Protein levels are the controlling switches and dials of cellular behavior, and most are very dynamic in response to circumstances. One important set of circumstances is the damage that accumulates over the course of aging. Cells react to that damage with epigenetic changes, chemical decorations to DNA that alter the pace of production of various proteins. In some cases this helps to compensate for damage, in others it makes things worse. This open access paper reviews what is known of age-related epigenetic alterations:
Aging is characterized by progressive functional decline at the molecular, cellular, tissue, and organismal levels. As an organism ages, it becomes frail, its susceptibility to disease increases, and its probability of dying rises. In humans, age is the primary risk factor for a panoply of diseases including neurodegeneration, cardiovascular disease, diabetes, osteoporosis, and cancer. Over the past decades, a large body of research has shown that the molecular and cellular decline of aging can be organized into several evolutionarily conserved hallmarks or pillars of aging. For example, in yeast and animals, mitochondrial dysfunction increases with age and may contribute to the progression of aging. The hallmarks of aging are interconnected, and age-associated perturbations of one can affect others. While significant progress has been made in our understanding of aging, many outstanding questions remain: Which age-associated changes are causative? How are the hallmarks of aging related to each other, and are there "hubs" in this network? Which age-dependent changes occur first? When does aging begin? Can therapeutics slow aging or even rejuvenate some aging hallmarks in an animal at any stage during lifespan, or is there a "point of no return"?
The study of gene regulation is central to many of these questions. The regulation of gene expression is not only necessary for nearly every aspect of a cell's function, but it can be sufficient to alter cellular fate. While it is clear that many biological systems and hallmarks play a crucial role in the progression of aging, we propose that epigenomic changes are particularly important because of the following: (1) Changes in gene regulation (often through expression of a single transcription factor) have been shown to be key for cellular identity. Thus, age-associated changes in transcription regulatory networks are likely to impact the function of a cell or tissue and give rise to aging phenotypes and diseases. (2) Gene regulation is a natural "hub" in the cell. Transcription regulators and chromatin modifiers receive cytoplasmic and extracellular signals and, in turn, alter the responses of the cell in an orchestrated manner. For example, in response to proteostatic stress, protein chaperone expression increases. (3) Chromatin marks are long lasting and show a progressive change with age that persists through cellular divisions. Thus, they can act as a memory that helps to propagate age-associated cellular dysfunction. (4) Recent evidence suggests that epigenomic changes can occur extremely early in the aging process and be causative.