Epigenetic Mechanism May Promote Healthy Aging

Aging is one of life’s inevitable processes, and has been a hot topic for scientific research over the last few years. As we know, aging has many epigenetic factors, and can be affected by a number of different things like depression, bipolar disorder, and menopause. Generally, aging results in negative health effects due to the decreasing ability for the body to repair damage done to tissues and DNA over time.

But Dr. Baris Tursun from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin hopes to find a way to prevent the damaging effects of aging. “We all want to age in a healthy manner,” said Dr. Tursun. “Once we understand the links between aging and all the accompanying detrimental effects, then we can begin to think about how to unlink them.”

So how do you identify which genes have an impact on aging? Scientists start with model organisms like the nematode Caenorhabditis elegans (C. Elegans), which have been widely characterized in labs, are easy to breed in a laboratory setting and closely parallel humans in known ways—such as C. elegans’ at least 83% homology with the human genome.

One common approach is to knock out genes that code for specific proteins and characterize the resulting effects, shedding light on that protein’s function. Dr. Tursun and his team knocked out LIN-53 in C. elegans, knowing that it is an epigenetic factor.

LIN-53 is a histone chaperone, which is a specific type of histone modification that facilitates histone orientation so that gene expression can either be activated or deactivated. But Dr. Tursun wanted to know if LIN-53 had effects on lifespan or even quality of life.

“Usually when we age, we experience aging symptoms accompanied by muscle loss,” Dr. Tursun notes. “Is this all coincidence or is it linked, and if so, how it is linked? Our paper is one of the first to show an epigenetic link.”

Knocking out LIN-53 affected both lifespan and quality of life, since knockout worms lived shorter lives with reduced mobility. This gave Tursun and his team the green light to dig into LIN-53 further. It turns out that this protein is involved in several different molecular complexes that all affect the structure and modification of chromatin.

There were two main complexes that emerged as being responsible for the physical effects Dr. Tursun and his team observed. Through the NuRD complex, LIN-53 affects the development of muscles, which is why in knockout worms there was a change in mobility. Imaging of these knockout nematodes showed that their muscle fibers were irregular. Through the Sin3 complex, LIN-53 affects lifespan, with knockout nematodes dying five days sooner than their healthy counterparts.

Although further study is needed, Dr. Tursun and his team started to learn a bit more about the function of LIN-53 when they observed that knockouts had low amounts of trehalose, which is needed for regulating lifespan in invertebrates.

Understanding how LIN-53 affects Sin3 and inhibits the production of this sugar, as well as how LIN-53 specifically interacts with the NuRD complex to produce irregular muscle fibers, are both next steps for the team’s research; but detection of the association between genes and molecular complexes is a significant milestone. 

And so, epigenetics strikes again—without directly changing the genetic sequence, epigenetic factors affect the way in which DNA is translated into proteins, altering the function of the cells to the point of reducing the nematode’s mobility and shortening its life. Working to extend this understanding and find the ways in which these effects observed in model organisms are paralleled in humans will be critical to the treatment and even prevention of disease.

Source: Tursun, B. et al. (2019). The conserved histone chaperone LIN‐53 is required for normal lifespan and maintenance of muscle integrity in Caenorhabditis elegans Aging Cell 17(2).

Reference: Max Delbrück Center for Molecular Medicine (MDC) A genetic chaperone for healthy aging?. MDC Press Releases 07 Aug 2019. Web.