The information theory of aging suggests that aging results from the accumulation of errors in an organism’s genetic code over its lifespan. The theory proposes that, as cells divide and replicate, their genetic information is subject to errors such as mutations or epigenetic changes. These errors can accumulate over time, leading to a decline in the functioning of cells, tissues, and organs, that ultimately results in aging. The theory also suggests that aging may be a form of “error catastrophe” in which the accumulation of errors in the genetic code reaches a critical point, leading to a decline in the overall functioning of the organism. However, it has been reported that genetic mutations are not as catastrophic as predicted. What might be of greater importance is the maintenance of molecular modifications residing on the surface of DNA. These epigenetic modifications act as an additional layer of genetic control and are vitally important for such things as cellular development, maintaining the specific character of specialized cell types.

Epigenetic modifications include DNA methylation, histone modification, and non-coding RNA molecules. These can be passed down from one cell generation to the next and play a crucial role in development, as well as in disease and aging.

Dr. David Sinclair et al. have published work describing both the importance of maintaining epigenetic fidelity and a means to reverse the loss of epigenetic information (Yang JH, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023;186(2):305-326.e27).

The Epigenome and How It Drives Aging

A common metaphor used to describe the relationship between the epigenome and DNA is that of a conductor and a musical score. Just as a conductor has the ability to interpret and control the performance of a musical piece, the epigenome controls the expression of the underlying DNA sequence. If the musical score is perfectly intact yet the conductor is impaired, then the execution of the piece deteriorates and potentially fails.

The epigenetic landscape is a dynamic and changing pattern of chemical modifications to DNA and its associated proteins that regulate gene expression. To understand the dynamics of the epigenome, consider the concept of the Waddington landscape, a visual representation of the process of cellular differentiation and development, named after the British developmental biologist Conrad Waddington.

The Waddington landscape is depicted as a multi-dimensional terrain, with different points representing different developmental outcomes. According to Waddington, cells move along valleys on the landscape as they differentiate into the necessary specialized cells, and the final developmental fate of a cell is determined by the particular valley it ends up in. The hills and valleys of the landscape represent the stability of different cell states. A hill represents the stability in maintaining correct developmental outcomes; a degraded hill allows for an environment in which a cell might easily switch between different cell states. The epigenome comprises this landscape of hypothetical hills and valleys, defining the nature of individual cells and holding them to that fate.

With increasing age, cells fail to maintain the fidelity of their epigenome, a phenomenon known as epigenetic drift. The causes of this perturbation to the epigenome are not fully understood. Ironically, one suspected cause is a mechanism for repairing damaged DNA, specifically the severing of both strands comprising DNA’s double helix structure. It is thought that subsequent to repair, the epigenetic modifiers at these double-strand breaks are lost or relocated. Over time these repairs can significantly alter the epigenetic landscape, resulting in a loss of cellular identity and systemic cellular dysfunction. In their recent paper, the Sinclair group demonstrated the validity of this through the development of a system in mice that induces double-strand breaks, the result of which is a phenotype of accelerated aging. Importantly, the double-strand breaks and the subsequent repairs do not result in mutations to the genetic sequence but do alter the epigenetic modifiers at these locations, demonstrating that the acceleration of aging in these animals is a result of epigenetic and not genetic alterations.

Yamanaka Factors—Reversing Aging Through Restoration of the Epigenome

The Yamanaka factors are a set of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) that were discovered by the Nobel Prize-winning researcher Shinya Yamanaka. These factors have the ability to reprogram mature cells by resetting the epigenetic marks on DNA and its associated proteins, such as histones, to a more embryonic-like state. This resetting of the epigenome results in changes in gene expression, allowing cells to become pluripotent and capable of differentiating into any cell type. Although the mechanism through which these factors restore the epigenetic landscape is not fully understood, their utilization can reverse the effects of epigenetic dysregulation seen in aging. Numerous recent studies have leveraged the utility of these factors to delay aging or, in some cases, to rejuvenate specific tissues and organ systems.

In an attempt to repair the accelerated aging observed in mice as a result of the induced epigenomic changes, Sinclair et al. forced the expression of select Yamanaka factors, Oct4, Sox2, and Klf4. In doing so, the epigenetic marks of these mice were restored to a youthful state consistent with mice that had not been subjected to the epigenetic disruption caused by double-strand breaks.

This study provides strong evidence that the progression of aging is driven by the cell’s reaction to DNA damage and the subsequent loss of epigenetic information, not by the introduction of mutations. This is consistent with aging following a predictable sequence of molecular and physiological changes, even though DNA damage can occur randomly in the genome. Importantly, these results bring greater clarity and understanding to the molecular drivers of aging and will aid in the pursuit of therapies to combat aging and its associated diseases.

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