lifestyle changes, medications, or other therapies) aimed at increasing the number of years we spend in robust health.
These findings highlight the importance of evolutionarily conserved pathways that directly affect how cells cope with stress, maintain genomic integrity, and control energy expenditure. As research uncovers more about how specific genetic variants influence aging, a growing field of “geroscience” seeks to harness these insights to develop targeted therapies.
The overarching aim is not merely to add years to life but to extend a healthy lifespan, potentially postponing or mitigating many age-related conditions. By targeting genes and their signaling networks, scientists hope to tailor interventions—ranging from small molecules to diet and lifestyle modifications—that support healthy aging on a personalized basis.
Longevity research seeks not only to extend lifespan but also to improve healthspan, the years lived in good health, and it focuses on both genetic and biological factors—like FOXO3, insulin/IGF-1, and mTOR—and environmental influences. Studies in model organisms (worms, yeast, and mammals) have shown that reducing insulin/IGF-1 signaling or inhibiting mTOR can extend life, with interventions such as caloric restriction, rapamycin, or compounds identified through yeast-based platforms. FOXO3, in particular, emerges as a key “longevity gene” in humans and other species: certain variants (e.g., rs2802292, rs768023, rs4946936, rs2253310) correlate with stress resistance, preserved telomere length, and improved vascular health. These variants often maintain higher FOXO3 levels, helping cells repair damage, regulate metabolism, and curb inflammation. In addition, living environments, urban vs. rural, interact with genetic predispositions to further influence mortality risks. By understanding how FOXO3 and similar pathways operate, researchers hope to tailor lifestyle and therapeutic strategies that bolster healthy aging.
