Can epigenetic reprogramming reverse aging?

Recent review proposes new theory to determine whether epigenetic reprogramming can restore youthful epigenetic information and reverse aging.

The field of aging research has made significant progress over the last three decades, reaching a stage where we now understand the underlying mechanisms of the aging process. Moreover, the knowledge has broadened to include techniques that quantify aging, decelerate its process, as well as sometimes reverse aging.

To date, twelve hallmarks of aging have been identified; these include reduced mitochondrial function, loss of stem cells, increased cellular senescence, telomere shortening, and impaired protein and energy homeostasis. Biomarkers of aging help to understand age-related changes, track the physiological aging process and predict age-related diseases [1].

Longevity.Technology: Biological information is stored in two main ways, the genomes consisting of nucleic acids, and the epigenome, consisting of chemical modifications to the DNA as well as histone proteins. However, biological information can be lost over time as well as disrupted due to cell damage. How can this loss be overcome? In the 1940s, American mathematician and communications engineer Claude Shannon came up with a neat solution to prevent the loss of information in communications, introducing an ‘observer’ that would help to ensure that the original information survives and is transmitted [2]. Can these ideas be applied to aging?

The Information Theory of Aging (ITOA) is formulated based on Shannon’s concepts. ITOA is appealing since unlike ‘somatic mutation theory of aging’, it explains the reason why separate individuals undergo similar aging changes even when they start with unique genomes and accumulate random mutations. ITOA also suggests storehouse of youthful epigenetic information within each cell that helps to restore gene expression for them to regain their cellular identity [3].

A new review in Nature Aging, by Yuancheng Ryan Lu, Xiao Tian and David Sinclair, used the ITOA approach to develop therapies for treating age-related diseases, injuries and aging itself.

Loss of epigenetic information

The somatic mutation theory suggests that aging occurs due to the accumulation of mutations that change the amino acid sequence of genes and proteins. However, recent research indicates that mutations causing epigenetic changes may be primary. Moreover, recent studies highlight that old cells and tissues be epigenetically reprogrammed to a more youthful state without reversing the mutations. This suggests aging has a non-genetic origin.

DNA damage, especially DNA double-strand break (DSB) has been observed to be a driver of epigenetic information loss in mammals and a cause of aging. ‘Silent information regulators’ (SIR2-SIR4) are genes found to control mating and gender in yeasts. One of them, SIR2 is known to mend broken DNA and can also extend the lifespan of yeasts, when overexpressed. Mammalian SIR2 homologs, SIRT1, SIRT7, and SIRT6 have also been observed to move to DNA damage sites to help in repair. However, epigenetic noise is created each time such chromatin modifiers leave their site causing loss of cell identity and senescence. Recent studies have also identified other proteins associated with the age-related loss of genetic information such as the Polycomb repressive complex 2 (PRC2), the REST complex, Wnt, HDAC1, PARP-1, and DNA methyltransferase (DNMT) 1. Such studies have led to ITOA which states that disturbances in the epigenome or ‘epigenetic noise’ play an important role in not only yeast but also multicellular organisms. Similar to antagonistic pleiotropy, ITOA also states that beneficial processes that improve fitness and reproduction in young organisms can disrupt the epigenome and drive aging later in life.

Plasticity of aging and epigenome

Several studies have shown that aging is not only driven epigenetically but also reversible. Four nuclear transcription factors, OCT4, SOX2, KLF4, and MYC (OSKM) were identified by Shinya Yamanaka and his team in 2006. These factors could reprogram somatic cells into induced pluripotent stem cells (iPSCs). These iPSCs possessed an epigenetic age of zero as well as showed rejuvenated characteristics [3].

Expression of the Yamanaka factors along with LIN28 and Nanog was found to reprogram centenarian and senescent fibroblasts into iPSCs into young cell signatures. Such cells were observed to retain their characteristics even after converting back to fibroblasts. This along with other studies indicates epigenetic age has plasticity and can be reset.

Types of epigenetic loss during aging

The epigenome is known to possess a high degree of instability that can further be worsened by environmental factors such as nutrient availability, high degree of instability, and adverse conditions. Along with mutations, epigenetic noise can be introduced in several ways such as transcription factor dysregulation, alteration to chromatin structure, noncoding RNAs, as well as DNA and histone modifications. Such epigenetic noise can in turn impact and accelerate the aging process.

Epigenetic reprogramming to reverse age-related information loss

As per the ITOA, cellular reprogramming is defined as a normal biological process that helps in tissue regeneration following inflammation, aging or injury. Although Yamanaka factors were known to help in epigenetic rejuvenation, they reprogrammed adult somatic cells into iPSCs and caused the epigenome to be set to age zero. However, this led to the complete resetting of the epigenome along with the loss of cellular identity. Transient expression of the factors for a few days was observed to partially reset the epigenome and protect cell identity from being lost. Also, expression of only OSK was found to protect from cell death without causing any negative effects. Rewriting of the DNA methylome was also found to be important for the recovery of epigenetic information from both damaged and old states.

In most cases, the epigenetic reprogramming factors are delivered to tissues via viral vectors. This can however limit widespread rejuvenation across the entire body due to viral infections. In such a scenario, secretory factors and chemicals can be useful since they can reach multiple tissues via the bloodstream more effectively. Small molecules can also be used for reprogramming since they are low-cost, can be delivered easily, and have good cell permeability.

Mechanism of epigenetic rejuvenation

The ITOA states that there is a copy of youthful information stored in every cell, similar to Shannon’s observer. This youthful information can be accessed in aged or damaged adult cells to recover epigenetic information and restore youthful functions. DNA demethylation carried out by DNA glycosylase TDG, DNA demethylases TET1–TET3, as well as DNA methylation by DNMTs has been indicated to play a role in rejuvenation [3]. The pioneer transcription factors OSK(M) are believed to play the role of master regulators that guide the

DNA methylation–demethylation machinery to specific sites in the genome. Moreover, the forms of youthful information storage have been reported to include DNA modifications, DNA–RNA hybrids such as R-loops, histone modifications, and protein–DNA interactions.

In theory…

ITOA makes several predictions but testing those will help to either support or refute the theory. If ITOA is proved to be correct then in vivo epigenetic reprogramming might be able to reverse aging hallmarks. Further studies are required to develop more accurate approaches to rejuvenate the epigenome as well as restore youthful tissue functions.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115486/
[2] https://ieeexplore.ieee.org/document/6773024
[3] https://www.nature.com/articles/s43587-023-00527-6