What are the key genetic and epigenetic determinants of longevity?

Longevity – length of life – is influenced by a complex interplay of genetic, environmental, and epigenetic factors. As the global population ages, understanding the determinants of longevity has become a central focus in the fields of genetics and precision medicine. We’ve recently been having some very interesting discussions around aging on The Genetics Podcast – so here, we explore the key genetic and epigenetic factors that contribute to human lifespan and highlight their potential impact on health outcomes as we age.

Genetic determinants of longevity

Genetic variation plays a significant role in determining how long we live. While environmental factors like diet, exercise, and healthcare access are of course crucial, genes account for about 20-30% of the variation in lifespan across individuals. Several genes have been implicated in longevity, many of which are involved in key biological processes such as metabolism, DNA repair, and immune function. A few include:

• FOXO3: One of the most well-known genes associated with longevity is FOXO3, a member of the Forkhead box O (FOXO) family of transcription factors. Studies have consistently shown that variants of FOXO3 are linked to increased lifespan across multiple populations . This gene influences processes like oxidative stress resistance, inflammation regulation, and cell cycle control, which are critical for maintaining cellular health.
• SIRT1: Another important player is SIRT1, part of the sirtuin family of proteins that regulate cellular aging processes. SIRT1 promotes DNA repair, regulates stress responses, and modulates metabolic pathways. It is thought to mimic the effects of caloric restriction, a well-known intervention that has been shown to extend lifespan in several species.
• APOE: The APOE gene, specifically the APOE E4 variant, has been linked to an increased risk of Alzheimer’s disease and shorter lifespan. Conversely, individuals with the E2 allele appear to have longer lifespans and a lower risk of neurodegenerative diseases . Understanding how different variants of APOE contribute to longevity could lead to new therapies aimed at delaying age-related cognitive decline.

Epigenetic determinants of longevity

While genetic factors set the stage, epigenetics—the modifications to gene expression that do not involve changes to the DNA sequence—plays a crucial role in how genes associated with aging are expressed over time. Epigenetic changes are influenced by various factors, including environment, lifestyle, and even stress levels. Two of the major epigenetic mechanisms that influence longevity are DNA methylation and histone modification.

• DNA methylation: This process involves the addition of a methyl group to DNA, which typically silences gene expression. DNA methylation patterns change significantly as we age, and these alterations are considered reliable markers of biological aging. The "epigenetic clock," developed by Steve Horvath, is a tool that uses DNA methylation patterns to predict biological age, often more accurately than chronological age. Slower epigenetic aging, as measured by this clock, has been associated with longer lifespans.
• Histone modification: Histones are proteins around which DNA is wound, and modifications to histones can either promote or inhibit gene expression. Acetylation and methylation of histones are the two best studied modifications; as we age, the balance of these modifications shifts, leading to changes in gene expression that can contribute to cellular aging.

Interplay of genetics and epigenetics in longevity

The interaction between genetic and epigenetic factors is critical in determining lifespan. For example, individuals with favorable longevity-associated genes may still be at risk for age-related diseases if they are exposed to adverse environmental or lifestyle factors that negatively impact their epigenome. Conversely, epigenetic modifications can sometimes counterbalance the effects of genetic predispositions, offering potential avenues for therapeutic interventions to extend healthspan and delay the onset of age-related diseases.

By continuing to study how these determinants work together, researchers can uncover new strategies for promoting healthy aging and extending lifespan. For clinical research and precision medicine, the integration of genetic and epigenetic data holds the potential to create tailored interventions that target aging at the molecular level, helping more people live longer, healthier lives.

To learn more, we recommend the following recent episodes of The Genetics Podcast: 

• Cracking the biological code of aging with Martin Borch Jensen, Co-Founder and Chief Scientific Officer at Gordian Biotechnology
• Understanding cell aging and its role in disease with Marco Quarta, Co-founder and CEO of Rubedo Life Sciences
• The biology of aging with Austin Argentieri, Research Fellow at Harvard Medical School, Affiliate Member of the Broad Institute, and Research Fellow at Massachusetts General Hospital