Systems biology of aging.

Abstract

Human aging occurs at rates that vary widely between organisms and cell types. We hypothesize that in both cases, variation is due to differences in heat production, heat management and molecular susceptibility to heat-induced change. Metabolic rates have long been implored for their contributions to the aging process, with a negative correlation observed between basal metabolic rate and lifespan (Savage et al., Proc Natl Acad Sci U S A 104:4718–4723, 2007, Economos, Exp Gerontol 17:145–152, 1982, Keys et al., Metabolism 22:579–587, 1973, O’Connor et al., Comp Biochem Physiol Part A, Molr & Integr Physiol 133:835–842, 2002, Speakman, J Exp Biol 208:1717–1730, 2005, Poehlman, J Am Geriatrics Soc 41:552–559, 1993). Small amounts of heat are the well-known byproduct of metabolism and other biological processes, and despite their magnitude, are sufficient to elicit alterations in biomolecular characteristics (Somero, Ann Rev Physiol 57:43–68, 1995). Existing theories of aging suggest that damage occurs to the conformations or sequences of molecules, which only shifts focus onto the implied failure of repair mechanisms. Contrarily, heat-induced changes affect the behavioral characteristics of molecules and are thus able to persist “under the radar” of heat shock proteins and other canalizing mechanisms, which recognize only physical aberrancies (Rutherford and Lindquist, Nature 396:336–342, 1998, Siegal and Bergman, Proc Natl Acad Sci U S A 99:10528–10532, 2002, Waddington, Nature 150:563–565, 1942). According to our hypothesis, behavioral changes to the binding affinities, kinetics, motilities, and functionalities are dependent on minute energetic fields within and between molecules. Exposure to the thermal byproducts of metabolism cause heritable shifts in molecular interaction schemes and diminish the integrity of genetic and epigenetic networks. Restructured topologies alter the emergent properties of networks and are observed as the increased variation and decreased functionality associated with “aging” (Moorad and Promislow, Proc Royal Soc B Biol Sci 276:2271–2278, 2009, Soltow et al., Integr Comp Biol 50:844–854, 2010, Siegal et al.,Genetica 129:83–103, 2007, Promislow,Proc Biol sci/The Royal Soc 271:1225–1234, 2004, Southworth et al., PLoS Genet 5:e1000776, 2009, Rodwell et al.,PLoS Biol 2:e427, 2004). A major hurdle in the development of this hypothesis was overcome with the discovery of protein moonlighting: the phenomenon by which proteins assume drastically different functions independent of conformational change (Jeffery, Trends Biochem Sci 24:8–11, 1999). This molecular mechanism validates the hypothesis that network and behavioral changes can undergo somatic inheritance, and be accumulated by daughter cells over the course of a lifetime. Once a damage threshold has been surpassed, a system can no longer sustain life, and death results.