Gene-Environment Interactions and Stochastic Variations in the Gero-Exposome.

The limited heritability of human life spans suggests an important role for gene-environment (G × E) interactions across the life span (T), from gametes to geronts. Multilevel G × E × T interactions of aging phenotypes are conceptualized in the Gero-Exposome as Exogenous and Endogenous domains. Stochastic variations in the Endogenous domain contribute to the diversity of aging phenotypes, shown for the diversity of inbred Caenorhabditis elegans life spans in the same culture environment, and for variegated gene expression of somatic cells in nematodes and mammals. These phenotypic complexities can be analyzed as 3-way interactions of gene, environment, and stochastic variations, the Tripartite Phenotype of Aging. Single-cell analyses provide tools to explore this broadening frontier of biogerontology.