Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies.

Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.

[Transdisciplinary approach in free radical theory of ageing. Contribution of Nikolay M. Emanuel and his scientific school to gerontology.]

The work is aimed to review the results of scientific studies of the effect of antioxidants-geroprotectors on the aging of experimental animals and the replicative aging of human diploid cells, carried out in the Department of Kinetics of Chemical and Biological Processes «KHIMBIO¼ of the Institute of Chemical Physics of the USSR Academy of Sciences under the leadership of academician Nikolay Markovich Emanuel in the 1960-1980s after pioneer work by D.Harman. By N.M.Emanuel and colleagues, it was established a previously unknown phenomenon of radical interaction of inhibitors in the oxidation of organic substances, which consists in the regeneration of a more effective inhibitor due to the transfer of a hydrogen atom to its free radical from a molecule of a less effective inhibitor. Antioxidants are polyvalent and can simultaneously affect many stages of aging processes. Data from the N.M.Emanuel scientific school on the increase of the average lifespan of mice by 25,3% and their maximum lifespan by 55,8% using antioxidants, discovered at the Institute of Chemical Physics of the USSR Academy of Sciences as a result of well-founded experimental and theoretical studies, became a powerful argument in favor of the free radical theory of aging in 1970-ties. This was further promoted by approaches based on the theory of reliability, the damage theory, and as well as an approach based on oxidative activation of the Nrf2 signaling pathway, which maintains the «nucleophilic tone¼ of protective oxidoreductases.

Evaluation of the anti-aging and antioxidant action of Ananas sativa and Moringa oleifera in a fruit fly model organism.

aging is an inevitable biological complex process. It involves the gradual loss of cellular vitality due to accumulative damage to cellular macromolecules by reactive oxygen species (ROS). These ROS are highly implicated in health, disease, and lifespan. The biochemical pathways involved in the aging process are highly influenced by both exogenous (environmental factors) and endogenous stress factors. These cellular processes are the same in most organisms including the fruit fly, nematode, yeast, mammalian cell line, and rodents. These model organisms have been extensively used in the screening of potent antioxidant botanicals for anti-aging bioactivity. Moringa oleifera and Ananas sativa are great sources of health-promoting nutrients and antioxidants, however, their anti-aging impact is still an evolving area of research interest. Therefore, this review focused on their anti-aging mode of action and some other anti-aging nutriceuticals in different model organisms including the fruit fly. PRACTICAL APPLICATIONS: Staying forever young and healthy is everyone's right. Aside from genetic trait, healthy feeding is peculiar to the world's longest-living people. Ananas sativa (pineapple) and Moringa oleifera leaves are highly valued fruit and herb with nourishing, antioxidant, and medicinal properties. Their extract exhibit antioxidant, anticancer, anti-inflammatory, and anti-aging activities. The ancient Greeks, Egyptians, and Romans used Moringa seed oil for cosmetics and perfumes. Moringa tea leaves is consumed for its nutritive and medicinal value. Its antioxidant potency endorses its use for anti-aging and other health-promoting purposes. The bioactive compound in pineapple, bromelain, promotes wound healing and it is a component of postsurgical applications due to its anti-inflammatory property. Consumption of Ananas fruit provides the recommended daily allowance of vitamin C, a potent antioxidant. To identify new anti-aging bioactive compounds of therapeutic importance, and understanding the mode of action of these nutriceuticals will contribute to new anti-aging research prospects.

What is the rate-limiting step towards aging? Chemical reaction kinetics might reconcile contradictory observations in experimental aging research.

Modern geroscience is divided as regards the validity of the free radical theory of aging. Thermodynamic arguments and observations from comparative zoology support it, whereas results from experimental manipulations in representative animal species sometimes strongly contradict it. From a comparison of the multi-step aging process with a linear metabolic pathway (glycolysis), we here argue that the identification of the rate-limiting kinetic steps of the aging cascade is essential to understand the overall flux through the cascade, i.e., the rate of aging. Examining free radical reactions as a case in point, these reactions usually occur as chain reactions with three kinetically independent steps: initiation, propagation, and termination, each of which can be rate-limiting. Revisiting the major arguments in favor and against a role of free radicals in aging, we find that the majority of arguments in favor point to radical propagation as relevant and rate-limiting, whereas almost all arguments in disfavor are based on experimental manipulations of radical initiation or radical termination which turned out to be ineffective. We conclude that the overall lack of efficacy of antioxidant supplementation (which fosters termination) and antioxidant enzyme overexpression (which inhibits initiation) in longevity studies is attributable to the fact that initiation and termination are not the rate-limiting steps of the aging cascade. The biological and evolutionary plausibility of this interpretation is discussed. In summary, radical propagation is predicted to be rate-limiting for aging and should be explored in more detail.

