The sirtuins, oxidative stress and aging: an emerging link

Abstract

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.

Figure 1. Reactive oxygen species: production and protection

Schematic showing the major reactive oxygen species associated with cellular respiration. Blue arrows indicate detoxification mechanisms while red arrows indicate reactivity for each ROS.

Figure 2. Regulation of ROS by sirtuins

Diagram showing how ROS, aging, and caloric restriction interact to influence the activity of the cytoplasmic/nuclear sirtuin, SIRT1, and the mitochondrial sirtuin, SIRT3. Upon activation, SIRT1 and SIRT3 deacetylate several proteins that promote resistance to oxidative stress. Arrows indicate positive regulation while hash-marks indicate negative regulation. Solid lines reflect robust experiment evidence for an interaction while dashed lines indicate putative interactions.

Figure 3. Aging and Mitohormesis

Theoretical curve showing how low doses of a stressor may have beneficial effects by activating intracellular stress response pathways. If the stressor exceeds the capacity of the stress response system to maintain homeostasis, then deleterious phenotypes are observed.

Figure 4. Hyperacetylation and Mitohormesis

Theoretical model linking mitochondrial hyperacetylation to the generation of ROS and mitohormesis.