Review-Key Symposium

The definition of aging remains a subject of debate, but it generally involves the dysregulation of biological mechanisms. Lifespan, healthspan, and longevity are distinct phenotypes with varying definitions. Healthspan, the number of years lived in good health, is crucial, as current increases in lifespan are not matched by increases in healthspan, leading to a burden on healthcare systems. Studying exceptionally healthy, long-lived individuals offers insights into promoting healthy aging. Longevity is considered heritable, and genetic studies of long-lived individuals may uncover mechanisms for healthspan extension. This review examines shared mechanisms between humans and model organisms to understand longevity genetics.

Studies on long-lived families demonstrate the heritability of longevity, although estimates vary (10-30%). The selection criteria for long-lived individuals in genetic studies significantly affect results. The top 10% of survivors in a birth cohort with additional family members meeting the same criteria provides a refined selection method. Different longevity scores exist, but their broad applicability needs further research.

Genetic studies of longevity have evolved from hypothesis-driven candidate gene approaches to more unbiased genome-wide association studies (GWAS) and whole-genome sequencing. Candidate gene studies, focusing on genes previously linked to lifespan regulation or age-related diseases, identified associations with APOE and FOXO3 loci. Pathway-based studies investigated the IIS, mTOR, DNA damage repair, and telomere maintenance pathways, revealing associations with longevity. Linkage studies, identifying chromosomal regions co-segregating in long-lived families, had limited success due to smaller sample sizes. GWAS identified APOE variants but struggled to replicate other findings due to limited sample size and control cohort issues. Polygenic score analysis showed depletion of Alzheimer's disease-associated variants in long-lived individuals. In vitro functional characterization has been performed on common variants in APOE and FOXO3, as well as rare variants in IGF1R and SIRT6, demonstrating causal relationships in some instances. In vivo studies are underway to validate additional findings.

Despite a significant increase in genetic studies over the past decades, only APOE and FOXO3 have consistently shown strong associations with human longevity. The lack of additional consistently replicated genes suggests that longevity is influenced by numerous rare variants with small effects. Pathway analysis integrating data from humans and model organisms (mice, fruit flies, nematodes) revealed five consistently associated pathways: (1) insulin/IGF-1 signaling (IIS), (2) DNA damage response and repair, (3) immune function, (4) cholesterol metabolism (APOE), and (5) telomere maintenance. Comparative genomic studies of mammals with varying lifespans further support the importance of these pathways. The IIS pathway is a particularly promising target for further investigation due to its involvement in multiple longevity-associated genes.

The findings highlight the complexity of longevity genetics, emphasizing the potential role of numerous rare variants with small effects acting synergistically. Current study limitations, including limited sample sizes and challenges in obtaining appropriate control cohorts, hinder the identification of additional longevity-associated variants. The consistent identification of several pathways across different study designs and organisms strengthens the validity of the findings. The limitations of current approaches necessitate a shift toward functional characterization of rare variants in selected candidate genes within the identified pathways.

Five major pathways consistently linked to longevity across human and model organism studies are: IIS, DNA damage response and repair, immune function, cholesterol metabolism, and telomere maintenance. Future research should focus on functional characterization of rare genetic variants in these pathways to establish causality and elucidate underlying molecular mechanisms. Combining bioinformatic and experimental approaches will be crucial for advancing our understanding of longevity and developing interventions.

The review's analysis might be biased due to the overrepresentation of well-studied genes and pathways. Human longevity studies are limited by small sample sizes, the difficulty of obtaining appropriate control groups, and population diversity. Model organism studies may not fully translate to human aging due to species-specific differences. The absence of comprehensive omics data for many human cohorts limits the depth of analysis.