A 13-Year-Long Study Identifies Fountain of Youth Using Gene Therapy

On January 12th, 2023, a groundbreaking study was published that changes the way we think about aging. If you believe aging to be an inevitable evolutionary course of action and the title of this page to be shameless clickbait, the summary of this new publication may shift your perspective.

This pioneering publication is the result of various experiments that have been conducted over the past decade. It represents a major milestone that changes the way scientists will design studies on aging research, and may also aid in the development of a uniform approach to treating age-related diseases.

Summary

The authors of this paper used a well-crafted, evocative metaphor to outline the key findings of this relatively complex publication:

• The genome of mammals can be considered our biological hardware.
• The epigenome can be thought of as our software. It does not impact the hardware but rather affects the way we utilize our hardware.
• Until now, we thought that a breakdown in hardware (i.e., DNA damage) is the main cause of aging.
• The results of this study’s experiments suggest the opposite. The software seems to be to drive the biological aging process.
• The researchers corrupted the lab mice’s software while ensuring their hardware remained unaffected. An accelerated aging process was observed. A ground-breaking discovery!

But it gets even better:

• In addition, they used gene therapy to restore the mice’s software to an earlier, more youthful state.
• They don’t know this worked, but it did, and this suggests that the cells of mice maintain a backup copy of their software.
• If their software gets corrupted due to natural aging processes, we can simply restore their youthfulness using the cell’s backup copy.

Overall, this is exciting news, as fixing our software is much easier than repairing or replacing the hardware.

Glossary

To get the most out of our study summary further below, we recommend familiarizing yourself with the following terms:

Background of the Study

This international study, titled Loss of epigenetic information as a cause of mammalian aging, was 13 years in the making and finally published on January 12th in the Cell Journal. It was authored by an international team, including David Sinclair, a professor of genetics from Harvard Medical School who is renowned for his groundbreaking research into aging and supplements NMN with a daily dose of 1 gram. The publication details numerous experiments that have been conducted to identify the causes of aging on a molecular level.

What supplements does Dr. Sinclair take? Read his longevity routine

Previous Findings and the RCM-Hypothesis

• Researchers have previously linked aging to double-stranded DNA breaks, which happen in around 10 to 50 cells a day.
• In recent times, however, there have been questions about whether DNA mutations are actually the primary driver of aging. Multiple findings suggested there may be more to the story.
  • Various types of older cells were found to have very few mutations, and some mice or people have not been found to age prematurely.
  • In addition, the results from yeast studies from 1997 indicated that loss of epigenetic information, rather than genetic, may potentially cause aging.
  • Subsequently, epigenetic changes were also correlated with aging in animals such as flies, worm,s and naked mole rats.

This lead Dr. Sinclair and his team to create the “RMC (Relocalization of Chromatin Modifiers)-hypothesis.

The RCM hypothesis presumes that aging in animal cells is the result of the loss epigenetic information and transcriptional networks over time. The underlying mechanism that causes this evolved to co-regulate our response to cellular damages like double-stranded DNA breaks (DSBs).

How ICE Tests the RCM Hypothesis

To test this hypothesis, the researchers developed methods that allowed them to first degrade and then reset the epigenetic information both in vitro (in cells) and in vivo (in mice).

The most important experiment consisted of creating temporary cuts in the lab mice’s DNA. These breaks were designed to mimic the low-grade breaks in chromosomes that happen in our cells and the cells of these mice on a daily basis over time in response to exposure to sunlight, chemicals, cosmic rays, and other environmental factors.

Remember that they want to test how epigenetic changes affect aging, so these breaks were designed to only change the epigenome, so they were not done within the coding region of the mice’s DNA to prevent gene mutations (i.e., non-mutagenic cuts)

The newly developed method for these intentional chromosomal breaks was called the ICE system. The test subjects were appropriately nicknamed ICE mice.

So, if the RCM hypothesis is correct, these mutagenic cuts should speed up the epigenetic aging of the ICE mice and also speed up other age-associated characteristics when compared to their close relatives (the control group that wasn’t subjected to any breaks).

What Happened After the Mice Suffered These Breaks?

At first, their behavior, level of activity, and consumption of food did not differ when compared to the negative controls. After suffering a break, the epigenetic factors simply shifted their focus from regulating genes to coordinating the repairs in the DNA breaks. After the break was repaired, they returned to their old job of regulating genes.

