The HMGA1-HP1β axis regulates premature aging in HGPS through chromatin remodeling, and a unique HMGA1 peptide (UHP) that prevents HP1β degradation ameliorates cellular senescence and significantly extends the lifespan of LmnaG609G/G609G mice.
Key Findings
Results
HMGA1 and HP1β show positive correlation in multiple tissues of both LmnaG609G/G609G premature aging mice and naturally aging mice.
The correlation was observed across multiple tissues in LmnaG609G/G609G mice, a classic genetic mouse model of HGPS that recapitulates typical premature aging features.
The positive correlation was also observed in naturally aging mice, suggesting relevance beyond the genetic model.
HP1β was decreased in Hmga1-/- mice, indicating HMGA1 is necessary for HP1β expression or stability.
Results
HMGA1 mitigates HGPS cellular senescence in a HP1β-dependent manner.
The dependency on HP1β was demonstrated through experimental manipulation of the HMGA1-HP1β axis in HGPS cellular models.
This finding establishes HP1β as a critical downstream effector of HMGA1's anti-senescence activity.
The relationship was characterized as a critical 'HMGA1-HP1β axis' in premature aging.
Results
Multi-omics analysis revealed that HP1β downregulates angiopoietin-like protein 2 (ANGPTL2) by reducing chromatin accessibility, thereby suppressing SASP factors and alleviating senescence.
The mechanism involves chromatin remodeling, specifically HP1β-mediated reduction of chromatin accessibility at the ANGPTL2 locus.
ANGPTL2 suppression leads to downregulation of senescence-associated secretory phenotype (SASP) factors.
The multi-omics approach was used to identify this regulatory pathway linking HP1β to SASP suppression.
Results
HMGA1 stabilizes HP1β by recruiting the de-ubiquitinating enzyme USP7.
HMGA1 acts as a scaffold that recruits USP7 to prevent HP1β ubiquitin-mediated degradation.
This mechanism explains how HMGA1 maintains HP1β protein levels in aging cells.
The interaction between HMGA1, HP1β, and USP7 formed the basis for therapeutic peptide design.
Results
A unique HMGA1 peptide (UHP) was developed based on the binding regions of HMGA1 with HP1β and USP7 that prevents HP1β degradation.
UHP was designed based on the specific binding regions of HMGA1 that interact with both HP1β and USP7.
The peptide prevents HP1β degradation, thereby maintaining the downstream chromatin remodeling functions.
UHP ameliorated HGPS cellular senescence in cell-based experiments.
Results
UHP treatment significantly extended the lifespan of LmnaG609G/G609G mice.
The lifespan extension was observed in LmnaG609G/G609G mice, which model HGPS premature aging.
The paper describes the lifespan extension as 'significant,' though specific numerical data (median lifespan values, percent increase) are reported in the full paper.
This in vivo finding supports the therapeutic potential of targeting the HMGA1-HP1β axis.
Background
HMGA1 exhibits differential expression patterns across aging models.
This differential expression was observed across multiple aging model systems.
The expression patterns prompted investigation into HMGA1's mechanistic role in aging.
Prior to this study, HMGA1's roles and mechanisms in aging were described as 'unclear.'
What This Means
This research suggests that a protein called HMGA1 plays an important protective role in a rare rapid-aging disease called Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by a mutation in a gene responsible for maintaining the structural integrity of cell nuclei. Children with HGPS age dramatically faster than normal and typically die in their teenage years from cardiovascular disease. The researchers found that HMGA1 works by stabilizing another protein called HP1β, which helps keep DNA properly packaged and organized in the cell nucleus. When HMGA1 is present, it recruits a molecular 'eraser' enzyme called USP7 that removes degradation tags from HP1β, keeping it stable. This in turn allows HP1β to reduce access to a gene called ANGPTL2, which when active promotes a harmful inflammatory state (called the senescence-associated secretory phenotype or SASP) that accelerates cellular aging.
Using mice engineered to carry the HGPS mutation, the researchers confirmed that this HMGA1-HP1β protective pathway is diminished in premature aging and in normal aging. Building on their molecular understanding of how HMGA1 connects HP1β and USP7, they designed a small therapeutic peptide called UHP (Unique HMGA1 Peptide) that mimics this protective function. When tested, UHP reduced cellular aging markers in HGPS cells and, importantly, significantly extended the lifespan of HGPS model mice.
This research suggests that the HMGA1-HP1β axis is a fundamental regulator of aging at the level of chromatin (DNA packaging), and that therapeutically maintaining HP1β stability through peptides like UHP could represent a new strategy for treating HGPS. The findings may also have broader implications for understanding normal aging, since similar molecular changes were observed in naturally aging mice, not just those with the HGPS mutation.
Hu Q, Sun Q, Xiang W, Zhou Z, Sun H, Hu Y, et al.. (2026). HMGA1-HP1β axis regulates premature aging in Hutchinson-Gilford progeria syndrome through chromatin remodeling.. Nature communications. https://doi.org/10.1038/s41467-026-76789-6