Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts

Abstract

Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism, are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging.

The African turquoise killifish: A research organism to study vertebrate aging and diapause

“…Since the discovery and characterization of the first long‐lived mutants in Caenorhabditis elegans and Saccharomyces cerevisiae more than two decades ago (Kaeberlein, McVey & Guarente, 1999; Kenyon, Chang, Gensch, Rudner & Tabtiang, 1993; Morris, Tissenbaum & Ruvkun, 1996; Ogg et al., 1997; Wang et al., 1993), the concept that aging is a malleable biological process has been well embraced (Finch & Ruvkun, 2001; Gems & Partridge, 2013; Kennedy, 2008; Kenyon, 2005, 2010). …”

The complex genetics of human insulin-like growth factor 2 are not reflected in public databases

“…Similar challenges affecting knowledge of other human genes should promote attempts to critically evaluate, interpret, and correct human genetic data in publicly available databases. ________________________________________ Insulin-like growth factor 2 (IGF2 1 ), a conserved 67-amino acid, single-chain secreted protein, is intimately involved in several critical physiological processes in humans and other mammals (1)(2)(3)(4)(5)(6). IGF2, along with IGF1 and insulin, also comprises a gene family that is found in most mammalian species (7)(8)(9).…”

Enhanced Oxidative Stress Resistance through Activation of a Zinc Deficiency Transcription Factor in Brachypodium distachyon

“…Considering that abiotic stress results in oxidative stress and that enhanced oxidative resistance increases viability from yeast to mammalian systems (Gems and Partridge, 2013), we propose a systematic analysis of conserved oxidative stress-resistant pathways using the monocot model organism B. distachyon to select viable strategies for stress-resistant crop identification through germplasm screening and/or genetic modification. To this end, we have identified protective oxidative stress reporter genes for assessment of the oxidative stress response (Fig.…”

“…The intersection of oxidative stress resistance and longevity is a well-researched field in the animal kingdom (Tullet et al, 2008;Ristow and Schmeisser, 2011;Calabrese et al, 2012;Gems and Partridge, 2013), with many stress and longevity pathways conserved in the plant kingdom. For example, micronutritional depravation of essential nutrients is associated with aging and cognitive decline in animal systems and growth and mass decline in plant systems.…”