Aging-modulating treatments: from reductionism to a system-oriented perspective.

Abstract

The delay of aging and healthy life extension is a primary concern of modern gerontological research. Based on theoretical assumptions and empirical findings, a number of bioactive agents have been proposed as promising “anti-aging” (geroprotective) preparations (de Magalhaes et al., 2012; Kennedy and Pennypacker, 2014). Usually, the substance is considered to have aging-modulating activity if its efficiency can be confirmed both in vitro and in vivo. In the first step of screening, a hypothetical geroprotective compound (e.g., antioxidant known to play a key role in ROS scavenging) is examined in in vitro models. If its effectiveness is confirmed, then its aging-modulating properties are studied in experimental in vivo models. In the case where supplementation of experimental animals with this agent causes life extension, it advertised as anti-aging drug. A logic discrepancy, however, can be generated between these two steps. Indeed, even if some substance is highly effective in in vitro model due to influencing a specific age-related pathway, its life-extending effects in animal models might be caused by unspecific (hormetic) mechanisms. Hormetic responses are commonly referred to as stimulatory effects occurring in response to low levels of exposure to stressors or agents that are harmful at high levels of exposure. The prevailing hypothesis explaining the hormetic phenomenon is that a low dose of a toxic agent induces damage; following this damage, a repair response is initiated which result in a slight overcompensation to the disruption of homeostasis, i.e., a general response of the organism (Calabrese, 2013). According to this hypothesis, various mild stresses and low-dose pharmacological treatments may cause rather similar beneficial effects because these effects are not mediated by specific receptors. There is a large corpus of data demonstrating that hormesis is implicated in health and disease across various species including human beings (Rattan and Le Bourg, 2014). Longevity hormesis was repeatedly obtained for a number of obviously harmful substances including herbicides, pesticides, heavy metals, and hydrocarbons (Neafsey, 1990). The hormetic model of dose response is usually described as U-shaped curve ranging from impairment at levels of deficient intake, to optimal function at intermediate levels, and to toxicity at excessive intake levels (Calabrese, 2013). All prospective aging-modulating agents are essential nutrients necessary to support health and well-being. These dietary components including minerals, trace elements, vitamins and antioxidants, however, similarly to hormetic compounds (“hormetins”) all exhibit toxic effects at excess levels, i.e., they show typical hormetic dose response (Rattan, 2008). Indeed, while the moderate daily levels of vitamins and minerals are both required and beneficial, their excessive dietary levels are known to cause hypervitaminosis, tissue mineralization, or electrolyte imbalance (Hayes, 2007). The excessive intake of antioxidants and hormones is known to destroy delicate control mechanisms of homeodynamics, and it seems therefore unlikely that they have a long-term beneficial impact (Goto, 2004). Furthermore, both presumably agingmodulating effects and hormetic effects do not preclude the coexistence of toxicity and other adverse outcomes. The predominance of beneficial (life-extending) or deleterious effects may vary not only with dose but also with species, gender, age, stage of life, disease or disability (Minois, 2000). In some cases, life extension caused by both hormetins and geroprotectors may be accompanied by side effects such as impairment of reproductive and immune functions, as well as stress resistance (Matsagas et al., 2009; Saul et al., 2013; McClure et al., 2014). In addition, pharmaceutical interventions can act as caloric restriction (CR) mimetics due to the suppression of the appetite, and their life-extending effects may be caused, at least partially, by the CR-inducing hormetic response (Masoro, 2007). Given all these consideration, it can be concluded that similarity may exist in the mode of action between hormetins and geroprotectors. Currently, however, these are no valid criteria to distinguish mechanistic pathways between them. Such criteria were first proposed and efforts were made to validate them as early as in the 60–70 s of the last century in works of George A. Sacher which distinguished the life-extending effects of substances acting by a “proper action” (a specific role of these agents in reducing the accumulation of age-associated lesions or protecting against age-related disorders) from the hormetic (non-specific) effects (Sacher, 1977). According to this point of view, a hormetic response is a function of the state of an organism, rather than a kind