Research progress about the anti-aging effect and mechanism of flavonoids from traditional Chinese medicine / 药学学报

Aging is a normal physiological process involving coaction of many factors. The anti-aging effects of natural products have been studied by many domestic and international scholars, but not far enough, which still needed to be explored. Flavonoids, as natural products, have a variety of pharmacological activities and present in many traditional Chinese medicines. In recent years, research results indicate that flavonoids can delay the aging process of the nervous, immune, and reproductive systems, and the liver, skin and other tissues. The anti-aging effects of flavonoids have attracted more and more attention. Therefore, development of anti-aging drugs from flavonoids is of great significance to improve the quality of life for the elderly and slow the process of aging. However, the mechanism of the anti-aging effect of flavonoids remains unknown at present. This review will discuss the anti-aging effect and mechanisms of flavonoids in traditional Chinese medicine from the aspects of cellular signaling pathways and metabolic pathways based on the modern theories of aging.

Effect of a Strawberry and Spinach Dietary Supplement on Spatial Learning in Early and Late Middle-Aged Female Rats.

The present experiment sought to determine the effect of an eight-week, high antioxidant, whole-foods dietary supplement on Morris Water Maze performance in early and late middle-aged female rats. To improve ecological validity over past experimental studies, rats in the current study received antioxidants by consuming freeze-dried organic strawberries and spinach rather than by being given food extracts or antioxidant injections. Latency and path length measures both indicated that late middle-aged rats fed the high antioxidant diet performed on a par with the younger animals earlier in training than their standard diet counterparts (p < 0.05). Superior performance was not due to improved fitness in the antioxidant-supplemented rats. Thus, our model showed that a high antioxidant diet of relatively short duration mitigated the mild cognitive decline that was seen in control animals during the developmental period of late middle-age. The current results offer support for the promising role of dietary antioxidants in maintaining cognitive health in normal aging and extend past findings to females, who have been relatively neglected in experimental investigations. Moreover, the current model suggests that the period of transition from early to late middle age is a promising target for dietary intervention in healthy adults.

Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions.

Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the "free radical theory of aging", including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age.

Testing the Effects of DL-Alpha-Tocopherol Supplementation on Oxidative Damage, Total Antioxidant Protection and the Sex-Specific Responses of Reproductive Effort and Lifespan to Dietary Manipulation in Australian Field Crickets (Teleogryllus commodus).

The oxidative stress theory predicts that the accumulation of oxidative damage causes aging. More generally, oxidative damage could be a cost of reproduction that reduces survival. Both of these hypotheses have mixed empirical support. To better understand the life-history consequences of oxidative damage, we fed male and female Australian field crickets (Teleogryllus commodus) four diets differing in their protein and carbohydrate content, which have sex-specific effects on reproductive effort and lifespan. We supplemented half of these crickets with the vitamin E isoform DL-alpha-tocopherol and measured the effects of nutrient intake on lifespan, reproduction, oxidative damage and antioxidant protection. We found a clear trade-off between reproductive effort and lifespan in females but not in males. In direct contrast to the oxidative stress theory, crickets fed diets that improved their lifespan had high levels of oxidative damage to proteins. Supplementation with DL-alpha-tocopherol did not significantly improve lifespan or reproductive effort. However, males fed diets that increased their reproductive investment experienced high oxidative damage to proteins. While this suggests that male reproductive effort could elevate oxidative damage, this was not associated with reduced male survival. Overall, these results provide little evidence that oxidative damage plays a central role in mediating life-history trade-offs in T. commodus.

Mitochondrial uncoupling as a regulator of life-history trajectories in birds: an experimental study in the zebra finch.

