Melatonin circadian rhythm in the retina of mammals

Melatonin has been traditionally considered to be derived principally from the pineal gland. However, several investigations have now demonstrated that melatonin synthesis occurs also in the retina (and in other organs as well) of several vertebrate classes, including mammals. As in the pineal, melatonin synthesis in the retina is elevated at night and reduced during the day. Since melatonin receptors are present in the retina and retinal melatonin does not contribute to the circulating levels, retinal melatonin probably acts locally as a neuromodulator. Melatonin synthesis in the retinas of mammals is under control of a circadian oscillator located within the retina itself, and circadian rhythms in melatonin synthesis and/or release have been described for several species of rodents. These rhythms are present in vivo, persist in vitro, are entrained by light, and are temperature compensated. The recent cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the only enzyme unique to the melatonin synthetic pathway) will facilitate localizing the cellular site of melatonin synthesis in the retina and investigating the molecular mechanism responsible for the generation of retinal melatonin rhythmicity. Melatonin has been implicated in many retinal functions, and the levels of melatonin and dopamine appear to regulate several aspects of retinal physiology that relate to light and dark adaptation. In conclusion, it seems that retinal melatonin is involved in several functions, but its precise role is yet to be understood.     

MELATONIN CIRCADIAN RHYTHM IN THE RETINA OF MAMMALS

Melatonin has been traditionally considered to be derived principally from the pineal gland. However, several investigations have now demonstrated that melatonin synthesis occurs also in the retina (and in other organs as well) of several vertebrate classes, including mammals. As in the pineal, melatonin synthesis in the retina is elevated at night and reduced during the day. Since melatonin receptors are present in the retina and retinal melatonin does not contribute to the circulating levels, retinal melatonin probably acts locally as a neuromodulator. Melatonin synthesis in the retinas of mammals is under control of a circadian oscillator located within the retina itself, and circadian rhythms in melatonin synthesis and/or release have been described for several species of rodents. These rhythms are present in vivo, persist in vitro, are entrained by light, and are temperature compensated. The recent cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the only enzyme unique to the melatonin synthetic pathway) will facilitate localizing the cellular site of melatonin synthesis in the retina and investigating the molecular mechanism responsible for the generation of retinal melatonin rhythmicity. Melatonin has been implicated in many retinal functions, and the levels of melatonin and dopamine appear to regulate several aspects of retinal physiology that relate to light and dark adaptation. In conclusion, it seems that retinal melatonin is involved in several functions, but its precise role is yet to be understood. (Chronobiology International, 17(5), 599–612, 2000)     

Essential actions of melatonin in protecting the ovary from oxidative damage

Free radicals and other reactive species are involved in normal ovarian physiology. However, they are also highly reactive with complex cellular molecules (proteins, lipids, and DNA) and alter their functions leading to oxidative stress. Oxidative damage may play a prominent role in the development of disorders that considerably influence female fertility. Melatonin, because of its amphiphilic nature that allows for crossing morphophysiological barriers, is an effective antioxidant for protecting macromolecules against oxidative stress caused by reactive species. The balance between reactive oxygen species and antioxidants within the follicle seems to be critical to the function of the oocyte and granulosa cells and evidence has accumulated showing that melatonin is involved in the protection of these cells. Melatonin appears to have varied functions at different stages of follicle development, oocyte maturation, and luteal stage. Melatonin concentration in the growing follicle may be an important factor in avoiding atresia, because melatonin in the follicular fluid reduces apoptosis of critical cells. Melatonin also has protective actions during oocyte maturation reducing intrafollicular oxidative damage. An association between melatonin concentrations in follicular fluid and oocyte quality has been reported; this would allow a preovulatory follicle to fully develop and provide a competent oocyte for fertilization. The functional role of reactive species and the cytoprotective properties of melatonin on the ovary from oxidative damage are summarized in this brief review.     

Melatonin: Nature's most versatile biological signal?

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.     

