In old age, the liver’s DNA packaging starts to come undone.

That breakdown does not change the genetic code itself. What it changes is the way the code is folded, packed, and managed inside the cell, which can decide which genes stay quiet and which ones switch on. A team at Bar-Ilan University now reports that it reversed many of those age-linked shifts in old mice by increasing levels of a protein called SIRT6.

The work, published in Nature Communications, points to aging as something more dynamic than simple wear and tear. In the mouse liver, the researchers found that aging loosened chromatin, the molecular structure that organizes DNA, while pushing inflammatory genes into a more active state and weakening gene programs tied to normal metabolism.

“As we age, the genome loses its proper organization,” said Prof. Haim Cohen, director of the Sagol Healthy Human Longevity Center at Bar-Ilan University’s Goodman Faculty of Life Sciences, who led the study. “Genes that should remain silent become activated, especially inflammatory genes, while genes required for normal liver function begin to shut down.”

That shift matters because chromatin acts as a control system. DNA is wrapped around histone proteins to form nucleosomes, and the tighter or looser that package becomes can influence whether the cell’s transcription machinery can reach certain genes. In youth, that system helps liver cells hold on to their identity and carry out their metabolic jobs. With age, the new analysis suggests, that control starts to fray.

To track those changes, the team studied liver tissue from young male mice aged 5 to 7 months and old male mice aged 18 to 21 months. They used ATAC-seq to map chromatin accessibility and RNA-seq to measure shifts in gene activity. They also worked with mice genetically engineered to overexpress SIRT6, a nuclear sirtuin already linked in earlier work to longer lifespan and better healthspan.

The broad pattern was clear. In ordinary old mice, chromatin became more open overall. Regions the researchers called aging-associated domains changed substantially with age, with 5,173 domains meeting their statistical threshold. Of those, 3,288 became more open and 1,885 became more closed.

That imbalance did not appear in old mice with extra SIRT6. Their chromatin landscape stayed far closer to that of young animals, and the researchers estimated that about 95 percent of age-related chromatin changes were protected to some degree in the SIRT6 mice.

The team also examined LINE-1 regions, stretches of repetitive DNA known to become more accessible with age. Those regions opened up in ordinary old mice, but that increase was not seen in the SIRT6 animals.

Changes in chromatin were closely tied to changes in liver behavior.

When the researchers looked at gene activity, aging in normal mice lined up with stronger inflammatory signaling, especially the interferon-alpha response. At the same time, pathways involved in fatty acid metabolism and oxidative phosphorylation declined. The picture was consistent with an aging liver that was losing metabolic sharpness while taking on a more inflamed state.

Old mice with elevated SIRT6 showed the reverse pattern. Metabolic pathways were more active, while inflammatory pathways were reduced.

“What we found is that SIRT6 can help rewind this process. In simple terms, we took an old liver and restored its DNA organization toward a much younger state,” Cohen said.

The group also traced some of the likely regulators behind those changes. Regions that opened with age were enriched for ETS family transcription factors, which are tied to immune signaling and other cell programs. Regions that closed with age were enriched for liver-enriched transcription factors such as HNF6, HNF1, CEBP, and FOXM1, factors important for maintaining liver identity and function. With age, ETS activity rose while the liver-enriched factors fell. SIRT6 largely pushed those trends back the other way.

One of the study’s strongest mechanistic clues involved a chromatin marker called H3K9ac.

SIRT6 can remove acetyl groups from several histone sites, but in this work H3K9ac stood out more clearly than another known SIRT6 target, H3K56ac. Using ChIP-seq, the team found that H3K9ac changed in a way that tracked with harmful chromatin opening in aging liver tissue. In old wild-type mice, H3K9ac rose at the opened aging-associated domains. In old SIRT6 mice, those levels stayed close to youthful levels.

That finding helped explain an apparent contradiction in the data. Global measurements of histone marks did not show a significant overall shift in H3K9ac with age, but the higher-resolution mapping showed that local increases at specific sites could still have major functional effects. In other words, the problem was not a uniform drift across the whole genome. It was concentrated at key regions linked to inflammation and tissue decline.

The researchers also found that DNA methylation dropped across the genome with age and that SIRT6 softened that decline. In liver-specific methylation sites, aging pushed the tissue away from its distinctive pattern, another sign of fading identity. That shift, too, was reduced in the SIRT6 mice.

The most striking test came late in life.

Because lifelong overexpression could reflect long-term protection rather than true reversal, the team injected 24-month-old male mice with a hepatocyte-specific AAV8 vector designed to raise SIRT6 in the liver. One month later, they measured chromatin accessibility again.

The overall chromatin profile did not completely reset, but the effect was still substantial. The induced SIRT6 expression reversed about 80 percent of the age-related chromatin changes seen between young and old wild-type mice. Opened aging-associated domains became less accessible, while closed ones regained accessibility. Pathways reduced by the treatment were mainly inflammation-related, while the pathways that rose included metabolic functions such as lipid catabolism.

Those results suggest SIRT6 does more than slow decline. Under these experimental conditions, it could partially restore an older liver’s chromatin landscape toward a younger state.

The research was led by PhD students Ron Nagar and Zacharia Schwartz from Bar-Ilan University’s Mina and Everard Goodman Faculty of Life Sciences and the Sagol Healthy Human Longevity Center, with collaborators from Tel Aviv University and the National Institute on Aging, including Prof. Rafael de Cabo and his team.

The findings come with important limits. The work was done in mice, not people. It focused only on male mice, because earlier work suggested SIRT6 has a stronger effect on lifespan in males, so it remains unclear whether the same chromatin role would look similar in females. The researchers also did not generate direct SIRT6 occupancy data to overlay where the protein itself was binding across the genome.

This work adds to a growing view that aging may involve the loss of epigenetic information, not just accumulated damage. In practical terms, that means some aspects of tissue aging might be adjustable if scientists can restore the molecular systems that keep genes properly organized.

For now, the study remains basic research. It does not show a treatment for people, and it does not prove that changing chromatin in one organ would extend life or prevent disease. Still, the results suggest that targeting SIRT6, or the pathways it controls, could become one route for reducing age-related inflammation and preserving tissue function. The appeal is that this approach aims at a root mechanism of aging rather than one disease at a time.

“This is exciting because it suggests aging may be more plastic than we once believed,” Cohen said. “If we can restore healthy chromatin organization, we may eventually be able to preserve tissue function, reduce inflammation, and improve health during aging.”