Review Aging: Somatic Mutations, Epigenetic Drift and Gene Dosage Imbalance Reiner A. Veitia, *,1 Diddahally R. Govindaraju, 2,3 Samuel Bottani, 4 and James A. Birchler 5 Aging involves a progressive decline of metabolic function and an increased incidence of late-onset degenerative disorders and cancer. To a large extent, these processes are influenced by alterations affecting the integrity of genome architecture and, ultimately, its phenotypic expression. Despite the progress made towards establishing causal links between genomic and epigenomic changes and aging, mechanisms underlying metabolic dysregulation and age-related phenotypes remain obscure. Here, we present a model linking genome-wide changes and their age-related phenotypic consequences via the alteration of macromolecular complexes and cellular networks. This approach may provide a better understanding of the dynamically changing genome–phenome map with age, but also deeper insights to developing more targeted therapies to prevent and/or manage late-onset degenerative disorders as well as decelerate aging. Facts and Theories of Aging The aging process is a universal property of most organisms, accompanied by a subtle, progressive, and often irreversible decline of physiological and reproductive functions. In principle, this process starts shortly after the formation of the zygote and continues over various stages throughout the lifespan of the individual [1]. Both intrinsic and extrinsic factors affect genome integrity both in somatic and reproductive tissues over time [2]. A recent review has enumerated nine tentative hallmarks of aging that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis (increased protein synthesis and decreased degradation) (see Glossary), deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [3]. Age-associated genomic changes, which are[4_TD$DIFF] discussed in detail below, can lead to a general dysregulation of genome architecture, accessibility and expression [3–5]. Moreover, such somatic genomic changes that accumulate in tissues and organs, interact with inherited variation [6,7], and cumulatively or synergistically influence healthspan and lifespan. Mutations are responsible for genetic variation that results in evolutionary change. While a large number of these mutations are benign, a fraction of them profoundly affect all aspects of survival and reproduction of cells and organisms, and hence their fitness [8]. Somatic tissues also acquire genomic alterations, which could lead to both genetic [6] and epigenetic loads. These alterations are often cell specific and show cumulative or synergistic effects with the classical mutation load (i.e., inherited) of an individual or more broadly of a population. As argued below, somatic alterations may affect the relationship between genotype–phenotype, and as such, perturb the function of biochemical networks and macromolecular complexes with age [4,9]. Trends Aging is a progressive phenomenon influenced by genetic and epigenetic alterations in interaction with the environment. The aging process is characterized by nine hallmarks that bear consequences at the molecular, cellular, tissue, and organismal levels. A perturbation of the crosstalk within the triangle genome, epigenome and macromolecular complexes may explain several hallmarks of aging. Experimental and clinical interventions can modulate aging and increase either lifespan or healthy aging. 1 Institute Jacques Monod, Paris, France and Université Paris Diderot, Paris, France 2 Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA 3 Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA 4 Laboratory Complex Systems and Matter, Université Paris Diderot, Paris, France 5 Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA *Correspondence: reiner.veitia@ijm.fr (R.A. Veitia). TICB 1304 No. of Pages 12 Trends in Cell Biology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tcb.2016.11.006 1 © 2016 Elsevier Ltd. All rights reserved.