Significance of melatonin in antioxidative defense system: reactions and products

Melatonin is a potent endogenous free radical scavenger, actions that are independent of its many receptor-mediated effects. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant. Melatonin has been reported to scavenge hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(.)), nitric oxide (NO(.)), peroxynitrite anion (ONOO(-)), hypochlorous acid (HOCl), singlet oxygen ((1)O(2)), superoxide anion (O(2)(-).) and peroxyl radical (LOO(.)), although the validity of its ability to scavenge O(2)(-). and LOO(.) is debatable. Regardless of the radicals scavenged, melatonin prevents oxidative damage at the level of cells, tissues, organs and organisms. The antioxidative mechanisms of melatonin seem different from classical antioxidants such as vitamin C, vitamin E and glutathione. As electron donors, classical antioxidants undergo redox cycling; thus, they have the potential to promote oxidation as well as prevent it. Melatonin, as an electron-rich molecule, may interact with free radicals via an additive reaction to form several stable end-products which are excreted in the urine. Melatonin does not undergo redox cycling and, thus, does not promote oxidation as shown under a variety of experimental conditions. From this point of view, melatonin can be considered a suicidal or terminal antioxidant which distinguishes it from the opportunistic antioxidants. Interestingly, the ability of melatonin to scavenge free radicals is not in a ratio of mole to mole. Indeed, one melatonin molecule scavenges two HO. Also, its secondary and tertiary metabolites, for example, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, N-acetyl-5-methoxykynuramine and 6-hydroxymelatonin, which are believed to be generated when melatonin interacts with free radicals, are also regarded as effective free radical scavengers. The continuous free radical scavenging potential of the original molecule (melatonin) and its metabolites may be defined as a scavenging cascade reaction. Melatonin also synergizes with vitamin C, vitamin E and glutathione in the scavenging of free radicals. Melatonin has been detected in vegetables, fruits and a variety of herbs. In some plants, especially in flowers and seeds (the reproductive organs which are most vulnerable to oxidative insults), melatonin concentrations are several orders of magnitude higher than measured in the blood of vertebrates. Melatonin in plants not only provides an alternative exogenous source of melatonin for herbivores but also suggests that melatonin may be an important antioxidant in plants which protects them from a hostile environment that includes extreme heat, cold and pollution, all of which generate free radicals.     

Melatonin and mitochondria in aging

The worldwide prolongation of mean life expectancy has resulted in a rapid increase of the size of the elderly population, both in numbers and as a proportion of the whole. In addition, the incidence of age-related diseases is obviously increasing as the population ages. Finding means to preserve optimal health in old age has become a primary goal of biomedical research. Aging is a multifactorial process that includes progressive cellular loss, endocrine and metabolic deficits, reduced defense mechanisms and functional losses that increase the risk of death. Mitochondria fulfill a number of essential cellular functions and play a key role in the aging process. Melatonin, which is synthesized in the pineal gland and other organs, plays a role in the biologic regulation of aging. Noctural melatonin serum levels are high during childhood and diminish substantially as people age. Melatonin preserves mitochondrial homeostasis, reduces free radical generation, e.g., by enhancing mitochondrial glutathione levels; it also safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. In this article, we review the role of melatonin and mitochondria in aging.     

Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study

Melatonin, the main hormone of the pineal gland, informs the body about the environmental light and darkness regimen, which in turn contributes to the photoperiodic adaptation of several physiological functions. Leptin, the hormone secreted mainly by adipocytes and some other tissues including the pituitary, informs the brain about the mass of adipose tissue, which plays an important role in energy homeostasis. Melatonin has been shown to decrease circulating leptin levels. It is currently not known whether melatonin has an effect on leptin synthesis in the pituitary. The aim of this study was to immunohistochemically examine the effects of pinealectomy and administration of melatonin on leptin production in the rat anterior pituitary. The pituitary samples obtained from 18 male Wistar rats including sham-pinealectomized, pinealectomized and melatonin-injected pinealectomized groups were immunohistochemically evaluated. Immunostaining of leptin was moderate (3+) in sham-pinealectomized rats, heavy (5+) in pinealectomized rats and low (1+) in melatonin-treated pinealectomized rats, respectively. The present results indicate that pinealectomy induces leptin secretion in anterior pituitary cells, and this increase of leptin synthesis can be prevented by administration of melatonin. Thus, melatonin seems to have both physiological and pharmacological effects on leptin production in the anterior pituitary of male rats.     