Mitochondria have a fundamental role in the transduction of energy from food into ATP. The coupling between food oxidation and ATP production is never perfect, but may nevertheless be of evolutionary significance. The 'uncoupling to survive' hypothesis suggests that 'mild' mitochondrial uncoupling evolved as a protective mechanism against the excessive production of damaging reactive oxygen species (ROS). Because resource allocation and ROS production are thought to shape animal life histories, alternative life-history trajectories might be driven by individual variation in the degree of mitochondrial uncoupling. We tested this hypothesis in a small bird species, the zebra finch (Taeniopygia guttata), by treating adults with the artificial mitochondrial uncoupler 2,4-dinitrophenol (DNP) over a 32-month period. In agreement with our expectations, the uncoupling treatment increased metabolic rate. However, we found no evidence that treated birds enjoyed lower oxidative stress levels or greater survival rates, in contrast to previous results in other taxa. In vitro experiments revealed lower sensitivity of ROS production to DNP in mitochondria isolated from skeletal muscles of zebra finch than mouse. In addition, we found significant reductions in the number of eggs laid and in the inflammatory immune response in treated birds. Altogether, our data suggest that the 'uncoupling to survive' hypothesis may not be applicable for zebra finches, presumably because of lower effects of mitochondrial uncoupling on mitochondrial ROS production in birds than in mammals. Nevertheless, mitochondrial uncoupling appeared to be a potential life-history regulator of traits such as fecundity and immunity at adulthood, even with food supplied ad libitum.

Mitochondrial free radical theory of aging: who moved my premise?

First proposed by D Harman in the 1950s, the Mitochondrial Free Radical Theory of Aging (MFRTA) has become one of the most tested and well-known theories in aging research. Its core statement is that aging results from the accumulation of oxidative damage, which is closely linked with the release of reactive oxygen species (ROS) from mitochondria. Although MFRTA has been well acknowledged for more than half a century, conflicting evidence is piling up in recent years querying the causal effect of ROS in aging. A critical idea thus emerges that contrary to their conventional image only as toxic agents, ROS at a non-toxic level function as signaling molecules that induce protective defense in responses to age-dependent damage. Furthermore, the peroxisome, another organelle in eukaryotic cells, might have a say in longevity modulation. Peroxisomes and mitochondria are two organelles closely related to each other, and their interaction has major implications for the regulation of aging. The present review particularizes the questionable sequiturs of the MFRTA, and recommends peroxisome, similarly as mitochondrion, as a possible candidate for the regulation of aging.

Proteomic analysis of mitochondria from senescent Podospora anserina casts new light on ROS dependent aging mechanisms.

The mitochondrial free radical theory of aging (MFRTA) states that reactive oxygen species (ROS) generated at the respiratory electron transport chain are active in causing age-related damage of biomolecules like lipids, nucleic acids and proteins. Accumulation of this kind of damage results in functional impairments, aging and death of biological systems. Here we report data of an analysis to monitor the age-related quantitative protein composition of the mitochondria of the fungal aging model Podospora anserina. The impact of senescence on mitochondrial protein composition was analyzed by LC-MS. In an untargeted proteomic approach, we identified 795 proteins in samples from juvenile and senescent wild-type cultures and obtained quantitative information for 226 of these proteins by spectral counting. Despite the broad coverage of the proteome, no substantial changes in known age-related pathways could be observed. For a more detailed analysis, a targeted proteome analysis was applied focusing on 15 proteins from respiratory, ROS-scavenging and quality control pathways. Analyzing six distinct age-stages from juvenile to senescent P. anserina cultures revealed low, but statistically significant changes for the mitochondrial respiratory complexes. A P. anserina PaSod3 over-expression mutant with a phenotype of mitochondrial ROS over-production was used for biological evaluation of changes observed during aging. LC-MS analysis of the mutant revealed severe changes to the mitochondrial proteome--substantially larger than observed during senescence. Interestingly the amount of ATP synthase subunit g, involved in cristae formation is significantly decreased in the mutant implicating ROS-induced impairments in ATP synthase dimer and cristae formation. The difference between protein-profiles of aging wild type and ROS stressed mutant suggests that oxidative stress within the mitochondria is not the dominating mechanism for the aging process in P. anserina. Collectively, while our data do not exclude an effect of ROS on specific proteins and in signaling and control of pathways which are governing aging of P. anserina, it contradicts increasing ROS as a cause of a gross general and non-selective accumulation of damaged proteins during senescence. Instead, ROS may be effective by controlling specific regulators of mitochondrial function.

