SIRT6 overexpression keeps aging mouse liver chromatin young and may even rewind it
In male mice, boosting SIRT6 prevented age-related chromatin opening in the liver, cut inflammatory signaling, and AAV delivery in old mice restored youthful accessibility.
Summary
Aging loosens chromatin in the liver, which is linked to rising inflammation and falling metabolic function. Researchers at Bar-Ilan University and the NIH examined male mouse livers using ATAC-seq, DNA methylation profiling, RNA-seq and ChIP-seq. In normal mice, chromatin became broadly more accessible with age. In mice overexpressing the histone deacetylase SIRT6, old livers stayed close to a young-like state. Inflammatory genes were dampened and metabolic pathways were better preserved. The age-linked opening was tied to H3K9 acetylation, which SIRT6 removes, but not to H3K56 acetylation. Delivering SIRT6 to the livers of already-old mice with an AAV vector partly restored youthful accessibility. The work suggests SIRT6 could be a target for reversing epigenetic aging, though it is so far limited to male mice.
Detailed Summary
Aging is accompanied by epigenetic drift, including loss of heterochromatin and altered histone marks. These changes are thought to feed the chronic inflammation and metabolic decline seen in old tissues. SIRT6 is a nuclear NAD+-dependent enzyme that deacetylates histone H3 at lysines 9, 18 and 56, and it is a known longevity factor: mice lacking it age prematurely, while mice overexpressing it live longer. How SIRT6 shapes genome-wide chromatin in old age had not been mapped, and this study addresses that gap in the liver.
The team used previously published SIRT6 transgenic C57Bl/6 mice and wild-type littermates. They profiled livers from young (5–7 months) and old (18–21 months) males, with 6–8 animals per group. Methods included ATAC-seq for chromatin accessibility, RNA-seq for gene expression, and genome-wide DNA methylation. ChIP-seq was used for histone acetylation marks. Separately, an AAV vector was used to overexpress SIRT6 in aged male mice.
In wild-type mice, accessibility across about 247,000 ATAC-seq peaks shifted upward with age, and LINE-1 repeat regions became more accessible. Old SIRT6 transgenic livers did not show this global opening and looked much like young wild-type livers. The effect was age-dependent, since young transgenic and young wild-type mice were similar, although LINE-1 regions were less accessible even in young transgenic animals. The authors defined about 5,200 aging-associated domains (AADs). Regions that opened with age tended to close again with SIRT6 overexpression, and the reverse held for regions that closed. DNA methylation was also analyzed within opened and closed AADs. Per the abstract, aging increased inflammatory gene expression and reduced metabolic pathway expression, and SIRT6 reversed both.
The abstract also reports that ETS-family transcription factor motifs were enriched in regions that gain accessibility with age. Liver-enriched transcription factor motifs were enriched in regions that lose accessibility. H3K9ac, but not H3K56ac, was associated with age-related opening, and SIRT6 reversed this. In aged mice, AAV-mediated SIRT6 overexpression not only slowed but reversed chromatin changes, returning accessibility toward a youthful pattern.
Taken together, the work suggests SIRT6 acts as a chromatin-level brake on liver aging by reducing H3K9 acetylation and modulating transcription factor access. The AAV result is the most translationally interesting, because it implies that established epigenetic aging may be reversible. Caveats are that the data come from male mice and a single organ, and the primary model uses lifelong transgenic overexpression. Functional consequences were inferred largely from transcriptomic and chromatin readouts rather than from detailed physiological outcomes.
Key Findings
- Chromatin accessibility rose broadly in old male wild-type mouse livers, including LINE-1 repeat regions, while old SIRT6 transgenic livers stayed young-like.
- SIRT6 overexpression reversed age-associated chromatin changes at about 5,200 aging-associated domains, closing regions that opened with age.
- Age-related opening was linked to H3K9 acetylation, not H3K56 acetylation, and SIRT6 reversed the H3K9ac effect.
- ETS-family motifs marked regions opening with age; liver-enriched transcription factor motifs marked regions closing with age.
- AAV-mediated SIRT6 overexpression in already-old male mice rejuvenated chromatin accessibility toward a youthful state.
Methodology
Livers from young (5–7 mo) and old (18–21 mo) male wild-type and SIRT6 transgenic mice (n≈6–8 per group) were analyzed by ATAC-seq, RNA-seq, DNA methylation profiling and ChIP-seq for histone acetylation. A separate AAV-based SIRT6 overexpression experiment was performed in aged male mice to test reversal. Peak-level differences were assessed with one-way ANOVA and Tukey's multiple comparisons.
Study Limitations
Only male mice and only liver were studied, so generalization to females, other tissues and humans is untested. The main model uses lifelong transgenic overexpression, which differs from therapeutic dosing, and PCA showed only moderate group separation. Associations with transcription factors and histone marks are largely correlative, and long-term functional or lifespan benefits of late-life AAV delivery were not established in the portions reviewed.
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