Age differences in neurokinin A and substance P from the hypothalamus,pituitary, pineal gland,and striatum of the rat. Effect of exogenous melatonin

Previous data showed that aging of the central nervous system (CNS) is associated with widespread changes in tachykinin gene expression. However, there are no data about the possible role of exogenous melatonin in modulating the tachykinergic system during aging. The aim of this work was to analyze the age-dependent changes on neurokinin A (NKA) and substance P (SP) levels in hypothalamus, pituitary, pineal gland and striatum and the role of exogenous melatonin on these changes. We studied female rats at three different ages: 5-month-old (cyclic), 15-month-old (preacyclic) and 25-month-old (acyclic). Hypothalamic tachykinin levels increase when female rats reached acyclicity, this increase was blunted in acyclic-melatonin-treated rats. However, melatonin treatment in young cyclic rats resulted in significantly increased values as compared to controls. Pituitary NKA concentrations did no show age-dependent changes in control rats, however, in both, preacyclic and acyclic-melatonin-treated rats significantly increased values of pituitary NKA were found compared to controls. In the pineal gland, a marked decrease of NKA levels was observed in acyclic-control rats. Melatonin treatment did not alter this decrease. In the striatum, NKA and SP concentrations were significantly reduced in preacyclic- and acyclic-control rats compared to young cyclic rats, melatonin had no effect on striatal tachykinins. Our results indicate that melatonin may regulate tachykinin stores during aging mainly on structures of the neuroendocrine-reproductive axis.     

Melatonin the "light of night" in human biology and adolescent idiopathic scoliosis

Melatonin "the light of night" is secreted from the pineal gland principally at night. The hormone is involved in sleep regulation, as well as in a number of other cyclical bodily activities and circadian rhythm in humans. Melatonin is exclusively involved in signalling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. The last decades melatonin has been used as a therapeutic chemical in a large spectrum of diseases, mainly in sleep disturbances and tumours and may play a role in the biologic regulation of mood, affective disorders, cardiovascular system, reproduction and aging. There are few papers regarding melatonin and its role in adolescent idiopathic scoliosis (AIS). Melatonin may play a role in the pathogenesis of scoliosis (neuroendocrine hypothesis) but at present, the data available cannot clearly support this hypothesis. Uncertainties and doubts still surround the role of melatonin in human physiology and pathophysiology and future research is needed.     

Effects of the blockade of high voltage-activated calcium channels on in vitro pineal melatonin synthesis

The presence of high voltage-activated calcium channels in the rat pineal gland is well known. However, their role in pineal metabolism is not completely understood and is even controversial. Better to understand this matter, we investigated the effects of L-, N- or P/Q-type calcium channel blockers (nifedipine, omega-conotoxin GVIA, omega-agatoxin IVA, respectively) on melatonin content and arylalkylamine-N-acetyltransferase activity of denervated rat pineal glands kept for 48 h in culture and stimulated with norepinephrine. Melatonin was measured by high performance liquid chromatography with electrochemical detection and arylalkylamine-N-acetyltransferase activity was quantified by radiometric assay. Pre-incubation with any of these high voltage-activated calcium channel blockers reduced the melatonin production induced by norepinephrine although arylalkylamine-N-acetyltransferase activity was reduced only by the N-type calcium channel antagonist, omega-conotoxin GVIA. The results indicate that calcium influx through L-, N- or P/Q-type of high voltage-activated calcium channels is necessary for the full expression of the metabolic process leading to melatonin synthesis in the rat pineal glands. However, the mechanisms involved in this process are different for the L- or P/Q- and N-type calcium channels.     

