Rapamycin Prevents Deterioration in Brain Circulation in Aged Rats

The mTOR inhibitor rapamycin is well known to slow aging in animal models. As for most of the methods shown to achieve this goal in short-lived species, upregulation of cellular maintenance processes such as autophagy features prominently in the changes produced by the drug. Every one of these approaches that produce sweeping changes in cellular metabolism and a general slowing of age-related decline provides the research community with an essentially unlimited range of projects to undertake when it comes to assessing specific metrics of aging and how they are affected.

Here, researchers look at how rapamycin affects age-related deterioration in blood circulation in the brain. There are many reasons why this might decline: a weakened or failing heart; loss of capillary network density; narrowing of blood vessels due to atherosclerosis; and so forth. The brain is an energy-hungry organ, and any reduction in the supply of oxygen and nutrients will have detrimental effects on tissue function, contributing to the onset of neurodegeneration.

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats.

Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging.

Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.

Link: https://doi.org/10.1111/acel.13057

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