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Review
. 2021 Aug 27:2:707372.
doi: 10.3389/fragi.2021.707372. eCollection 2021.

The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging

Stephanie A Fernandes  1   2 , Constantinos Demetriades  1   2   3
Affiliations
Review

The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging

Stephanie A Fernandes et al. Front Aging. .

Abstract

The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.

Keywords: aging; amino acids; dietary restriction; mTORC1; nutrient sensing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
mTORC1 positively or negatively regulates multiple cellular functions via key effector proteins. Proteins that are regulated by mTORC1 only indirectly are shown in red. See text for details. Created with BioRender.com
FIGURE 2
FIGURE 2
Amino acids regulate mTORC1 at the lysosomal surface via a complex upstream regulatory protein network that impinges upon the Rag GTPase dimers. Positive mTORC1 regulators shown in green; negative regulators shown in red. Additional subcellular locations, where mTOR was previously found, are also depicted. See text for details. Created with BioRender.com
FIGURE 3
FIGURE 3
Intra- and extra-cellular stimuli control mTORC1 activity through diverse signaling cascades and upstream mTORC1 regulatory proteins. See text for details. Created with BioRender.com
FIGURE 4
FIGURE 4
A central role for mTORC1 in aging. Interventions and upstream cellular components that regulate mTORC1 activity, and downstream effectors and functions that are regulated by mTORC1, participate in the aging process. Components with anti-aging properties shown in green; components with pro-aging properties shown in red. See text for details. Created with BioRender.com
See this image and copyright information in PMC

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