Melatonin as a chronobiotic/cytoprotector: its role in healthy aging

Preservation of sleep, a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging causes sleep alterations, and in turn, sleep disturbances lead to numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep loss impairs the clearance of waste molecules like amyloid-β or tau peptides. Melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, is effective both as a chronobiotic and a cytoprotective agent to maintain a healthy aging. The late afternoon increase of melatonin “opens the sleep doors” every night and its therapeutic use to preserve slow wave sleep has been demonstrated. Melatonin reverses inflammaging via prevention of insulin resistance, suppression of inflammation and down regulation of proinflammatory cytokines. Melatonin increases the expression of α- and γ-secretase and decreases β-secretase expression. It also inhibits tau phosphorylation. Clinical data support the efficacy of melatonin to treat Alzheimer’s disease, particularly at the early stages of disease. From animal studies the cytoprotective effects of melatonin need high doses to become apparent (i.e. in the 40–100 mg/day range). The potentiality of melatonin as a nutraceutical is discussed.     

Multiple binding sites for melatonin on Kv1.3

Melatonin is a small amino acid derivative hormone of the pineal gland. Melatonin quickly and reversibly blocked Kv1.3 channels, the predominant voltage-gated potassium channel in human T-lymphocytes, acting from the extracellular side. The block did not show state or voltage dependence and was associated with an increased inactivation rate of the current. A half-blocking concentration of 1.5 mM was obtained from the reduction of the peak current. We explored several models to describe the stoichiometry of melatonin-Kv1.3 interaction considering one or four independent binding sites per channel. The model in which the occupancy of one of four binding sites by melatonin is sufficient to block the channels gives the best fit to the dose-response relationship, although all four binding sites can be occupied by the drug. The dissociation constant for the individual binding sites is 8.11 mM. Parallel application of charybdotoxin and melatonin showed that both compounds can simultaneously bind to the channels, thereby localizing the melatonin binding site out of the pore region. However, binding of tetraethylammonium to its receptor decreases the melatonin affinity, and vice versa. Thus, the occupancy of the two separate receptor sites allosterically modulates each other.     

Melatonin and 5-methoxytryptamine in non-metazoans.

Melatonin seems to be an almost ubiquitous substance, which has been detected not only in metazoans, but also in all major non-metazoan taxa investigated, including bacteria, dinoflagellates, euglenoids, trypanosomids, fungi, rhodophyceans, pheophyceans, chlorophyceans and angiosperms. Despite its vast abundance, little is known to date about its functions. Its presence is not necessarily associated with circadian rhythmicity, which is evident in yeast. Circadian rhythms of melatonin have been reported in non-metazoans only for several unicellular organisms and in one angiosperm. In dinoflagellates, which have been studied in the most detail, the effects on enzyme activities and on phase shifting are known, but the most spectacular actions concerning the stimulation of bioluminescence, changes in cytoplasmic pH and induction of resting stages, can be related to a metabolite of melatonin, the 5-methoxytryptamine; therefore, melatonin should also be considered as a source of other agonists.     

Melatonin as a potential inhibitor of colorectal cancer: Molecular mechanisms

Colorectal cancer (CRC) is a prevalent disease and a major cause of mortality in the world. Several factors including population aging, poor dietary habits, obesity, insufficient physical activity, and smoking can explain its increased prevalence. CRC is a heterogeneous disease both histopathologically and in term of its molecular and genetic aspects. Melatonin a derivative of tryptophan, is synthesized and released from pineal gland but it is also found in numerous extrapineal tissues including retina, testes, lymphocytes, Harderian gland, gastrointestinal tract, etc. This molecule has several tasks which enhance physiological functions such as antioxidant, antiaging, immunomodulatory, and tumor inhibition. Multiple immunocytochemical studies reported melatonin in the intestinal mucosa where its concentration is greater than in the blood. These findings suggest that melatonin may have a potential inhibitory role in CRC progression. The purpose of this review is to examine the effects of melatonin in molecular pathogenesis and signaling pathways of CRC.     

