Aging Reversal by Epigenetic Reprograming

Written by A. Hammouda: Aging reversal was successful by epigenetic reprograming, according to a recent Cell article. This article summarizes the results of years of research on the epigenetic biological clock. It emphasizes the validity of the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

How do epigenetic changes relate to aging or aging reversal?

Epigenetic changes include changes of histone proteins and methylation of specific cytosine bases, which alters how the nuclear DNA is folded. There is no change of the genetic code, but with altering DNA folding, epigenetic factors regulate which genes are active or inactive in any given cell at any given time.

By acting as a toggle for gene activity, these epigenetic changes help define cell type and function. Since each cell in an organism has basically the same DNA, it is the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell, etc.

Epigenetics is like a cell’s operating system, telling it how to use the same genetic material differently. With the same genetic material, body cells can function properly, or their function may deteriorate in a process of aging. Restoring the proper function is the hopeful aging reversal.

What did the researchers do for aging reversal?

The team developed a system called “ICE” (inducible changes to the epigenome). They created temporary, fast-healing cuts in the DNA of lab mice, not within the coding regions of DNA. The breaks altered the way DNA is folded. Epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. This advanced aging at physiological, cognitive, and molecular levels, seen as advancement of the DNA methylation clock.

Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they had caused, like rebooting a malfunctioning computer. The therapy delivered a trio of genes — Oct4, Sox2, and Klf4, together named OSK — that are active in stem cells and can help rewind mature cells to an earlier state. The researchers already used this cocktail to restore sight in blind mice in 2020.

By OSK-mediated rejuvenation, the ICE mice’s organs and tissues resumed a youthful state, a permanent reset. How exactly OSK treatment achieved that remains unclear.

What did the researchers conclude about OSK-mediated aging reversal?

The discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state. By manipulating the epigenome, aging can be driven forwards and backwards.

Implications of the Study

The ICE method offers researchers a new way to explore the role of epigenetics in aging and other biological processes. The findings will transform the way we view the process of aging and the way we approach the treatment of diseases associated with aging. The work points to new avenues that focus on epigenetics rather than genetics to prevent or treat age-related damage.

First, the results need to be replicated in larger mammals and in humans. Studies in nonhuman primates are currently underway.

The work will hopefully inspire other scientists to study how to control aging to prevent and eliminate age-related diseases and conditions in humans, such as cardiovascular disease, type 2 diabetes, neurodegeneration, and frailty.

Imagine taking someone old or sick and making their whole body or a specific organ young again, so the disease goes away. It’s not how we typically do medicine.

Sources:

Loss of epigenetic information as a cause of mammalian aging.

Loss of Epigenetic Information Can Drive Aging, Restoration Can Reverse It.

Reversing Aging: Is It Possible?

Exclusive Conversation with Geneticist & Harvard Professor David Sinclair