Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice

Li, Xinna; McPherson, Madaline; Hager, Mary; Lee, Michael; Chang, Peter S.; Miller, Richard A.

doi:10.1007/s11357-023-00770-0

Cited by 8 publications

(1 citation statement)

References 90 publications

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“…Accumulating evidence supports the critical role of adipose tissue thermogenesis in longevity and delayed aging. Several genetic models and anti-aging interventions that delay aging and extend lifespan are associated with BAT activation and increased UCP1 expression in adipose depots [46][47][48][49][50][51][52][53][54] . These studies suggest that stimulation of adipose thermogenesis could have a beneficial impact on systemic aging and potentially delay the onset of age-related diseases.…”

Section: Ucp1-dependent Thermogenesis Predominantly Occurs In Classic...mentioning

confidence: 99%

The metabolic benefits of thermogenic stimulation are preserved in aging

Natarajan,

Plakkot,

Tiwari

et al. 2024

Preprint

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Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the US (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Our study provides foundational evidence for targeting adipose thermogenesis to improve age-related metabolic dysfunction.

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Section: Ucp1-dependent Thermogenesis Predominantly Occurs In Classic...mentioning

confidence: 99%

The metabolic benefits of thermogenic stimulation are preserved in aging

Natarajan,

Plakkot,

Tiwari

et al. 2024

Preprint

View full text Add to dashboard Cite

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Proteomic changes induced by longevity-promoting interventions in mice

Burns,

Wiedrick,

Feryn

et al. 2023

GeroScience

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Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice

Hager,

Chang,

Lee

et al. 2023

GeroScience

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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.

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Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice

Cited by 8 publications

References 90 publications

The metabolic benefits of thermogenic stimulation are preserved in aging

The metabolic benefits of thermogenic stimulation are preserved in aging

Proteomic changes induced by longevity-promoting interventions in mice

Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice

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