Genetics of human longevity: From variants to genes to pathways

Abstract

The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity‐associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin‐like growth factor 1 signalling, (2) DNA‐damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways.

Genetik, Epigenetik und Umweltfaktoren der Lebenserwartung – Welche Rolle spielt Nature-versus-Nurture beim Altern?

“…Ein Gen, für das der Zusammenhang mit Langlebigkeit in vielen unabhängigen Studien repliziert wurde, ist APOE , das für Apolipoprotein E (Apo-E) codiert [ 3 , 16 ]. Apo‑E ist ein Strukturbestandteil von Lipoproteinen, die für den Transport von Cholesterin und Triglyceriden im Blut zuständig sind.…”

“…Neben APOE konnte in genetischen Studien auch für das FOXO3 -Gen eine Verbindung zur Langlebigkeit reproduzierbar nachgewiesen werden [ 3 , 16 , 19 , 20 ]. Der durch FOXO3 codierte Transkriptionsfaktor ist Teil eines evolutionär konservierten Regulationsnetzwerks, das durch Insulin und den insulinähnlichen Wachstumsfaktor 1 gesteuert wird und dessen Aktivität negativ mit der Lebensspanne korreliert [ 1 , 2 ].…”

Genetic, Environmental, and Stochastic Components of Lifespan Variability: The Drosophila Paradigm

“…According to Perls et al, siblings of long-lived individuals are 17 and 8 times more likely, respectively, to reach the same age than the population average [112]. This means that human longevity may be associated with genetic variants that are rare in the population [113][114][115], although variants that are common in the population are also important for longevity [116,117].…”

The role of longevity-related genetic variant interactions as predictors of survival after 85 years of age

“…Since the world is facing ageing of the global population, with the proportion of elderly expected to almost double by 2050 ( World Health Organization, 2023 ), the importance of research on this topic has never been greater. Most basic ageing mechanisms and candidate genes that affect them were discovered in model organisms ( Antebi, 2007 ), but many retain the same function in humans due to high conservation of those genes among species ( Smulders and Deelen, 2023 ). Research into these mechanisms is essential for a better understanding of what drives the ageing process, as well as for discovering the factors that contribute to successful ageing and longevity.…”

“…Age is a major risk factor for developing age-related chronic conditions ( Niccoli and Partridge, 2012 , Dillin et al, 2014 , Hou et al, 2019 ), which is why genes modulating the risk for chronic disease have also been studied as candidate genes for longevity. The most well-known example is the APOE gene – associated with the risk for cardiovascular diseases ( Eichner et al, 1993 , Wilson et al, 1994 , Bennet et al, 2007 ) and Alzheimer’s disease ( Zuo et al, 2006 , Farrer et al, 1997 ) – which was first identified in candidate gene studies and later confirmed in genome-wide association studies (GWAS) as the most important genetic factor influencing longevity ( Smulders and Deelen, 2023 ).…”