Melatonin, melatonin receptors and melanophores: a moving story

Melatonin (5-methoxy N-acetyltryptamine) is a hormone synthesized and released from the pineal gland at night, which acts on specific high affinity G-protein coupled receptors to regulate various aspects of physiology and behaviour, including circadian and seasonal responses, and some retinal, cardiovascular and immunological functions. In amphibians, such as Xenopus laevis, another role of melatonin is in the control of skin coloration through an action on melanin-containing pigment granules (melanosomes) in melanophores. In these cells, very low concentrations of melatonin activate the Mel(1c) receptor subtype triggering movement of granules toward the cell centre thus lightening skin colour. Mel(1c) receptor activation reduces intracellular cAMP via a pertussis toxin-sensitive inhibitory G-protein (Gi), but how this and other intracellular signals regulate pigment movement is not yet fully understood. However, melanophores have proven an excellent model for the study of the molecular mechanisms which coordinate intracellular transport. Melanosome transport is reversible and involves both actin- (myosin V) and microtubule-dependent (kinesin II and dynein) motors. Melanosomes retain both kinesin and dynein during anterograde and retrograde transport, but the myosin V motor seems to be recruited to melanosomes during dispersion, where it assists kinesin II in dominating dynein thus driving net dispersion. Recent work suggests an important role for dynactin in coordinating the activity of the opposing microtubule motors. The melanophore pigment aggregation response has also played a vital role in the ongoing effort to devise specific melatonin receptor antagonists. Much of what has been learnt about the parts of the melatonin molecule required for receptor binding and activation has come from detailed structure-activity data using novel melatonin ligands. Work aiming to devise ligands specific for the distinct melatonin receptor subtypes stands poised to deliver selective agonists and antagonists which will be valuable tools in understanding the role of this enigmatic hormone in health and disease.     

Melatonin inhibits fatty acid-induced triglyceride accumulation in ROS17/2.8 cells: implications for osteoblast differentiation and osteoporosis

Melatonin is produced not only by the pineal gland but by cells of the bone marrow. Moreover, melatonin is known to promote osteogenic differentiation in several cell line models and in multipotential bone marrow mesenchymal stem cells. Fatty acids have been independently shown to direct such cells to acquire the phenotype and molecular characteristics of adipocytes. To examine the effect of melatonin on intracellular triglyceride accumulation, an indicator of adipogenic differentiation in the rat osteoblast-like ROS17/2.8 cell line, cells were incubated with added oleic acid (100 muM), fixed and stained with Oil Red O. Cellular lipid accumulation was quantitated by an Oil Red O method highly specific for triglycerides and expressed as a triglyceride accumulation index (TGAI, triglyceride per cell). Melatonin in nanomolar concentrations inhibited oleic acid-induced triglyceride accumulation. To identify the mechanism by which melatonin reduces triglyceride accumulation, cells were incubated with the two melatonin receptor antagonists, luzindole and S20928, or forskolin, a stimulator of adenylyl cyclase and cAMP production. These compounds prevented the inhibitory effect of melatonin on triglyceride accumulation, indicating that melatonin acts through known melatonin receptor-mediated mechanisms. In view of the previously demonstrated positive effects of melatonin in promoting osteoblastic differentiation in ROS17/2.8 cells and their reciprocal adipocytic differentiation induced by fatty acids, our observations may serve to relate the known age-related decreases of melatonin production, the shift in the bone marrow toward an adipocytic line of cell development, and the development of osteoporosis during aging.     

