Unraveling genetic origin of aging-related traits: evolving concepts

Abstract

Discovering the genetic origin of aging-related traits could greatly advance strategies aiming to extend health span. The results of genome-wide association studies (GWAS) addressing this problem are controversial, and new genetic concepts have been fostered to advance the progress in the field. A limitation of GWAS and new genetic concepts is that they do not thoroughly address specifics of aging-related traits. Integration of theoretical concepts in genetics and aging research with empirical evidence from different disciplines highlights the conceptual problems in studies of genetic origin of aging-related traits. To address these problems, novel approaches of systemic nature are required. These approaches should adopt the non-deterministic nature of linkage of genes with aging-related traits and, consequently, reinforce research strategies for improving our understanding of mechanisms shaping genetic effects on these traits. Investigation of mechanisms will help determine conditions that activate specific genetic variants or profiles and explore to what extent these conditions that shape genetic effects are conserved across human lives and generations.

FIG. 1.

The role of genes in aging-related traits: Deterministic and dynamic concepts. Currently prevailing strategies traditionally consider genetic susceptibility to aging-related traits in framework of a concept of heritability. This concept assumes that a phenotype (P) can be represented as an additive superposition of genetic (G) and environmental (E) effects (A). Linkage of genes to a phenotype within this concept is implicitly assumed to be of deterministic nature. This concept, however, was developed for reproduction-related phenotypes used in breeding experiments with plants and referred to “the genetic contribution to variance within a population and in a specific environment.” Extension of this concept to aging-related human traits is, therefore, at best problematic because of: (1) Lack of directly programmed deterministic mechanisms linking genes with those traits and (2) uncontrolled changes in environmental exposures for humans. Given these constraints, B illustrates the dynamic concept when the effects of genes on aging-related traits have to be inevitably shaped by aging-related processes (senescence) in dynamic environment. The role of environment in this concept is through activation of genes at different periods of life and modulation of gene actions over the life course and across generations. Color images available online at www.liebertpub.com/rej

FIG. 2.

Conceptual hypotheses of structure of linkage of genes (G) with aging-related traits (D). (A) The basic concept, known as the common disease–common variants (CDCV) hypothesis, adopts linear structure when few genes can influence a given trait. (B) The CDCV hypothesis becomes discouraging whereas the risk hypothesis is strengthened; the risk hypothesis emphasizes the concept of polygenicity (many genes–one phenotype). (C) Recognition of fundamental role of pleiotropy (one gene–multiple phenotypes) in aging-related traits implies that the pleiotropy concept should complement the concept of polygenicity. (D) Superposition of these two concepts constitutes qualitative transition from the linear structure to the net structure formalized as the diseasome. (E) Recognition of the dynamic concept of genetic susceptibility to aging-related traits (Fig 1B) leads to the concept of the dynamic diseasome.