The quest for genetic determinants of human longevity: challenges and insights

Abstract

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

Figure 1. Large variation in lifespan within a birth cohort

The distribution of age at death is shown for a twentieth century Western population that did not experience any world wars — the Swedish female 1900 birth cohort. Data are from The Human Mortality Database.

Figure 2. Some of the molecular pathways that lengthen lifespan in Caenorhabditis elegans and the corresponding components in humans

The C. elegans insulin–IGF-1 (insulin-like growth factor 1) like signal-transduction pathway is shown on the left, and human homologues of the proteins that are involved are shown on the right. This pathway involves a cascade of phosphorylation events that ultimately regulate the nuclear translocation of DAF-16 (REF. 10). INS-N is an unknown insulin-like peptide, and DAF-2 is its cell-surface receptor, which has tyrosine kinase activity. AGE-1 encodes a phosphatidylinositol 3-kinase (PI3K). IP3 is phosphatidylinositol-3,4,5-trisphosphate (for simplicity, it is shown here as part of the pathway, although it is actually a membrane component), which is produced as a result of AGE-1 activity and activates PDK-1. PTEN is a phosphatase with IP3 substrate activity and suppresses AGE-1. PDK-1 is an IP3-dependent kinase that activates AKT-1, AKT-2 and SGK-1, which are serine/threonine kinases. DAF-16 is a forkhead class transcription factor that is homologous to the FOXO class of human transcription factors, and is probably orthologous to human FOXO3A. The target of rapamycin (TOR), JNK and RAS pathways also feed into the insulin-like signalling pathway at the level of DAF-16 regulation. TOR is a kinase that responds to intracellular amino acids, especially leucine, among other activities; RAS and JNK are involved in numerous signal-transduction cascades in mammals. Numerous other genes in which mutations lead to life extension in C. elegans (for example, sir-2 and mitochondrial genes) are not shown.

Figure 3. Epidemiological evidence for a genetic component to variation in human lifespan. a

Similarity in lifespan for monozygotic and dizygotic Danish twins of the same sex from cohorts born between 1870 and 1900 and who survived to at least the age of 6. Each dot in the graphs represents a twin pair. The pattern indicates that approximately one-quarter of the variation in lifespan can be attributed to genetic factors. Data are from REF. . b. Similarity in longevity between siblings in a US population. The relative chance of survival until the age of 60–94 for siblings of centenarians versus siblings of individuals who died at 73 years of age.

Figure 4. The frequencies of apolipoprotein E alleles vary with age

Frequencies of the three common apolipoprotein E (APOE) alleles — E2, E3 and E4 — are shown, taken from data in 13 published studies. Each line connects the frequencies in various age-groups within a given population. Reproduced with permission from REF. © (2000) Wiley-Liss.