Hormesis, cell death and aging
Article by Isabelle Martins, Lorenzo Galluzzi and Guido Kroemer Hormesis, cell death and aging
published in Aging magazine, August 2011, volume 3, No. 8.
Translated by Evgenia Ryabtseva
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Often, low doses of toxins or other stressful factors not only do not harm the body, but also activate adaptive stress reactions that form the body's resistance to high doses of the same agents. The most obvious example of this phenomenon, known as "hormesis", is ischemic preconditioning – a situation where short episodes of ischemia protect the brain and heart from prolonged lack of oxygen and nutrients. Many molecules that cause cell death simultaneously trigger autophagy, a cytoprotective mechanism based on the digestion of intracellular structures that pose a potential danger, mainly mitochondria. Exposure to high doses of such agents causes permeabilization (change in permeability) of the outer mitochondrial membranes and cell death. Low doses of such cytotoxic compounds, on the contrary, are capable of triggering several mechanisms of hormesis, which may explain the ability of autophagy inducers, such as resveratrol and a low-calorie diet, to increase life expectancy.
IntroductionHormesis (a neologism derived from the ancient Greek word "hormaein", literally meaning "to set in motion, to urge, to urge") is a favorable biological reaction to harmless doses of toxins and other stressful factors.
Hormesis-stimulating compounds initiate an adaptive stress reaction that ensures the formation of resistance of cells and organisms to high (usually fatal) doses of the same agent. Theoretically, hormesis can be represented by a single or several mechanisms that allow cells exposed to stress to avoid physiological aging and death and, accordingly, is potentially capable of having a certain effect on (patho)the physiology of aging. Thus, the effect of approaches that, according to available data, increase the life expectancy of many species, such as a low-calorie diet and resveratrol intake [1-6], may be due to the triggering of mechanisms of hormesis [7, 8]. In this article, we will analyze the molecular signaling cascades linking cellular stress with cell death, as well as the mechanisms of their separation triggered by the development of the hormesis reaction.
Mechanisms of excessive activation leading to apoptotic cell deathApoptosis is often considered as a mechanism of caspase-dependent cell death, when triggered, activation of a number of specific cysteine proteases occurs in the form of a cascade consisting of several stages of proteolytic maturation [9, 10].
The effect of cell death-inducing signals stimulates the activity of the so-called initiating caspases (caspases-8 and -9) [11, 12], which activate the so-called effector caspases (caspases-3, -6 and -7) [13], which, in turn, destroy a large number of proteins. This leads to the stoppage of vital cell functions and the triggering of lethal catabolic reactions [14-16]. Two events lead to the activation of the initiating caspases. When the external mechanism is triggered, caspase-8 is involved and activated inside the cell death-inducing signaling complex (DISC, from the English "death–inducing signaling complex") – a multi–protein complex formed on the intracellular terminal segment of a special class of cell surface receptors - the so-called cell death receptors - when they bind to the corresponding ligands [12, 17-19]. When the internal mechanism is triggered, caspase-9 is activated inside the so–called apoptosome - a supramolecular structure consisting of dATP (deoxyadenosine-5-triphosphate), cytoplasmic protein APAF1 and mitochondrial intermembrane space factor cytochrome C. Apoptosomes are formed only when the conductivity of the outer mitochondrial membrane is disrupted, usually separating the APAF1 protein (outside) and cytochrome C (inside) [20-24].
Nevertheless, inhibition of caspases rarely completely prevents cell death (although in some cases it smooths out morphological manifestations of apoptosis) [10, 25-27], since numerous caspase-independent mechanisms can come into play [9, 28, 29]. For example, a violation of the permeability of the mitochondrial membrane can lead to the release of apoptosis-inducing factor (AIF) and cofilin, both of which act as caspase-independent effectors of cell death [30-33]. This moves the mechanism of cell death control to the level of mitochondria, or rather, to the level of mitochondrial membranes, the violation of the permeability of which is regulated by a variety of effectors and processes, including various classes of stress-activated kinases [24, 34-43], the tumor growth suppressor protein p53 [44-46], epigenetic changes [47-51], (de)acetylases [52, 53], cell cycle disorders [54, 55] and damage to the nucleus [56-60].
According to the key role of mitochondria in the management of many (if not all) apoptotic mechanisms [61-65], the functions and integrity of mitochondria are regulated by a whole set of unrelated mechanisms. Proteins of the Bcl-2 family are considered to be the main modulators of mitochondrial apoptosis [66-68], however, other proteins not directly related to BCL-2 can also induce or suppress a violation of the permeability of the outer membrane of mitochondria. Thus, in addition to BCL-2 and its close relatives BCL2L1 (better known as Bcl-X L) and MCL1, the proteins PRELI [69], uncoupling protein 2 [70] and X-linked inhibitor of apoptosis are able to suppress the violation of the permeability of the outer membrane of mitochondria [22]. Proapoptotic proteins, such as the multidomain proteins BAX and BAK [71], as well as numerous "BH3-only" proteins, stimulate a violation of the permeability of the outer membrane of mitochondria [72-74]. In addition, a violation of the permeability of the outer membrane of mitochondria can stimulate pro-oxidants [75-77], membrane destabilizing lipids (such as ceramide) [52] and free Ca 2+ ions (whose concentration is modulated by the concentration of other divalent cations, such as Mg 2+ and Zn 2+, as well as, possibly, a monovalent Li+ cation) [21, 23, 78-80].
