Enhancing and Extending Biological Performance and Resilience

Abstract

Human performance, endurance, and resilience have biological limits that are genetically and epigenetically predetermined but perhaps not yet optimized. There are few systematic, rigorous studies on how to raise these limits and reach the true maxima. Achieving this goal might accelerate translation of the theoretical concepts of conditioning, hormesis, and stress adaptation into technological advancements. In 2017, an Air Force-sponsored conference was held at the University of Massachusetts for discipline experts to display data showing that the amplitude and duration of biological performance might be magnified and to discuss whether there might be harmful consequences of exceeding typical maxima. The charge of the workshop was "to examine and discuss and, if possible, recommend approaches to control and exploit endogenous defense mechanisms to enhance the structure and function of biological tissues." The goal of this white paper is to fulfill and extend this workshop charge. First, a few of the established methods to exploit endogenous defense mechanisms are described, based on workshop presentations. Next, the white paper accomplishes the following goals to provide: (1) synthesis and critical analysis of concepts across some of the published work on endogenous defenses, (2) generation of new ideas on augmenting biological performance and resilience, and (3) specific recommendations for researchers to not only examine a wider range of stimulus doses but to also systematically modify the temporal dimension in stimulus inputs (timing, number, frequency, and duration of exposures) and in measurement outputs (interval until assay end point, and lifespan). Thus, a path forward is proposed for researchers hoping to optimize protocols that support human health and longevity, whether in civilians, soldiers, athletes, or the elderly patients. The long-term goal of these specific recommendations is to accelerate the discovery of practical methods to conquer what were once considered intractable constraints on performance maxima.

Keywords: J-shaped; U-shaped; adaptation; biphasic; caloric restriction; conditioning; dietary restriction; dose–response; endurance; epigenetics; fitness; hormesis; preconditioning; stress; tolerance.

Figure 1.

The traditional biphasic dose–response curve. Biological fitness as a function of stimulus intensity. The mathematical features of a typical biphasic dose–response curve in the literature are displayed. At low doses, a single exposure to a stimulus elicits a modest increase in cellular fitness according to the principles of hormesis. With increasing stressor intensity, cellular defense systems are overwhelmed, and frank toxicity emerges at stimulus levels greater than the no observable adverse effect level (NOAEL).

Figure 2.

Kinetics of stress protein accumulation after repetitive exposure to cocaine. Repeated exposure to the biochemical stress of cocaine leads to chronic changes in activator protein -1 (AP-1) complex protein ΔFosB in the lower panel. This “staircase” pattern in induced gene expression is analogous to the proposed “layered” hormetic effects of repetitive conditioning and might be measured at the level of the “hormesis proteome.” The accumulated level of ΔFosB isoform expression continues after the cessation of the stimulus (arrows at bottom of figure). Adapted from Nestler et al. (2008).

Figure 3.

Idealized hormesis enhancement/extension curve. Biological fitness (ie, integrated indices of health) as a function of repeated exposures to optimized hormetic stimuli applied at rhythmic intervals. The amplitude of the hormetic maximum is extended to the genetically determined peak until age-related loss of fitness overwhelms natural defense systems and the inevitable (but perhaps delayed) engagement of senescence programs culminates in death. Note that death should result because of the passage of time rather than stimulus exposures per se. A single hormetic stimulus exposure results in a modest amplitude effect and a time-limited response, but repeated exposures build, in stepwise manner, the layers of a strong foundation for an extended, high-amplitude response. Other assumptions of this idealized graph include that environmental stimuli such as dietary/lifestyle factors are optimized so that the maximal epigenetic/genetic potential can be reached. Hormetic maxima may vary with gender, genetic vulnerabilities, geographic region (eg, altitude), age, comorbidities, etc.