Korean mistletoe (Viscum album coloratum) extract extends the lifespan of nematodes and fruit flies

Viscum album coloratum (Korean mistletoe) is a semi-parasitic plant that grows on various trees and has a variety of biological functions such as immunomodulation, apoptosis, and anti-tumor activity. In this study, we investigated the effects of Korean mistletoe extract (KME) on lifespan in experimental models using Caenorhabditis elegans and Drosophila melanogaster. Supplementation of KME at 50 μg/ml extended the mean survival time by 9.61 and 19.86 % in worms and flies, respectively. The longevity benefit of KME was not due to reduced feeding, reproduction, and/or locomotion in flies and worms. The supplementation of KME also did not increase resistance to various stresses including heat shock, oxidative, or starvation stresses. Furthermore, KME did not further extend the lifespan of flies fed a dietary restricted diet but did increase the expression of Sir2, one of the target genes of dietary restriction, suggesting that KME may function as a putative dietary restriction mimetic. These results also suggest that the longevity promoting effects of KME may be an example of mild stress-induced hormesis.     

Black tea theaflavins extend the lifespan of fruit flies

Black tea extract (BTE) is a mixture of epicatechins and theaflavins. The present study investigated the effect of BTE on the lifespan of Drosophila melanogaster. Results showed the mean lifespan was significantly extended from 51 to 56 days upon BTE treatment. Gene expression of superoxide dismutase (SOD1 and SOD2), catalase (CAT), and methuselah (MTH) was characterized by an increase in young and then a decrease in aged fruit flies. Higher gene expression of SOD1 and CAT was observed in the BTE-treated group than the control flies. However, BTE exerted a minimal effect on the expression of SOD2 and MTH genes. Dietary fat could induce oxidative stress and shorten the maximum lifespan to 15 days, while addition of 10 mg/ml BTE into diet extended it to 28 days. Paraquat and H₂O₂ challenge tests demonstrated that BTE prolonged the survival time only for Oregon-R wild type flies but not for SODⁿ¹⁰⁸ or Catⁿ¹ mutants. This suggests that the lifespan-prolonging activity of BTE is mediated at least in part through SOD and CAT.     

Lutein extends the lifespan of Drosophila melanogaster

Lutein is one of the major carotenoids in most fruits and vegetables. The effect of lutein on the lifespan of Drosophila melanogaster was investigated. Results revealed that 0.1 mg lutein/ml diet could prolong their mean lifespan from 49.0 to 54.6 days. This was consistent with a significant reduction in malonyldialdehyde (MDA) level and increase in antioxidant enzyme activities of the flies fed with lutein-treated diet compared with those fed with basal diet. Paraquat (PQ) and H₂O₂ treatment tests demonstrated that lutein could prolong the survival time of the flies. Real-time polymerase chain reaction (RT-PCR) analysis indicated the gene expression of superoxide dismutase (SOD; SOD1 and SOD2), and catalase (CAT) in the lutein-treated group was up-regulated relative to that of the control group. It was concluded that the lifespan-prolonging activity of lutein was partially by up-regulation of endogenous antioxidant enzymes.     

DDS, 4,4'-diaminodiphenylsulfone, extends organismic lifespan

DDS, 4,4'-diaminodiphenylsulfone, is the most common drug prescribed to treat Hansen disease patients. In addition to its antibacterial activity, DDS has been reported to be involved in other cellular processes that occur in eukaryotic cells. Because DDS treatment significantly enhances the antioxidant activity in humans, we examined its effect on lifespan extension. Here we show that DDS extends organismic lifespan using Caenorhabditis elegans as a model system. DDS treatment caused a delay in aging and decreased the levels of a mitochondrial complex. The oxygen consumption rate was also significantly lowered. Consistent with these data, paraquat treatment evoked less reactive oxygen species in DDS-treated worms, and these worms were less sensitive to paraquat. Interestingly enough, all of the molecular events caused by DDS treatment were consistently reproduced in mice treated with DDS for 3 mo and in the C2C12 muscle cell line. Structural prediction identified pyruvate kinase (PK) as a protein target of DDS. Indeed, DDS bound and inhibited PK in vitro and inhibited it in vivo, and a PK mutation conferred extended lifespan of C. elegans. Supplement of pyruvate to the media protected C2C12 cells from apoptosis caused by paraquat. Our findings establish the significance of DDS in lowering reactive oxygen species generation and extending the lifespan, which renders the rationale to examining the possible effect of DDS on human lifespan extension.     

