Discussion

Lifespan is not determined by metabolic rate: evidence from fishes and C. elegans

Several studies have demonstrated that high glucose feeding induced oxidative stress and apoptosis thereby affecting growth, fertility, aging and lifespan in Caenorhabditis elegans. Earlier studies from our laboratory had clearly established the propensity of monocrotophos, an OPI to alter the physiological and behavioral responses of C. elegans. The present study was aimed to investigate the effect of monocrotophos (MCP) on physiological/behavioral and biochemical responses in C. elegans that were maintained on high glucose diet. We exposed the worms through development to high glucose diet (2%) and then treated with sublethal concentrations of MCP (0.5, 0.75, 1.5 mM). We measured the behavioral responses in terms of locomotion, physiological responses in terms of egg laying, brood size, lifespan; morphological alterations; and biochemical responses including glucose content. The worms exposed from egg stage through development to high glucose diet showed enhanced toxic outcome of MCP in terms of physiological, behavioral and biochemical responses. Our studies showed that C. elegans is a good model to study glucose–OPI interactive neurotoxicity since all the responses could be studied at ease in this organism and the outcome could be well extrapolated to those that one would expect in higher animals.

Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seems to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters. In addition, old rats also conserve the capacity to respond to 7 weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA.

The quest to understand why we age has given rise to numerous lines of investigation that have gradually converged to include metabolic control by mitochondrial activity as a major player. That is, the ideal balance between nutrient uptake, its transduction into usable energy, and the mitigation of damaging byproducts can be regulated by mitochondrial respiration and output (ATP, reactive oxygen species (ROS), and heat). Mitochondrial inefficiency through proton leak, which uncouples substrate oxidation from ADP phosphorylation, can comprise as much as 30% of the basal metabolic rate. This uncoupling is hypothesized to protect cells from conditions that favor ROS production. Uncoupling can also occur through pharmacological induction of proton leak and activity of the uncoupling proteins. Mitochondrial uncoupling is implicated in lifespan extension through its effects on metabolic rate and ROS production. However, evidence to date does not suggest a consistent role for uncoupling in lifespan. The purpose of this review is to discuss recent work examining how mitochondrial uncoupling impacts lifespan.

The processes that determine an organism's lifespan are complex and poorly understood. Yet single gene manipulations and environmental interventions can substantially delay age-related morbidity. In this review, we focus on the two most potent modulators of longevity: insulin/insulin-like growth factor 1 (IGF-1) signaling and dietary restriction. The remarkable molecular conservation of the components associated with insulin/IGF-1 signaling and dietary restriction allow us to understand longevity from a multi-species perspective. We summarize the most recent findings on insulin/IGF-1 signaling and examine the proteins and pathways that reveal a more genetic basis for dietary restriction. Although insulin/IGF-1 signaling and dietary restriction pathways are currently viewed as being independent, we suggest that these two pathways are more intricately connected than previously appreciated. We highlight that numerous interactions between these two pathways can occur at multiple levels. Ultimately, both the insulin/IGF-1 pathway and the pathway that mediates the effects of dietary restriction have evolved to respond to the nutritional status of an organism, which in turn affects its lifespan.

The free radical theory of aging is one of the most prominent theories of aging and senescence, but has yet to be definitively proven. If free radicals are the cause of senescence, then the cellular anti-oxidant system should play a large role in lifespan determination. Because superoxide dismutase (SOD) plays a central role in detoxifying superoxide radicals, we have examined the effects of mutational inactivation of each isoform of sod on normal lifespan and lifespan extension by dietary restriction (DR) or cold-/hypothermic-induced longevity (CHIL). We find no significant decrease in lifespan for control worms or worms undergoing DR when sod isoforms are knocked-out even though sod mutational inactivation produces hypersensitivity to paraquat. In contrast, sod-1 inactivation significantly reduces lifespan extension by CHIL, suggesting that CHIL requires a specific genetic program beyond simple reduction in metabolic rate. Furthermore, CHIL paradoxically increases lifespan while reducing resistance to oxidative stress, further disassociating oxidative stress resistance and lifespan.

Available information indicates that long-lived mammals have low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, many studies have consistently shown that dietary restriction (DR) in rodents also decreases mitochondrial ROS (mtROS) production and oxidative damage to mitochondrial DNA and proteins. It has been observed that protein restriction also decreases mtROS generation and oxidative stress in rat liver, whereas neither carbohydrate nor lipid restriction change these parameters. This is interesting because protein restriction also increases maximum longevity in rodents (although to a lower extent than DR) and is a much more practicable intervention for humans than DR, whereas neither carbohydrate nor lipid restriction seem to change rodent longevity. Moreover, it has been found that isocaloric methionine restriction also decreases mtROS generation and oxidative stress in rodent tissues, and this manipulation also increases maximum longevity in rats and mice. In addition, excessive dietary methionine also increases mtROS generation in rat liver. These studies suggest that the reduced intake of dietary methionine can be responsible for the decrease in mitochondrial ROS generation and the ensuing oxidative damage that occurs during DR, as well as for part of the increase in maximum longevity induced by this dietary manipulation. In addition, the mean intake of proteins (and thus methionine) of Western human populations is much higher than needed. Therefore, decreasing such levels to the recommended ones has a great potential to lower tissue oxidative stress and to increase healthy life span in humans while avoiding the possible undesirable effects of DR diets.