ASAP3 deficiency alleviates hepatic senescence and correlates with extended healthspan in mice
Zhen Tian1, Yuhua Song1, Xinyue Ao1
1National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, 150081, China; NHC Specialty Laboratory Cooperation Unit of Food Safety Risk Assessment and Standard Development, Heilongjiang, 150081, China.
Abstract:
The aging liver not only declines in function but also accelerates systemic aging and shortens lifespan. Identifying key molecular targets to delay liver aging is important for promoting health and longevity. ASAP3 is involved in cytoskeletal remodeling, but its role in aging remains unexplored. Here, we found that ASAP3 expression was upregulated in aged mouse livers and H2O2-induced AML12 cells. In AML12 hepatocytes, ASAP3 knockdown attenuated H2O2-induced senescence, enhanced autophagic flux, reduced mitochondrial ROS, and restored mitochondrial membrane potential, whereas ASAP3 overexpression had opposite effects. Phalloidin staining and Western blot analysis showed that ASAP3 knockdown significantly reduced the abnormal accumulation of F-actin and F-actin/G-actin ratio, while ASAP3 overexpression aggravated F-actin accumulation, and increased F-actin/G-actin ratio in AML12 cells. In addition, inhibition of autophagy abolished the alleviating effect of ASAP3 knockdown on senescence, whereas enhancing autophagy protected against cellular senescence induced by ASAP3 overexpression. Furthermore, disruption of F-actin assembly with cytochalasin D rescued the suppression of autophagic flux caused by ASAP3 overexpression. In vivo, ASAP3 knockout extended lifespan, improved cognitive and motor functions, and remodeled systemic metabolism in both sexes. ASAP3 knockout mice also showed reduced senescence phenotype, maintained F-actin structure, and enhanced autophagic flux in the liver. Furthermore, serum lipidomics revealed significant enrichment of pathways related to actin cytoskeleton regulation, autophagy, and primary bile acid biosynthesis in Asap3-/- mice. Collectively, these findings demonstrate that ASAP3 is a novel regulator of liver aging, promoting senescence and impairing autophagy and mitochondrial function by disrupting actin cytoskeleton dynamics. Targeting ASAP3 may represent a promising strategy to delay hepatic aging and extend healthspan.
Insights
ASAP3 accelerates liver aging by disrupting actin cytoskeleton dynamics, promoting senescence, and impairing autophagy. Targeting ASAP3 may extend healthspan and lifespan.
Area of Science:
- Gerontology
- Cell Biology
- Molecular Biology
Background:
- Liver aging impairs function and accelerates systemic aging, shortening lifespan.
- Identifying molecular targets to delay liver aging is crucial for health and longevity.
- The role of ASAP3 in aging was previously unexplored.
Purpose of the Study:
- To investigate the role of ASAP3 in liver aging.
- To elucidate the molecular mechanisms by which ASAP3 influences cellular senescence, autophagy, and mitochondrial function.
- To evaluate the therapeutic potential of targeting ASAP3 for age-related decline.
Main Methods:
- ASAP3 expression analysis in aged mouse livers and H2O2-induced AML12 cells.
- ASAP3 knockdown and overexpression in AML12 hepatocytes to assess effects on senescence, autophagy, and mitochondrial function.
- Phalloidin staining and western blot analysis to evaluate F-actin dynamics.
- In vivo studies using ASAP3 knockout mice to assess lifespan, cognitive and motor functions, systemic metabolism, and liver aging phenotypes.
- Serum lipidomics analysis in ASAP3 knockout mice.
Main Results:
- ASAP3 expression is upregulated in aged liver and H2O2-treated hepatocytes.
- ASAP3 knockdown attenuated senescence, enhanced autophagy, and improved mitochondrial function, while overexpression had opposite effects.
- ASAP3 regulates F-actin dynamics, impacting cellular senescence and autophagic flux.
- ASAP3 knockout extended lifespan, improved physical and cognitive functions, and ameliorated liver aging phenotypes in mice.
- ASAP3 knockout mice exhibited enhanced autophagic flux and maintained F-actin structure in the liver.
Conclusions:
- ASAP3 acts as a negative regulator of liver aging.
- ASAP3 promotes senescence and impairs autophagy and mitochondrial function via disruption of actin cytoskeleton dynamics.
- Targeting ASAP3 is a potential strategy to delay hepatic aging and extend healthspan.