A genetic model of methionine restriction extends Drosophila health- and lifespan

Loss of metabolic homeostasis is a hallmark of aging and is characterized by dramatic metabolic reprogramming. To analyze how the fate of labeled methionine is altered during aging, we applied ¹³C5-Methionine labeling to Drosophila and demonstrated significant changes in the activity of different branches of the methionine metabolism as flies age. We further tested whether targeted degradation of methionine metabolism components would “reset” methionine metabolism flux and extend the fly lifespan. Specifically, we created transgenic flies with inducible expression of Methioninase, a bacterial enzyme capable of degrading methionine and revealed methionine requirements for normal maintenance of lifespan. We also demonstrated that microbiota-derived methionine is an alternative and important source in addition to food-derived methionine. In this genetic model of methionine restriction (MetR), we also demonstrate that either whole-body or tissue-specific Methioninase expression can dramatically extend Drosophila health- and lifespan and exerts physiological effects associated with MetR. Interestingly, while previous dietary MetR extended lifespan in flies only in low amino acid conditions, MetR from Methioninase expression extends lifespan independently of amino acid levels in the food. Finally, because impairment of the methionine metabolism has been previously associated with the development of Alzheimer’s disease, we compared methionine metabolism reprogramming between aging flies and a Drosophila model relevant to Alzheimer’s disease, and found that overexpression of human Tau caused methionine metabolism flux reprogramming similar to the changes found in aged flies. Altogether, our study highlights Methioninase as a potential agent for health- and lifespan extension.

Aging is the primary risk factor for many major human pathologies (1). Age-dependent metabolic reprogramming has been noted in different organisms (2), including worms (3), mice (4), and humans (5–7). Moreover, we have previously demonstrated that metabolism in general, and methionine metabolism in particular, is perturbed during aging in Drosophila (8). In addition, methionine metabolism is altered in the tissues of several long-lived species, such as naked mole rats (9), in long-lived mutants, such as flies selected for delayed reproductive senescence (8, 10), and in long-lived Ames mice (11).Although alterations in levels of specific metabolites suggest that the activity of the methionine metabolism pathway is affected, it is difficult to determine if the flux via methionine metabolism is up- or down-regulated. For example, deficiencies of enzymes involved in methionine metabolism (MAT, CBS, GNMT, AHCY) lead to methionine and homocysteine elevation (hypermethioninemias and hyperhomocysteinemias), and elevated levels of methionine and homocysteine reflect a disruption of flux in methionine metabolism (12). Additionally, metabolite changes do not explain how the flux is reprogrammed between different branches of methionine metabolism, as it is possible that the absolute levels of metabolites do not change if metabolites get processed via different routes.Impairment of methionine metabolism flux results in the accumulation of detrimental metabolites belonging to the methionine cycle, such as S-adenosylhomocysteine (SAH) and homocysteine, and leads to different pathological manifestations (13). Lifespan can be extended by up-regulating the clearance of these metabolites via activation of methionine metabolism flux. In fact, methionine restriction (MetR) extends lifespan in yeast, flies, rodents, and human diploid fibroblasts (14–17) and exerts beneficial effects on metabolic health and inflammatory responses (18–20). Moreover, lifespan in worms and flies can be extended through manipulation of different enzymes, either belonging to the methionine metabolism pathway or those that affect the levels of methionine metabolism metabolites. Some of these manipulations include the overexpression of Cbs (21) and Gnmt (22, 23), and the down-regulation of SamS (24) and AhcyL1/AhcyL2 (8). In addition, manipulation of methionine metabolism in just one tissue is sufficient for lifespan extension (8, 21, 22).Restoring age-reprogrammed activity of methionine metabolism can be an attractive option for the extension of health- and lifespan. However, studies relating to MetR have the following challenges: 1) MetR does not decrease levels of methionine equally across different organs; 2) it is impossible to study tissue-specific effects of MetR via manipulations of methionine levels in the food; and 3) the activation of methionine metabolism enzymes is difficult to achieve due to a lack of small-molecule activators. To solve these problems, we created transgenic flies carrying the enzyme Methioninase, which allows for the rapid, inducible, and tissue-specific degradation of methionine.l-Methionine α-deamino-γ-mercaptomethane-lyase (Methioninase) is a bacterial enzyme that is capable of degrading methionine to ammonia, α-ketobutyrate, and methanthiol. Because methionine dependency was attributed to various cancers, recombinant Methioninase (rMetase) has been tested in various cancer models in vitro and in vivo (25, 26). Methioninase has also entered several clinical trials in humans (26–28). Based on this, Methioninase may provide an alternative option to dietary MetR, since it can be expressed in a tissue-specific manner, and its recombinant form can be used in humans.To understand how methionine metabolism is reprogrammed with age or neurodegeneration, we supplemented flies with a labeled ¹³C5-methionine tracer and estimated its fate between different branches of methionine metabolism. We further created transgenic flies with inducible expression of Methioninase (genetic MetR) and performed metabolomics profiling to demonstrate that the effect was similar to the effects of MetR caused by the depletion of methionine from fly food (dietary MetR). It has been previously shown that dietary MetR extends the lifespan in flies only in low amino acid conditions (15). We demonstrate that either whole-body or tissue-specific expression of Methioninase (genetic MetR) can extend Drosophila lifespan without lowering levels of amino acids in the food. Altogether, our studies offer a strategy for restoring age-dependent defects related to impaired methionine metabolism that has strong potential for lifespan extension and treatment of neurodegenerative diseases in humans.     

