Longevity 101: Reversing Epigenetic Alterations
An overview of what you’ll learn from this blog post:
What epigenetic alterations are
How epigenetic alterations happen
What cellular reprogramming is
What are epigenetic alterations?
As we get older changes to our gene expression happen, these are known as epigenetic alterations. These harm the function and behavior of our cells and can increase the risk of cancer and other age-related diseases. Epigenetic alterations are one of the nine proposed reasons we age.
A good example of this is how epigenetic alterations can change the behavior of the immune system. These changes can prevent activation and suppress immune cell response, leaving us vulnerable to invading pathogens. This is partly the reason why older people have less robust immune systems and are at greater risk from viral and bacterial infections.
So, how do these epigenetic alterations happen in the first place? There are four main ways these changes occur:
Changes to DNA methylation patterns - Modifies which genes are expressed or silenced which can cause harmful alterations to cell function and behavior.
Histone modification - Changes how tightly DNA is packed into the nucleus and helps condense it into chromatin. More histone expression supports longevity.
Transcriptional alterations - A variance in gene expression leading to increasingly harmful influence over cellular function.
Remodeling of chromatin - Alteration to the DNA support structure which helps or hinders gene expression.
Rewinding the aging clock
A proposed solution to these harmful changes is partial cellular reprogramming. In simple terms, this means exposing aged cells to reprogramming factors that can reset a cell's epigenetic state from that of an old cell to that of a young one. These reprogramming factors are called Yamanaka factors, after their discoverer Dr. Shinya Yamanaka.
The tricky part is exposing the cells to these factors just long enough to reset the epigenetic state that determines if they are young or old, but not too long so they forget what kinds of cells they are.
Overexposure means the cells become pluripotent, essentially becoming stem cells which can become any other cell type in the body. This full reprogramming is great when you need to create lots of cells of one kind but not useful when the goal is to reverse cellular aging in people. Overexposure also carries the risk of cancer.
Partial cellular reprogramming seems to be a way that we can have our cake and eat it. The challenge currently is to work out how to partially reprogram all our cells at once without overexposure to the factors and loss of cell identity or cancer.
But can it be done in living animals?
The good news is it has been shown that it is possible to partially reprogram cells in living animals in this way. In 2016 Professor Juan Carlos Izpisua Belmonte and his research team at the Salk Institute reported that they had successfully rejuvenated the cells and organs of mice using partial reprogramming.
The researchers used a type of mouse that ages faster than normal as well as normally aging mice. Both types of mice were modified so that they expressed Yamanaka factors when exposed to an antibiotic called doxycycline in their drinking water.
The researchers included doxycycline in the water for two days which turned on the Yamanaka factors and started reprogramming the cells. Then they halted doxycycline treatment giving the mice a 5 day rest period before they resumed treatment for another 2 days. This cycle of 2 days doxycycline and 5 days rest continued for the duration of the study.
It took just 6 weeks of this to gradually reprogram the cells of both types of mice. The researchers reported the mice had improved appearance including a reduction of spinal curvature, a common feature in aged mice. Treatment also appeared to improve tissue regeneration in the normally aging mouse group.
The researchers also compared the skin, kidneys, stomachs, and spleens of both mouse groups with an untreated control group. Amazingly, the treated mice had a number of aging markers halted or even reversed! This reversal also included some of the epigenetic changes that had happened as part of the aging process.
While this did not stop or reverse all aspects of aging in the animals and those that were resumed if treatment stopped, these initial results confirmed that reprogramming could be achieved in living animals.
Another step closer
In October 2020 another important step was taken, when researchers reported that partial cellular reprogramming improved memory in old mice. It also confirmed what the previous 2016 study showed, that it was possible to activate reprogramming factors transiently to reset the age of cells without erasing their identities.
Just like the previous study, the mice were engineered to express Yamanaka factors in the presence of doxycycline. During a four-month period, the researchers transiently exposed the mice to the programming factors. This periodic exposure was enough to improve their cognitive function without increasing any increase in mortality.
In late 2020, a team of researchers, including Dr. David Sinclair, reported that they had successfully restored lost vision to old mice and mice with damaged retinal nerves. They achieved this using just three of the four Yamanaka Factors.
Finally, in January 2021, researchers showed that partial cellular reprogramming rejuvenates human cells so they become functionally age 25 again. The interesting thing was this happened with cells aged 40 as well as 60 with both settling on a biological age around 25. This suggests that there is a sweet spot for optimal cell age and cells favor it when being reprogrammed, regardless of their original age.
The race is now on to refine and develop safer partial reprogramming that can be translated to humans.
A number of companies including Turn.bio, AgeX, Iduna Therapeutics, and Altos Labs are all developing partial cellular reprogramming. When this technology will be available is hard to say, though at least a decade or so seems likely given its highly novel nature and its potential to change how we age.
It’s never too late to start thinking about healthy longevity
In a future article, we will be taking a look at how you can start to develop your own personal longevity strategy and some simple changes you can make that could potentially help you maintain your health as you age.