However, after 1 month of ICE, some changes started to take place. The ICE mice developed hair loss and lost pigments on their nose, ears, feet, and tail. These physiological changes are typically associated with middle-aged mice.

After 10 months, the ICE mice also lost body weight, had a lower respiratory exchange ratio, and had less motion in the dark phase. All of these are typical characteristics indicating old age in mice. The findings under the microscope were consistent with these observations: the researchers noticed that the aforementioned epigenetic factors did not revert back to their job after repairing DNA breaks. This resulted in chaos and malfunction within the epigenome.

While we can already be quite sure that the ICE mice did, in fact, age faster. The researchers went one step further and used a tool developed by their lab, which allowed them to measure the biological age of the mice. The DNA methylation clock can be used on cells, tissues, or organisms. The biological age of the ICE mice was significantly higher compared to the untreated negative controls.

To sum it up, the experiment showed that the non-mutagenic DNA breaks in mice, which imitate DNA breaks during everyday life:

• Speed up aging as indicated by physiological changes, such as hair loss, loss of pigmentation, lower body weight, lower motion during dark phases and a lower RER (respiratory exchange ratio).
• Sped-up aging as defined by the DNA methylation clock that measures age biologically and not chronologically.
• Negatively affected the epigenetic landscape when epigenetic factors did not return to DNA regulation after regulating repairs of induced DNA breaks.

These results support the assumptions made by the RCM hypothesis.

image from CellPress

Rejuvenation of ICE Mice

However, at this point, the researchers could not yet be certain that DNA mutations did not cause these effects. To rule out this possibility, they had to reset the epigenome in both in vivo and in vitro experiments.

To conduct this “gene therapy” to restore the epigenome, they administered three genes known as Oct4, Sox2, and Klf4. The trio is referred to as OSK. These genes are normally switched on during embryonic development and are naturally present in stem cells. They help mature cells return to a more youthful state.

Fun fact: In 2020, Sinclair’s lab was able to restore vision in blind lab mice using these three genes

The Results of this Gene Therapy

The ICE mice’s tissues, and organs, were successfully restored into an earlier state associated with youthfulness.  We don’t yet know how OSK-based gene therapy achieves this, but all we know is that it works. We also know that a backup is required to restore data. Since the backup cannot be inside the OSK genes, it has to be within the mammalian cells of the ICE mice. In other words: The cells of mice contain a potential fountain of youth, and we found a way to tap into it!

The Takeaways

The researcher’s extensive sets of experiments confirm that the main cause of aging is not DNA changes. Instead, aging seems to be fueled by changes to the structure of chromatin, which is an epigenetic factor that is responsible for forming chromosomes.

For anti-aging researchers, these new findings are extremely uplifting and exciting because the manipulation of molecules that control epigenetic factors is much easier than the reversal of DNA mutations. The study showed that we could precisely control the age of mice. We can speed it up, slow it down, or reverse it as we wish.

The publication further showed that the mammalian cells of mice save a backup copy of their epigenetic information. Using three genes known as OSK, the epigenome was restored to a youthful status using this backup copy.

Would ICE and OSK Gene Therapy Work in Humans?

Lab mice share many similarities with humans in terms of genetics, and physiology. However, there are also significant differences between the two species that need to be taken into account when interpreting the results of preclinical studies.

One major difference is that mice have a much shorter lifespan than humans, which can affect the development and progression of certain diseases. Additionally, the size and organization of certain organs, such as the brain, can be different between the two species.

Despite these differences, many of the cellular and molecular processes that occur in mice are also present in humans, making them useful models for studying human diseases. Since humans and mice are very similar at a cellular level (both are mammalian cells), it is likely that human cells also have backup copies of their epigenome.

Moving Forward

The ICE method is a major milestone for anti-aging research. Future experiments on the epigenome of mice will likely be more cost- and time-efficient, since ICE mice enter “old age” after only six months instead of the usual 1.5 to 2 years.

Further experiments should be conducted to determine how OSK gene therapy induces the remarkable “rejuvenation program” observed in mice. Perhaps other, more efficient ways of restoring the epigenetic backup can be identified.

The researchers hope that this publication will not only inspire scientists to further learn how to control our biological age but also to prevent diseases and conditions associated with mature age, such as type 2 diabetes, neurodegenerative diseases, and cardiovascular disease (the no. 1 killer in most countries).

A compelling human trial on NMN supplementation: continue reading this promissing study on NMN.