Reviewing the State of Knowledge of Age-Related Epigenetic Change
The field of aging research has always been more interested in changes in gene expression that can be connected to age-related decline and disease than in deeper causes of aging that might be behind those gene expression changes. Altered gene expression is driven by epigenetics. Epigenetic regulatory systems, such as DNA methylation of sites on the genome, alter the pace at which specific proteins are manufactured from their genetic blueprints. Epigenomic alterations are dynamic, responsive to the environment and changes in cell state. It is a highly complex system, understood at the high level, but far from completely mapped in all of its fine details.
Two technologies have led to a greatly increased interest in the epigenetics of aging. Firstly, there are the epigenetic clocks, produced by analysis of epigenomic data in search of patterns that correlate with age. These clocks show a strong correlation with chronological age, as well as some ability to reflect biological age, in that a higher clock age than chronological age indicates an increased risk of mortality and age-related disease. Secondly, reprogramming cells via exposure to Yamanaka factors not only produces induced pluripotent stem cells, but also reverses a sizable fraction of age-related epigenetic change. Even partial reprogramming, a short exposure to reprogramming factors insufficient to change a somatic cell into a stem cell, produces this epigenetic rejuvenation.
The hope here is that there is a path to both a class of rejuvenation therapies that force cells in aged tissues into more youthful behavior, as well as tools that can rapidly assess the performance of any rejuvenation therapy via its effect on epigenetic patterns. While the path such reprogramming therapies could be rapid given a healthy appetite for risk, a great deal of work remains on the more conservative, usual road to clinical development and adoption. Large-scale funding is now devoted to this path, given the advent of Altos Labs, and we shall have to see how it progresses.
As of the year 2021, aging is considered both an intriguing process that research attempts to understand and a universal burden that the scientific community and the industry seek to intervene with. Currently, various theories have been put forward as to how we age, which physical alterations occur during aging and how we could substantially increase healthy life span or even maximal life span. In 2013, a comprehensive review proposed a detailed framework incorporating nine hallmarks of aging to characterize this complex process. These hallmarks comprise epigenetic alterations, telomere attrition, genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, deregulated nutrient sensing, and altered intercellular communication. Intriguingly, these attributes are highly interconnected. Here, we will focus on age-related epigenetic alterations and how targeting the epigenetic landscape might enable extension of life span.
Underlying epigenetic mechanisms such as histone modifications and DNA methylation were discovered at the end of the 20th century and now have a well-established role in the regulation of gene expression. In general, histones are bound to DNA in order to compact it to accommodate the size of the nucleus. This DNA-histone interaction is dynamic. The modifications of the tail domain of histones by small molecules can alter the interaction between the DNA and histone thus changing the accessibility of that specific genomic area.
Here, we present recent findings on epigenetic changes involving histone modifications and DNA methylation during aging and age-associated maladies such as neurodegeneration and cancer. In this regard, we also outline the emergence of DNA methylation clocks to determine biological aging. We will cover the utility of epigenetic signatures as biomarkers and the physiological implications of respective alterations. Age-associated metabolic dysregulation, which could underlie epigenetic changes, and other risk factors for age acceleration, will be described before we finally explore therapeutic interventions aiming to prevent age-associated maladies and to increase healthy life span including the emerging field of cellular reprogramming.