To follow on from the post on reactive oxygen species in aging earlier today, I thought I'd direct your attention to a few more recent papers that approach this topic from various directions. To recap, it has long been known that the level of oxidative damage in cells increases with age, a state of affairs called oxidative stress, and that this is largely a product of changes in mitochondria, the power plants of the cell where more energetic chemistry takes place. What does this mean? Cells are intricate, dynamic, mostly fluid bundles of molecular machinery, and roving reactive molecules - such as reactive oxygen species (ROS) - cause harm by reacting with this machinery so as to prevent it from functioning correctly. When there are more such reactive molecules, there is a higher rate of ongoing damage, and cells must work harder to maintain correct functionality and behavior.
Oxidative stress in the general sense of the flux of cell damage versus cell repair features prominently in the past generation of theories of aging, but since those theories were first proposed, further investigation of the roles and relationships involving ROS has considerably complicated the picture. It isn't a straightforward case of more oxidative stress creating faster aging, with a clear set of changes driving degeneration at every step. The bulk of oxidative stress inside cells may be largely irrelevant in comparison to other facets and consequences of mitochondrial dysfunction, such as the generation of oxidized lipids that then enter the bloodstream.
The big picture is still incomplete, but it nonetheless seems that there is no straightforward relationship between aging, varying levels of ROS inside cells, and the many ways to measure oxidative stress. As it turns out ROS molecules are as much useful signals inside cells as they are a part of the damage and dysfunction of aging: methods of modestly extending life span in laboratory species can involve either higher or lower levels of ROS, depending on the details, and some long-lived species have all of the biochemical markers of high levels of oxidative stress but none of the expected dysfunction. Like all aspects of metabolism, complexity is the rule, and attempts to manipulate ROS-related mechanisms to obtain health benefits via the standard process of drug discovery and development will no doubt prove to be just as slow and expensive as other, similar approaches to shifting metabolism into a more advantageous state.
Oxidative stress and the generation of reactive oxygen species (ROS) can lead to mitochondrial dysfunction, DNA damage, protein misfolding, programmed cell death with apoptosis and autophagy, and the promotion of aging-dependent processes. Mitochondria control the processing of redox energy that yields adenosine triphosphate (ATP). Ultimately, the generation of ROS occurs with the aerobic production of ATP. Although reduced levels of ROS may lead to tolerance against metabolic, mechanical, and oxidative stressors and the generation of brief periods of ROS during ischemia-reperfusion models may limit cellular injury, under most circumstances ROS and mitochondrial dysfunction can lead to apoptotic caspase activation and autophagy induction that can result in cellular demise. Yet, new work suggests that ROS generation may have a positive impact through respiratory complex I reverse electron transport that can extend lifespan. Such mechanisms may bring new insight into clinically relevant disorders that are linked to cellular senescence and aging of the body's system. Further investigation of the potential "bright side" of ROS and mitochondrial respiration is necessary to target specific pathways that can impact oxidative stress-ROS mechanisms to extend lifespan and eliminate disease onset.
Signals from reproductive tissues and germ cells influence the lifespans of many organisms, including mammals. How germ cells, which give rise to the next generation, control the aging of the animal in which they reside is poorly understood. Counter-intuitively, we found that removing germ cells in Caenorhabditis elegans triggers the generation of two potentially toxic substances, reactive oxygen species (ROS) and hydrogen sulfide (H2S), in nonreproductive somatic tissues. These substances, in turn, induce protective responses that slow aging. A cytoskeletal protein, KRI-1, plays a key role in the generation of H2S and ROS. These kri-1-dependent redox species, in turn, promote life extension by activating SKN-1/Nrf2 and the mitochondrial unfolded-protein response, respectively. Both H2S and, remarkably, kri-1-dependent ROS are required for the life extension produced by low levels of the superoxide-generator paraquat and by a mutation that inhibits respiration. Together our findings link reproductive signaling to mitochondria and define an inducible, kri-1-dependent redox-signaling module that can be invoked in different contexts to extend life and counteract proteotoxicity.
Physical frailty in the elderly is driven by loss of muscle mass and function and hence preventing this is the key to reduction in age-related physical frailty. Our current understanding of the key areas in which ROS contribute to age-related deficits in muscle is through increased oxidative damage to cell constituents and/or through induction of defective redox signalling. Recent data have argued against a primary role for ROS as a regulator of longevity, but studies have persistently indicated that aspects of the aging phenotype and age-related disorders may be mediated by ROS. There is increasing interest in the effects of defective redox signalling in aging and some studies now indicate that this process may be important in reducing the integrity of the aging neuromuscular system. Understanding how redox-signalling pathways are altered by aging and the causes of the defective redox homeostasis seen in aging muscle provides opportunities to identify targeted interventions with the potential to slow or prevent age-related neuromuscular decline with a consequent improvement in quality of life for older people.
Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.