Research into mTOR and aging is becoming quite diverse. Researchers here present evidence for mTOR to be involved in the aging of the vasculature, and thus also in the development of vascular dementia. One of the noteworthy aspects of aging is the declining ability of the vascular system to deliver sufficient nutrients and oxygen to cells, and this is considered important in the decline of both brain and muscles, two of the more energy-hungry tissue types.
The research here is a good example of the way in which most researchers restrict their scope to relationships between areas of protein machinery that are very close to the disease state, without looking back down the chain of cause and consequence towards any sort of root cause. Detailed changes in proteins and their interactions are cataloged, but there is next to no consideration of why these changes in levels and interactions of proteins take place in aging. Instead of working further backwards - or better, starting with the known root causes of aging and working forwards - the impetus is to intervene in order to adjust the protein interactions of the disease state in some way.
At the SENS Research Foundation, the home of interventions that target root causes in aging, this tendency in the scientific community is known as "messing with metabolism." It fails as a strategy precisely because it doesn't look to the root causes, but instead becomes distracted into mapping and tinkering with the details of the immensely complicated dysfunctional state of cellular biochemistry exhibited in age-related conditions. If root causes are left alone to fester and continue to produce any number of downstream issues, then there is very little that can be usefully done to cure such a condition - no amount of tinkering will help greatly.
Brain vascular dysfunction is involved in the etiology of dementias. Cerebrovascular dysfunction is one of the earliest events in these dementias, best exemplified by diminished cerebral blood flow (CBF). A recent study suggested that vascular dysfunction indicated by decreased CBF may be the first abnormal biomarker in Alzheimer's disease (AD) progression, as well as the one that shows the largest magnitude of change. A significant barrier to effective treatments for AD, which are currently unavailable, is that we still do not sufficiently understand the mechanisms that drive its onset and progression. While the neuronal contributions to AD pathogenesis have been extensively studied, cerebrovascular mechanisms of AD, which show substantial overlap with those of vascular cognitive impairment and dementia (VCID), are only partially understood.
The mechanistic/mammalian target of rapamycin (mTOR) may be a critical effector of cerebrovascular dysfunction in AD and potentially other dementias. mTOR is a major signaling hub that integrates nutrient/growth factor availability with cellular metabolism. mTOR also regulates the rate of aging across phyla, including invertebrates and mammals. Rapamycin, an mTOR inhibitor, is the first drug that has been experimentally proven to slow down the rate of aging in mice. Work from our lab and others has identified mTOR as a major regulator of cerebrovascular damage and dysfunction in AD. While mTOR has a critical role in the regulation of cellular metabolism through actions at multiple signaling pathways, some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function.
Underlying the CBF reductions observed in AD are decreases in regional and global vascular density. mTOR drives cerebromicrovascular density loss, leading to profound CBF deficits, by decreasing microvascular nitric oxide (NO) bioavailability in brains of mice modeling AD through inhibition of NO synthase (NOS) activity. Therefore, mTOR attenuation with rapamycin induces endothelium-dependent cortical vasodilation via NO release. In agreement with this notion, prior in vitro studies showed that mTOR inhibits endothelial NOS (eNOS) phosphorylation and activation and NO-dependent arterial vasodilation.
Aβ, causally implicated in AD, is generated in the brain by cleavage of the amyloid precursor protein (APP) in association with neuronal activation. Aβ is released at synaptic sites into the interstitial fluid. Several physiological mechanisms act to prevent Aβ accumulation, but the largest contributor is transvascular Aβ clearance, as over 85% of Aβ is continuously cleared out of the brain through the blood-brain barrier (BBB). Consistent with a critical role of microvascular integrity and function in Aβ removal from the brain, systemic mTOR inhibition reduces Aβ levels in the brain and improves cognitive function in mouse models of AD. In these AD models, mTOR promotes the accumulation of Aβ in the brain by inhibiting autophagy and by decreasing Aβ clearance as a result of decreased vascular density and reduced CBF.
The BBB is formed by a monolayer of vascular endothelial cells that line the brain microvasculature and dynamically regulate the exchange of molecules. Studies indicate that BBB breakdown is one of the earliest events in the pathogenesis of AD. It was found that mTOR attenuation reduces or prevents BBB breakdown in several models of age-associated neurological disorders, suggesting a broad role of mTOR in BBB dysfunction in age-related brain disease states. The exact mechanisms by which mTOR promotes BBB breakdown, however, have not yet been sufficiently studied.
Rapid increases in blood flow to areas of the brain with high neuronal activity are required to maintain cellular homeostasis and function. This is accomplished through neurovascular coupling, a homeostatic response mediated by complex intercellular signaling events. Significant neurovascular coupling deficits are observed in patients with AD. NO production via activation of the neuronal form of NOS (nNOS) contributes significantly to the neurovascular coupling response by inducing local vasodilation in response to neuronal activation. Dysfunctional neurovascular coupling in mouse models has been reported to occur both from reduced neuronal NO production as well as from a diminished CBF response to otherwise unimpaired NO signaling. Since mTOR is a key driver of cerebrovascular damage and disintegration in several mouse models of AD, it is reasonable to hypothesize that mTOR contributes, at least indirectly, to neurovascular coupling deficits in these models. Very little is known at present, however, about the role of mTOR in the regulation of neurovascular coupling.