Autophagy as a cytoprotective mechanismMacroautophagy (which we usually call "autophagy") is a mechanism of lysosomal degradation, during which cytoplasmic fragments (organelles or cytosol) are enclosed inside vesicles surrounded by a two-layer membrane (autophagosomes), which merge with lysosomes, where their degradation occurs under the action of lysosomal hydrolase enzymes [81-84].
It is important to note that at many levels autophagy and apoptosis show a pronounced mutual influence [85-87].
The result of autophagy may be the removal of damaged potentially dangerous mitochondria, which increases the threshold for triggering the mechanisms of cell death under the action of agents inducing a violation of the permeability of the outer membrane of mitochondria, or other stressful factors. Thus, both selective autophagy of mitochondria (mitophagy) and autophagy in general are able to reduce the predisposition of cells to apoptosis [1, 76, 88-90].
Caspase-dependent apoptosis is associated with the degradation of the Beclin 1 protein under the action of caspases. Beclin 1 is necessary to trigger the first stage of autophagy, so activation of caspases most often leads to inhibition of the autophagy mechanism [16, 91, 92]. This reflects the general trend according to which pro-apoptotic signals lead to suppression of the functioning of systems that ensure survival.
Some stress-recognizing molecular mechanisms can simultaneously induce autophagy and apoptosis. This applies, for example, to BH3 proteins (as well as to pharmacological preparations – BH3 mimetics), which can relieve Beclin 1 from inhibitory interactions with BCL-2 family proteins, creating favorable conditions for triggering autophagy, as well as stimulate disruption of the permeability of the outer mitochondrial membrane by activating BAX or BAK [93-101]. It is believed that a relatively high concentration of different representatives of the Bcl-2 family, as well as their intracellular localization and activated state, can determine the mechanism (autophagy or apoptosis) induced by BH3 proteins or their mimetics [66, 67]. Moreover, the stress experienced by the endoplasmic reticulum can also trigger autophagy or apoptosis, depending on the interaction of threshold effects, which scientists have yet to decipher [88, 102, 103]. According to one possible scenario, mild stress can induce an autophagy reaction that raises the threshold for the induction of apoptosis. Such a scheme is a typical variant of hormesis (Fig. 1).
Figure 1. Autophagy and hormesis. Under normal conditions, autophagy helps maintain cellular homeostasis by removing potentially dangerous mitochondria (or other damaged organelles) and recycling protein aggregates. This can slow down aging and increase the duration of a healthy life by increasing the threshold amount of damage, the achievement of which leads to disruption of the functioning of the cell or its death. In this case, high doses of agents that simultaneously stimulate autophagy and cell death (for example, BH3 mimetics) are toxic (A); low doses of the same agents can trigger a hormesis reaction and, thus, contribute to the adaptation of cells to stressful conditions (B). (MOMP – a change in the permeability of the outer membrane of mitochondria, mitochondrial outer membrane permeabilization.)
Autophagy as a mechanism to slow down agingPharmacological and genetic manipulations aimed at increasing life expectancy induce autophagy in the cells of various model organisms, including yeast, roundworms and fruit flies.
At the same time, inhibition of autophagy often (perhaps always) prevents an increase in the lifespan of these organisms. This pattern extends to an increase in life expectancy induced by a low-calorie diet, genetic or pharmacological activation of sirtuin 1, inhibition of mammalian rapamycin target protein (mTOR) using rapamycin, as well as the use of a histone deacetylase inhibitor spermidine [3, 4, 81, 104-107]. There is indirect evidence that exposure to one of these stimuli, sirtuin 1 (activation of which occurs when using a low-calorie diet and resveratrol and is an inducer of autophagy), triggers the mechanism of hormesis. One of the most well-known examples of hormesis is ischemic preconditioning (IPC), in which short-term episodes of ischemia protect the brain from a subsequent more severe and prolonged decrease in the supply of oxygen and nutrients. In this system, the use of resveratrol can mimic the effects of IPC; at the same time, both resveratrol and IPC induce similar changes in the acetylation profile of brain cell proteins [53].
To date, the mechanisms by which autophagy can increase life expectancy remain a mystery [108, 109]. One of the obvious options is the cytoprotective, apoptosis-suppressing effect of autophagy (see above), however, other possibilities should be taken into account. For example, there is a large amount of evidence that inhibition of mTOR (stimulating autophagy, and possibly having other metabolic effects) slows down the onset of physiological aging [105, 110-115]. Thus, it can be assumed that autophagy can delay the physiological aging induced by DNA-damaging agents [116-119], as well as slow down the process of stem cell depletion occurring in the late stages of aging [120-123], but this has yet to be proven. At the same time, there is quite convincing evidence that autophagy acts as a mechanism for suppressing tumor growth, which allows avoiding genetic instability that stimulates the multi-stage process of carcinogenesis [3, 114, 124-130].
In addition to all this, autophagy intensifies the turnover of cellular proteins prone to the formation of aggregates, which reduces the concentration of neurotoxic factors, including huntingtin protein aggregates [131]. However, the possible effect of autophagy on the accumulation of potentially toxic extracellular proteins (such as beta-amyloid, etc.) has yet to be understood [32, 132-134].
At the present stage, it is unclear which (if any) of the above-mentioned alleged mechanisms play the most important role in the ability of autophagy to increase life expectancy. Future research should clarify this issue, which may have a decisive impact on the development of strategies to increase the duration of a healthy human life.
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14.11.2011