Protective action of melatonin against oxidative DNA damage: chemical inactivation versus base-excision repair

Melatonin is a hormone-like substance that has a variety of beneficial properties as regulator of the circadian rhythm and as anti-inflammatory and anti-cancer agent. The latter activity can be linked with the ability of melatonin to protect DNA against oxidative damage. It may exert such action either by scavenging reactive oxygen species or their primary sources, or by stimulating the repair of oxidative damage in DNA. Since such type of DNA damage is reflected in oxidative base modifications that are primarily repaired by base-excision repair (BER), we tried to investigate in the present work whether melatonin could influence this DNA-repair system. We also investigated the ability of melatonin to inactivate hydrogen peroxide, a potent source of reactive oxygen species. Melatonin at 50 microM and its direct metabolite N(1)-acetyl-N(2)-formyl-5-methoxykynuramine reduced DNA damage induced by hydrogen peroxide at approximately the same ratio. Melatonin stimulated the repair of DNA damage induced by hydrogen peroxide, as assessed by the alkaline comet assay. However, melatonin at 50 microM had no impact on the activity in vitro of three glycosylases playing a pivotal role in BER: Endo III, Fpg and ANPG 80. On the other hand, melatonin chemically inactivated hydrogen peroxide, reducing its potential to damage DNA. And finally, melatonin did not influence the repair of an a-basic (AP) site by cellular extracts, as was evaluated by a functional BER assay in vitro. In conclusion, melatonin can have a protective effect against oxidative DNA damage by chemical inactivation of a DNA-damaging agent as well as by stimulating DNA repair, but key factors in BER, viz. glycosylases and AP-endonucleases, do not seem to be affected by melatonin. Further study with other components of the BER machinery and studies aimed at other DNA-repair systems are needed to clarify the mechanism underlying the stimulation of DNA repair by melatonin.     

Role of melatonin in the dynamics of acute spinal cord injury in rats

Melatonin is well-documented to have the ability of reducing nerve inflammation and scavenging free radicals. However, the therapeutic effect of melatonin on spinal cord injury has not been fully described. In this study, we assessed the effect of melatonin on T9 spinal cord injury established by Allen method in rats. Melatonin deficiency significantly delayed the recovery of sensory and motor functions in SCI rats. Treatment with melatonin significantly alleviated neuronal apoptosis and accelerated the recovery of spinal cord function. These results suggest that melatonin is effective to ameliorate spinal cord injury through inhibition of neuronal apoptosis and promotion of neuronal repair.     

Lack of peroxisomal catalase causes a progeric phenotype in Caenorhabditis elegans

Studies using the nematode Caenorhabditis elegans as a model system to investigate the aging process have implicated the insulin/insulin-like growth factor-I signaling pathway in the regulation of organismal longevity through its action on a subset of target genes. These targets can be classified into genes that shorten or extend life-span upon their induction. Genes that shorten life-span include a variety of stress response genes, among them genes encoding catalases; however, no evidence directly implicates catalases in the aging process of nematodes or other organisms. Using genetic mutants, we show that lack of peroxisomal catalase CTL-2 causes a progeric phenotype in C. elegans. Lack of peroxisomal catalase also affects the developmental program of C. elegans, since Deltactl-2 mutants exhibit decreased egg laying capacity. In contrast, lack of cytosolic catalase CTL-1 has no effect on either nematode aging or egg laying capacity. The Deltactl-2 mutation also shortens the maximum life-span of the long lived Deltaclk-1 mutant and accelerates the onset of its egg laying period. The more rapid aging of Deltactl-2 worms is apparently not due to increased carbonylation of the major C. elegans proteins, although altered peroxisome morphology in the Deltactl-2 mutant suggests that changes in peroxisomal function, including increased production of reactive oxygen species, underlie the progeric phenotype of the Deltactl-2 mutant. Our findings support an important role for peroxisomal catalase in both the development and aging of C. elegans and suggest the utility of the Deltactl-2 mutant as a convenient model for the study of aging and the human diseases acatalasemia and hypocatalasemia.