Tier 3 — preclinical

Hepatic SIRT6 Deficiency Accelerates Female-Specific Aging Through SULT1E1-Mediated Estrogen Depletion

Yonghui Liu, Ziliang Zhang, Tingting Wang, Xiuyan Yang, Qiufen Zhang, Xinyi Liu, Xuefeng Lu, Jian Zhang, Li Feng
International Journal of Molecular Sciences 2026 27(15):7039

Bibliography

PubMed
PMID 42589691
DOI
10.3390/ijms27157039
Funding
National Key R&D Program of China; National Natural Science Foundation of China; Shanghai and Ningxia research programs.

Study snapshot

DesignLongitudinal hepatocyte-specific Sirt6 knockout study in male and female mice with metabolic, histologic, transcriptomic and lifespan outcomes; pharmacological rescue in aged females.
ModelMale and female hepatocyte-specific Sirt6 knockout mice and aged female mice treated with MDL-800.
SampleMouse cohorts; group sizes reported in the full paper.
InterventionHepatocyte-specific Sirt6 deletion; MDL-800 SIRT6 activation in aged female mice.
DurationLongitudinal aging/lifespan plus late-life pharmacological intervention.
EndpointsMedian lifespan; Estradiol; SULT1E1; Liver steatosis/MAFLD; Body composition; DNA damage; Cellular senescence; Metabolic gene expression

What the study showed, in plain terms

Hepatocyte-specific SIRT6 loss shortened median lifespan by 17.6% in female mice and caused severe age-related metabolic decline, while males showed a different compensatory phenotype. In aged females, MDL-800 improved estrogen and gerometabolic readouts. The study strengthens the case that SIRT6 effects are strongly sex- and tissue-dependent.

Key findings

Female liver-specific Sirt6 knockout reduced lifespan and depleted active estradiol through SULT1E1 upregulation. MDL-800 suppressed Sult1e1, increased estradiol and improved multiple metabolic, senescence and DNA-damage markers in aged female mice.

What this study can and cannot tell us

Mouse study; hepatocyte-specific genetic loss is not equivalent to consumer SIRT6 activation; pharmacological rescue was preclinical; findings should not be converted into hormone or menopause treatment claims.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability