Hormesis, cell death and aging.

Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress response that raise the resistance of the organism against high doses of the same agent. This phenomenon, which is known as "hormesis", is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction.


INTRODUCTION
Hormesis (a neologism coined from the ancient Greek term hormáein, which literally means "to set in motion, impel, urge on") describes a favorable biological response to harmless doses of toxins and other stressors. Hormesis-stimulating compounds initiate an adaptive stress response that renders cells/organisms resistant against high (and normally harmful) doses of the same agent. On the theoretical level, hormesis may constitute (one of) the mechanisms that allows stressed cells to avoid senescence and death, and hence might have some impact on the (patho)physiology of aging. Thus, measures that reportedly prolong the healthy lifespan of multiple species, such as caloric restriction and the administration of resveratrol [1][2][3][4][5][6], may do so by inducing a hormetic response [7,8]. In this article, we Review will examine the molecular circuitries that link cellular stress and death, and how these pathways can get uncoupled during hormetic responses.

Redundant pathways leading to apoptotic cell death
Apoptosis is frequently viewed as a caspase-dependent cell death pathway in which a series of specific cysteine proteases are activated in a cascade of proteolytic maturation steps [9,10]. In response to cell deathinducing signals, so-called initiator caspases (i.e., caspase-8 and -9) [11,12] get engaged and activate socalled effector caspases (i.e., caspase-3, -6 and -7) [13], which in turn degrade multiple proteins causing the arrest of vital cellular functions as well as the initiation of lethal catabolic reactions [14][15][16]. Two upstream events account for the activation of initiator caspases. In the extrinsic pathway, caspase-8 is recruited to and gets activated within the death-inducing signaling complex (DISC), a multiprotein complex that forms at the cytoplasmic tails of a specific class of cell surface receptors, the death receptors, upon their occupancy by their respective ligands [12,[17][18][19]. In the intrinsic pathway, caspase-9 is activated at the socalled apoptosome, a supramolecular entity that involves dATP, the cytoplasmic protein APAF1 and the mitochondrial intermembrane space factor cytochrome c, and that only forms when the outer mitochondrial membrane, which usually separates APAF1 (outside) and cytochrome c (inside) is permeabilized [20-24].

Autophagy as a cytoprotective mechanism
Macroautophagy (to which we refer to as "autophagy") is a lysosomal degradation pathway in which portions of the cytoplasm (organelles or cytosol) are enwrapped in double-membraned vesicles (called autophagosomes) that fuse with lysosomes and get degraded by lysosomal hydrolases [81][82][83][84]. Importantly, autophagy and apoptosis exhibit a consistent degree of crosstalk, at multiple levels [85][86][87].
Autophagy can lead to the removal of damaged, potentially dangerous mitochondria, thereby increasing the threshold for cell death induction by MOMPinducing agents or other stressors. Thus, both mitochondrion-specific autophagy (mitophagy) and general autophagy can reduce the propensity of cells to undergo apoptosis [1,76,[88][89][90].
Caspase-dependent apoptosis is associated with the degradation of Beclin 1 by caspases. As Beclin 1 is essential for the initial steps of autophagy, caspase activation most often result into the inhibition of the autophagic pathway [16, 91,92]. This reflects a general pattern according to which pro-apoptotic signals result in the inhibition of pro-survival systems.
Some molecular mechanisms that sense cellular stress can induce both autophagy and apoptosis. This applies for instance to BH3 proteins (as well as pharmacological BH3 mimetics), which can liberate Beclin 1 from inhibitory interactions with BCL-2-like proteins, thereby favoring autophagy, and also stimulate MOMP by activating BAX or BAK [93][94][95][96][97][98][99][100][101]. It is thought that the relative abundance of different Bcl-2 family members, as well as their subcellular localization and activation state may determine whether BH3 proteins/mimetics induce autophagy or apoptosis [66,67]. Moreover, endoplasmic reticulum stress can either result in autophagy or in apoptosis, depending on a yetto-elucidated interplay among threshold effects [88,102,103]. One possible scenario suggests that mild stress would induce an autophagic response that elevates the threshold for apoptosis induction. This would represent a typical case of hormesis (Figure 1).

Autophagy as an anti-aging mechanism
Pharmacological or genetic manipulations designed to prolong lifespan induce autophagy in multiple model organisms, including yeast, nematodes and flies, and the inhibition of autophagy often (always?) prevents longevity extension in such settings. This applies to www.impactaging.com lifespan extension induced by caloric restriction, genetic or pharmacological activation of Sirtuin 1, inhibition of the mammalian target of rapamycin (mTOR) with rapamycin, and administration of spermidine, a histone acetylase inhibitor [3,4,81,[104][105][106][107]. Among these stimuli, there is circumstantial evidence that Sirtuin 1 (whose activation occurs during and is necessary for starvation-and resveratrolinduced autophagy) acts in a hormetic fashion. One of the best-known systems of hormesis is ischemic preconditioning (IPC), whereby short episodes of ischemia protect the brain against a later, more severe reduction in oxygen and nutrient supply. In this system, the administration of resveratrol can mimic IPC, and both resveratrol and IPC induce similar changes in the acetylproteome of the brain [53].
At this stage, it is not clear which (if any) among these putative mechanisms plays a preponderant role in the longevity-increasing potential of autophagy. Future work will have to clarify this issue, which may have a major impact on how we design strategies for prolonging healthy lifespan.