Obesity Increases Vascular Senescence and Susceptibility to Ischemic Injury Through Chronic Activation of Akt and mTOR

Abstract

Obesity and age are important risk factors for cardiovascular disease. However, the signaling mechanism linking obesity with age-related vascular senescence is unknown. Here we show that mice fed a high-fat diet show increased vascular senescence and vascular dysfunction compared to mice fed standard chow and are more prone to peripheral and cerebral ischemia. All of these changes involve long-term activation of the protein kinase Akt. In contrast, mice with diet-induced obesity that lack Akt1 are resistant to vascular senescence. Rapamycin treatment of diet-induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke. These findings indicate that long-term activation of Akt-mTOR signaling links diet-induced obesity with vascular senescence and cardiovascular disease.

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

“…17 It was recently demonstrated [18][19][20] that chronic reduction of mammalian target-of-rapamycin (mTOR) signaling by rapamycin extends lifespan in mice by delaying aging. 19 Consistent with this observations, inhibition of mTOR delays EC senescence in vivo 21 and in vitro, 22 improves vascular outcomes of stroke, 23,24 and has been shown to have EC-dependent vasodilatory effects. 25,26 Although distal EC dysfunction has been observed with rapamycin-eluting stents implanted in coronary heart disease patients, 27,28 recent studies have shown that this effect may be due to delayed or absent re-endothelization of the stent, 29 or to effects of the stent itself.…”

Cognitive Rehabilitation Reduces Cognitive Impairment and Normalizes Hippocampal CA1 Architecture in a Rat Model of Vascular Dementia

“…47 It is noteworthy that a diet high in fats and refined sugars (HFS) did not exacerbate histopathological damage or behavioral impairments as previously reported in focal ischemia models. 10,11 Although it is possible that a HFS diet does not have an effect on pathologic or behavioral injury in the present 2-VO model, other explanations for this lack of effect exist. For example, it has been (A) Animals exposed to 2-vessel occlusion (2-VO) plus the physical and cognitive activity (PA/CA) rehabilitation paradigm displayed significantly shorter latencies to locate the hidden platform during the acquisition trials indicating superior learning abilities compared with 2-VO animals that did not receive rehabilitation at PSW 16 (*Po0.01).…”

“…3 However, other modifiable lifestyle choices may significantly influence vascular health as well. For example, high-fat diets accelerate vascular senescence 10 and exacerbate ischemic stroke damage when exposure extends from the early post-weaning period. 11 Preclinical studies often overlook the importance of modeling co-morbid conditions (e.g., old age, unhealthy diet) when assessing intervention efficacy 12 and this failure to reflect key aspects of the clinical setting undoubtedly contributes to the so-called translational roadblock.…”

The functions of mTOR in ischemic diseases

“…In general, mTORC1 is rapamycin-sensitive, and mTORC2 is rapamycin-insensitive. Within the mTORC1 and mTORC2 complexes, mTOR is resistant to acute rapamycin treatment, but prolonged exposure to rapamycin can block the assembly of mTORC2 components (1) and Akt activation (2). In recent studies focused on ischemic disease, the role of signaling pathways has not been identified clearly (2,3).…”