SIRT1 represses LINE-1 through heterochromatin and limits senescence
In cell-based experiments, the SIRT1 protein repressed LINE-1, a DNA element that can copy itself, and reduced signs of cellular aging
On August 30, 2026, Aging Cell published a study of the SIRT1 protein and the repetitive DNA element LINE-1. The authors altered SIRT1 levels in cultured cells and induced senescence, a state in which a cell stops dividing after stress and changes the set of signaling molecules it produces, by exposing the cells to radiation.
LINE-1, or L1, is a repetitive DNA element that can generate new copies through an RNA intermediate. Cells normally keep such elements inactive within heterochromatin, which consists of densely packed regions of the genome. In the study, the authors examined how SIRT1 contributes to this protection.
Increasing SIRT1 levels reduced both the amount of L1 RNA and the activity of its promoter, the region where transcription begins. SIRT1 deficiency increased both measures. A genetic reporter based on the green fluorescent protein GFP showed that new L1 copies appeared less often when SIRT1 levels were elevated. SIRT1 variants lacking enzymatic activity also repressed the L1 promoter and reduced DNA damage. These experiments distinguished the enzymatic activity of SIRT1 from its role in assembling a protein complex.
The authors then examined which proteins SIRT1 recruits to L1. SIRT1 bound directly to Lamin B1 and strengthened its association with KAP1. Both proteins help maintain tightly packed DNA. This interaction preserved more H3K9me3, a chemical mark of compact chromatin, at the L1 promoter. SIRT1 deficiency reduced Lamin B1, KAP1, and H3K9me3 at the same site. SIRT1 therefore helps assemble proteins at L1 that keep the element inactive.
The researchers next irradiated the cells and measured markers of senescence after 7–10 days. Increasing SIRT1 reduced the proportion of cells positive for the senescence marker SA-β-gal from approximately 30% to 13% in one cell line and from 38% to 20% in another. SIRT1 deficiency increased the levels of p16 and p21, which are protein markers of senescence. At the same time, TBK1 and STING were more often present in their activated forms. These proteins participate in cGAS-STING, a cellular alarm system that responds to DNA outside the nucleus.
Lamivudine (3TC) inhibits reverse transcription, the conversion of RNA into DNA that LINE-1 uses to copy itself. In cells deficient in SIRT1, lamivudine reduced the RNA levels of the inflammation-associated genes CCL2 and MMP3. In this cell model, loss of SIRT1 weakened DNA compaction at L1, while L1 activation was accompanied by cellular alarm signaling and markers of senescence.