A novel approach to aging – epigenetics and cellular variability

Cellular stochasticity and epigenetic drift in aging can not only provide Longevity targets but also give a deeper understanding of the origins of cancer.

Current theories of aging are based strongly on the accumulation of random genetic mutations, and with good reason; however, many aging phenomena remain unexplained, so what is science missing?

Longevity.Technology: Previously epigenetic links to aging have been explained as casual, yet Jean-Pascal Capp and Frédéric Thomas reconsider this [1]. While genetics focuses on genes encoded in DNA, epigenetics allows gene expression control through chemical tags, such as histone and DNA methylation. With age, an epigenetic drift occurs, where stochastic – a fancy word for random – methylation events lead to a diverging epigenome.

A diverging epigenome is one of the factors leading to more variability between cells, correlated to both in aging and cancer. The Landau group in the Dana-Farber Cancer Institute in Boston, found that highly methylated promoters in chronic lymphocytic leukaemia leads to high cell-to-cell expression of the corresponding gene [2]. This supports the argument that epigenetic methylation correlates more than casually to cellular variation.

DNA damage has many causes, but nature has developed intricate biological repair systems to mend the breakage or remove the affected cells. With age, these restoration machines falter, leading to a cause for further epigenomic variation. These epimutations deviate from the template for healthy gene expression, resulting in aging and cancer phenotypes.

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging
Illustration of adherent mammalian cells. Source: Toulouse Biotechnology Institute, Bio & Chemical Engineering

Other factors affecting cell heterogeneity include cell identity and tissue type. It has been found that different tissues and organs age at a different rate. It is proposed that this is in fact an evolutionary adaptation, whereby organs with a higher risk of cancer age more slowly, thus decreasing cell variation and probability of cancer.

This, along with cell-to-cell variation and origins of cancer can potentially be explained by Thomas and Capp’s novel aging theory – Tissue Disruption-induced cellular Stochasticity (TiDiS). As cells develop, they tend towards homogeneity through differentiation.

Chromatin is epigenetically programmed to become less accessible, leaving only genes that need to be expressed for the specific cell type. Yet with natural epigenomic variation, some cells regain their stem-like properties.

Most cells return to their specialised form by taking cues from their environment in order to maximise nutrition resource allocation and to achieve optimal proliferation. Some cells lose the ability to do so, failing to set up cellular interactions crucial for differentiation and thus become cancerous stem cells (CSC) – key in TiDiS. Interestingly, this theory doesn’t require a faulty genetic framework, which may explain why an oncogenic event does not necessarily develop into a malignant cancer.

“More research with cell-to-cell interactions and epigenetic markers must be conducted for solid therapeutic applications…”

Parallels between cancer and aging have been outlined in numerous reviews [3]. However, here we find a hypothesis of how cellular variation due to age can lead to stochastic changes increasing cancer risk. More research with cell-to-cell interactions and epigenetic markers must be conducted for solid therapeutic applications.

Single-cell analyses can reveal cellular interactions, while more systemic analyses can reveal ligand-receptor pairs without the need for previous knowledge. Fluorescent microscopy can further provide understanding of localisation of key biomarkers for aging. Diseased and healthy aging tissues must be studied and compared, yet samples of the later are hard to come by.

What Thomas’ team illustrate is an undeniable link between epigenetic stochasticity and cellular interactions with Longevity and cancer. Longevity and age-related diseases are in need of a deeper understanding of underlying mechanisms – a new direction focusing on cell heterogeneity and stochasticity may just be the answer to a therapeutic approach to aging and cancer.

[1] https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.202000140
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302418/
[3] https://go.nature.com/35ICwbF

Image courtesy of: Toulouse Biotechnology Institute, Bio & Chemical Engineering