Reversing Age-Related Decline in Mice Livers

Researchers from Bar-Ilan University, along with the US National Institute on Aging and Tel Aviv University, have discovered a way to counteract significant signs of age-related liver decline in older mice by enhancing levels of SIRT6, a protein associated with longevity.

The findings, which went through a peer-review process, were published in Nature Communications. This research hints that the biological alterations connected to aging may be more reversible than we previously thought.

Employing advanced tools to examine DNA structure and gauge gene activity in real-time, the team focused on older mice that received additional SIRT6. This protein helps silence genes linked to inflammation and aging.

According to Prof. Haim Cohen, the head of the Sagol Healthy Human Longevity Center at Bar-Ilan University, the team managed to “rewind” age-induced changes in liver cells. “We took an old liver and restored its DNA organization toward a much younger state,” he simplified.

The study, led by doctoral students Ron Nagar and Zacharia Schwartz, indicates, as noted by Cohen, that elevating SIRT6 might one day help maintain tissue function, cut down inflammation, and promote better health through aging.

The Importance of SIRT6

Cohen’s lab investigates the fundamental biological processes underlying aging and seeks ways to mitigate age-related diseases.

Back in 2012, Cohen was the first in the world to extend longevity in mice by boosting their SIRT6 levels, representing a significant breakthrough.

SIRT6 primarily resides in the cell nucleus and plays a crucial role in DNA repair, metabolic regulation, and the aging process.

Reversing Age-Related Changes

SIRT6 can also affect chromatin, which organizes DNA within the cell nucleus. Aging in mammals typically leads to a loosening and disorganization of this structure, resulting in inflammation and potential diseases. The research team aimed to determine if increasing SIRT6 could guide chromatin back to a more organized state.

In their experiments, the researchers allowed normal mice to age naturally until they were about 24 months old, roughly equivalent to 70 to 80 years in human terms, before elevating SIRT6 levels.

In one group, they activated SIRT6 directly in the liver, while the control group had a different gene activated—one that was not expected to impact aging, purely serving as a benchmark.

The results suggested that raising SIRT6 levels in older mice helped reverse many age-related chromatin changes rather than just slowing them down.

The researchers identified a specific marker, H3K9ac, which functions as a chemical switch to modulate chromatin structure. As the lab mice aged, this switch often remained stuck in the “on” position, inadvertently activating genes that promote harmful inflammation. SIRT6 intervened by closing these switches, restoring the DNA structure to a more youthful state.

“This is the hidden language of longevity,” Cohen remarked.

This current study builds on Cohen’s earlier findings regarding SIRT6’s crucial role in longevity and healthy aging. He has also started a biotechnology company, SirTlab, aiming to develop methods for increasing or restoring SIRT6 levels, as its activity tends to decline with age.

Dr. Nir Barzalai, head of the Institute for Aging Research at the Albert Einstein College of Medicine and president of the Academy of Geroscience, mentioned that his research addresses how aging involves specific biological drivers that could be targeted to prevent age-related illnesses. However, he wasn’t involved with Cohen’s study.

Having observed numerous centenarians, Barzalai noted a few who possessed mutations in SIRT6, suggesting that these mutations may contribute to a slower aging process. “The observation of SIRT6 in both animals and humans points towards the possibility of enhancing healthspan and longevity,” he stated. “This could be one of the most significant discoveries in human biology.”

Cohen expressed that while humans often think of themselves as the pinnacle of evolution, there are longer-lived mammals like whales. His lab is on a quest to uncover ways to replicate the evolutionary advantages seen in creatures like whales to extend human life.

“This is thrilling because it suggests aging may not be as rigid as we once believed,” Cohen concluded. “Considering SIRT6’s effects on longevity in mice, we might find similar outcomes in humans.”