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Hepatic SIRT6 Deficiency Accelerates Female-Specific Aging Through SULT1E1-Mediated Estrogen Depletion
Yonghui Liu1, Ziliang Zhang2, Tingting Wang2
1School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
International Journal of Molecular Sciences
|August 13, 2026
Summary
Hepatic SIRT6 deficiency accelerates aging in female mice by disrupting estrogen homeostasis, leading to metabolic decline. Activating SIRT6 rescues these aging phenotypes, highlighting a sex-specific therapeutic target.
Area of Science:
- Aging research
- Metabolic diseases
- Genetics and epigenetics
Background:
- Sexual dimorphism significantly impacts aging, but liver-specific mechanisms are unclear.
- SIRT6, a key deacetylase, regulates metabolism and longevity, yet its sex-specific roles in aging are not fully understood.
Purpose of the Study:
- To investigate the sex-specific functions of hepatocyte-specific SIRT6 in aging.
- To elucidate the molecular mechanisms by which SIRT6 influences aging trajectories in a sex-specific manner.
Main Methods:
- Generated hepatocyte-specific Sirt6 knockout (HKO) mice of both sexes.
- Conducted longitudinal lifespan studies, metabolic profiling, histopathology, and transcriptomics.
- Utilized pharmacological SIRT6 activation with MDL-800.
Main Results:
- Female HKO mice showed accelerated aging, reduced lifespan, metabolic decline, and fatty liver disease (MAFLD).
- Male HKO mice exhibited compensatory metabolic reprogramming.
- Hepatic Sirt6 deficiency in females upregulated estrogen sulfotransferase (SULT1E1), lowering estradiol and triggering lipogenesis, genomic instability, and senescence.
- MDL-800 treatment suppressed SULT1E1, restored estrogen levels, and rescued aging phenotypes in female mice.
Conclusions:
- Hepatic SIRT6 is crucial for regulating female lifespan and healthspan by maintaining estrogen homeostasis.
- The SIRT6-SULT1E1 axis represents a druggable, sex-stratified therapeutic target for age-related metabolic decline.
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