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Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice
Mary Hager1, Peter Chang1, Michael Lee1
1College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA.
Abstract:
The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.
Insights
Overexpressing the PTEN gene in mice extends lifespan by promoting thermogenesis, altering macrophage polarization, and enhancing brain function. These changes suggest PTEN influences aging rate indicators across multiple tissues.
Area of Science:
- Aging and Longevity
- Molecular Biology
- Metabolism
Background:
- The PTEN gene is a key negative regulator of the PI3K-AKT pathway, crucial in cell growth and survival.
- PTEN's role in lifespan extension is known, but the underlying mechanisms remain unclear.
- PTEN overexpression in mice results in a longer lifespan compared to controls.
Purpose of the Study:
- To investigate the molecular and physiological mechanisms by which PTEN overexpression extends lifespan in mice.
- To identify shared characteristics between PTEN-overexpressing mice and other known long-lived mouse models.
- To explore PTEN's impact on aging rate indicators across various tissues.
Main Methods:
- Analysis of young adult PTEN-overexpressing (PTENOE) mice.
- Assessment of white adipose tissue (WAT) for UCP1 levels and macrophage polarization (M1/M2 markers like iNOS and Arg1).
- Measurement of FNDC5, irisin, GPLD1, BDNF, and DCX levels in relevant tissues and plasma.
- Comparison of PTENOE mice with established slow-aging models.
Main Results:
- PTENOE mice exhibit characteristics similar to other long-lived models, including those with altered GH/IGF1 pathways or calorie restriction.
- Increased UCP1 in WAT suggests enhanced thermogenesis.
- Shift in macrophage polarization towards M2 phenotype (increased Arg1, decreased iNOS).
- Elevated FNDC5 and irisin in muscle and plasma, linked to WAT browning.
- Increased plasma and liver GPLD1, associated with cognitive improvement.
- Enhanced BDNF and DCX in the hippocampus, indicating increased neurogenesis and brain resilience.
Conclusions:
- PTEN overexpression induces a multi-tissue biochemical profile consistent with delayed aging.
- Changes in WAT, macrophages, muscle, liver, and brain function may serve as aging rate indicators.
- PTENOE mice represent a valuable model for studying aging and longevity, sharing a common set of biochemical characteristics with other long-lived mouse models.
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