Calorie Restriction Mimetics: Upstream-Type Compounds for Modulating Glucose Metabolism

Abstract

Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2-deoxy-d-glucose, d-glucosamine, and d-allulose, which show antiaging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs.

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

“…Based on its mode of action involving core machineries (SIRT1 and AMPK) causally involved in the hallmarks of aging, such as epigenetic alterations, deregulated nutrient sensing, or mitochondrial dysfunction [62,95], RSV has classically been considered an archetype member of the downstream type of calorie restriction mimetics (CRMs) including rapamycin, metformin, and polyamines (spermidine). Intriguingly, because normal human aging is characterized by a progressive decline in immune surveillance that is accompanied by PD-L1 upregulation to favor cancer initiation and progression even in the absence of a more complex mutational landscape [96][97][98][99][100], the suppression of PD-L1 signaling via direct targeting of PD-L1 glycosylation enzymes could represent a new immunometabolic mechanism through which RSV might prevent immune dysfunction and cancer development in the context of aging.…”

“…In an attempt to provide a computational explanation for the inhibitory activity of RSV against GAA, we performed molecular docking and molecular dynamics (MD) assays of RSV against high-resolution crystal structures of the yeast (4J5T [57]) and human (5NN4 [58]) forms of GAA. RSV was predicted to occupy the catalytic site of yeast GAA with a higher binding energy than that predicted for acarbose, a well-known competitive inhibitor of GAA [59][60][61][62][63] (Figure 3A-3C; supplementary information, Supplementary Figure S1 and Table S1). Conversely, several RSV clusters were predicted to interact with enzymatic pockets distant to the active site of human GAA (Figure 4, top panels), which was accurately predicted to be occupied by acarbose ( Figure 4, bottom panels; Supplementary Table S2).…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…CR mimetics are compounds that mimic the benefits of CR at the molecular, cellular, and physiological levels, leading to health-promoting effects [100]. Recently, there has been an increased interest in CR mimetics due to the benefits of using these anti-aging interventions in terms of extended health and lifespan [101][102][103]. Although the valuable effects of CR mimetics on lifespan and health have been extensively highlighted, limitations persist because it is difficult to implement such diet regimens in humans.…”

Food Industrial Production of Monosaccharides Using Microbial, Enzymatic, and Chemical Methods

“…On the other hand, if we identify the new uses of monosaccharides, research on the production of such monosaccharides may progress rapidly. Moreover, these compounds may have various beneficial effects on health [18,37,78,82,83]. Accordingly, the addition of hexoses to foods during food production may improve the health and quality of life of consumers.…”