Immunostimulatory activity of lifespan-extending agents

Abstract

During the past two decades, several interventions have been shown to increase the healthy lifespan of model organisms as evolutionarily distant from each other as yeast, worms, flies and mammals. These anti-aging maneuvers include (but are not limited to) cycles of caloric restriction, physical exercise as well as the administration of multiple, chemically unrelated agents, such as resveratrol, spermidine and various rapamycin-like compounds collectively known as rapalogs. Most, if not all, lifespan-extending agents promote macroautophagy (hereafter referred to as autophagy), an evolutionarily old mechanism that contributes to the maintenance of intracellular homeostasis and plays a critical role in the adaptive response of cells to stress. In line with this notion, the activation of autophagy appears to mediate significant anti-ageing effects in several organisms, including mice. Here, we focus on rapalogs to discuss the possibility that part of the beneficial activity of lifespan-extending agents stems from their ability to exert immunostimulatory effects. Accumulating evidence indicates indeed that the immune system can recognize and eliminate not only cells that are prone to undergo malignant transformation, but also senescent cells, thus playing a significant role in the control of organismal aging. In addition, it has recently become clear that rapamycin and other rapalogs, which for a long time have been viewed (and used in the clinic) as pure immunosuppressants, can mediate robust immunostimulatory functions, at least in some circumstances.

Resveratrol Suppresses Oxidised Low-Density Lipoprotein-Induced Macrophage Apoptosis through Inhibition of Intracellular Reactive Oxygen Species Generation, LOX-1, and the p38 MAPK Pathway

“…The beneficial effects of RSV were originally thought to derive from its antioxidant properties [26]. Moreover, RSV has been shown to possess anti-platelet, anti-cancer and lifespan-extending effects in various experimental models [27,28,29,30]. It has been reported that SIRT1 regulates both inflammatory processes and cholesterol metabolism in macrophages by reducing the uptake of ox-LDL and preventing the formation of macrophage foam cells [31].…”

Immunity and longevity

“…Rapamycin was originally isolated from Streptomyces hygroscopicus, which is indigenous in the Easter Islands and was used originally for declining immune response in the case of organ transplantation. However, later its robust immuneenhancing effect was also cleared [105]. Its target is the mammalian target of Rapamycin (mTOR), which is a serin/threonin kinase, encoded by the mTOR gene in men.…”

HDAC inhibitors and immunotherapy; a double edged sword?

“…HDAC inhibitors were previously reported to exhibit strong anti-inflammatory effects[ 34 - 36 ]. Rapamycin, however, previously viewed as a pure immune suppressant drug, was more recently also shown to mediate strong immune stimulating effects as reviewed in[ 37 , 38 ]. Similarly, a recent study showed that the Class I HDAC inhibitor Entinostat markedly enhanced anti-tumor vaccination[ 39 ].…”