Manipulating reproductive effort leads to changes in female reproductive scheduling but not oxidative stress.

The trade-off between reproductive investment and lifespan is the single most important concept in life-history theory. A variety of sources of evidence support the existence of this trade-off, but the physiological costs of reproduction that underlie this relationship remain poorly understood. The Free Radical Theory of Ageing suggests that oxidative stress, which occurs when there is an imbalance between the production of damaging Reactive Oxygen Species (ROS) and protective antioxidants, may be an important mediator of this trade-off. We sought to test this theory by manipulating the reproductive investment of female mice (Mus musculus domesticus) and measuring the effects on a number of life history and oxidative stress variables. Females with a greater reproductive load showed no consistent increase in oxidative damage above females who had a smaller reproductive load. The groups differed, however, in their food consumption, reproductive scheduling and mean offspring mass. Of particular note, females with a very high reproductive load delayed blastocyst implantation of their second litter, potentially mitigating the costs of energetically costly reproductive periods. Our results highlight that females use strategies to offset particularly costly periods of reproduction and illustrate the absence of a simple relationship between oxidative stress and reproduction.

Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials.

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction.

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 7weeks 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 7weeks 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.

Stressed out mitochondria: the role of mitochondria in ageing and cancer focussing on strategies and opportunities in human skin.

Mitochondrial DNA damage has been used as a successful and unique biomarker of tissue stress. A valuable example of this is sun damage in human skin which leads to ageing and skin cancer. The skin is constantly exposed to the harmful effects of sunlight, such as ultraviolet radiation, which causes it to age with observable characteristic features as well as clinical precancerous lesions and skin cancer. Formation of free radicals by the sun's harmful rays which contribute to oxidative stress has been linked to the induction of deletions and mutations in the mitochondrial DNA. These markers of mitochondrial DNA damage have been proposed to contribute to the mechanisms of ageing in many tissues including skin and are associated with many diseases including cancer. In this article we highlight the role of this important organelle in ageing and cancer with particular emphasis on experimental strategies in the skin.

Mechanism of aging and prevention

Aging is a senescence and defined as a normal physiologic and structural alterations in almost all organ systems with age. As Leonard Hayflick, one of the first gerontologist s to propose a theory of biologic aging, indicated that a theory of aging or longevity satisfies the changes of above conditions to be universal, progressive, intrinsic and deleterious. Although a number of theories have been proposed, it is now clear that cell aging (cell senescence) is multifactorial . No single mechanism can account for the many varied manifestations of biological aging. Many theories have been proposed in attempt to understand and explain the process of aging. Aging is effected in individual by genetic factors, diet, social conditions, and the occurrence of age-related diseases as diabetes, hypertension, and arthritis. It involves an endogenous molecular program of cellular senescence as well as continuous exposure throughout life to adverse exogenous influences, leading to progressive infringement on the cell's survivability so called wear and tear. So we could say the basic mechanism of aging depends on the irreversible and universal processes at cellular and molecular level. The immediate cause of these changes is probably an interference in the function of cell's macromolecules-DNA, RNA, and cell proteins-and in the flow of information between these macromolecules. The crucial questions, unanswered at present, concerns what causes these changes in truth. Common theories of aging are able to classify as followings for the easy comprehension. 1. Biological, 1) molecular theories-a. error theory, b . programmed aging theory, c. somatic mutation theory, d. transcription theory, e. run-out-of program theory, 2) cellular theories-a. wear and tear theory, b . cross-link theory, c. clinker theory, d. free radical theory, e. waste product theory, 3) system level theory-a. immunologic/autoimmune theory, 4) others-a. telomere theory, b . rate of living theory, c. stress theory, etc. Prevention of aging is theoretically depending on the cause or theory of aging. However no single theory is available and no definite method of delaying the aging process is possible by this moment . The most popular action is anti-oxidant therapy using vitamin E and C, melatonin and DHEA, etc. Another proposal for the reverse of life-span is TCP-17 and IL-16 administration from the mouse bone marrow B cell line study for the immunoglobulin VDJ rearrangement with RAG-1 and RAG-2. Recently conclusional suggestion for the extending of maximum life-span thought to be the calory restriction.