Vitamin E extends lifespan in the short-lived rotifer Asplanchna brightwelli

Supplementation with vitamin E at a concentration of 25 μg/ml significantly increased the mean lifespan of the rotifer Asplanchna brightwelli. Of the three life stages, the preproductive, reproductive and postreproductive, only the prereproductive stage was significantly extended by vitamin E supplementation. Vitamin E supplemented rotifers were larger than control rotifers in their early stages of life, but noth groups attained the same size by the end of their lifespan.     

Rejuvenation of the disposable soma: Repeated injury extends lifespan in an asexual annelid

The disposable soma theory of senescence proposes that aging is the result of the accumulation of somatic damage with age resulting from insufficient somatic maintenance and repair. Comparative studies that show a positive correlation between longevity and DNA excision repair efficiency in mammals provide support for the theory but their validity has been questioned. A more satisfactory approach to investigate the role of somatic damage accumulation in aging would be to manipulate experimentally the levels of somatic repair and observe its effect on longevity. Here I report the results of studies in the asexual annelid Paranais litoralis where I have experimentally extended the worms' lifespan by subjecting them to repeated injury. I propose that repeated injury enhanced the normal level of repair of the worms, resulting in a rejuvenation of the soma. These results provide experimental support for the disposable soma theory of senescence.     

Simian virus 40 efficiently infects human T lymphocytes and extends their lifespan

The relevance of viral infections to the onset and progression of human hematologic malignancies and other blood diseases is still a matter of active investigation. Purified human T lymphocytes isolated from the peripheral blood mononuclear cells of healthy blood donors were experimentally infected with simian virus 40 (SV40), a small DNA tumor virus. SV40-positive T lymphocytes extended their lifespan up to day 80 postinfection (PI). Expression of viral antigens, such as the large T antigen and the viral capsid protein VP1 from the early and late regions, respectively, was detected up to day 40 PI. SV40 viral progeny were continuously produced from day 10 to 40 PI. SV40 DNA sequences were detected in infected T cells for up to 80 days. Our data indicate that human T lymphocytes can be efficiently infected with SV40. Although T cells infected by SV40 were not immortalized, 30% of these lymphocytes appeared to be morphologically transformed with an enlarged T-cell shape. Our investigation provides a simple model for studying the interactions of human T lymphocytes with this small DNA tumor virus and it might represent an experimental tool for investigating new biomarkers and targets for innovative therapeutic approaches.     

Experimental evolution of learning ability in fruit flies

The presence of genetic variation for learning ability in animals opens the way for experiments asking how and under what ecological circumstances improved learning ability should evolve. Here we report experimental evolution of learning ability in Drosophila melanogaster. We exposed experimental populations for 51 generations to conditions that we expected to favor associative learning with regard to oviposition substrate choice. Flies that learned to associate a chemical cue (quinine) with a particular substrate, and still avoided this substrate several hours after the cue had been removed, were expected to contribute more alleles to the next generation. From about generation 15 on, the experimental populations showed marked ability to avoid oviposition substrates that several hours earlier had contained the chemical cue. The improved response to conditioning was also expressed when the flies were faced with a choice of novel media. We demonstrate that these behavioral changes are caused by the evolution of both a higher learning rate and a better memory.     

Discovering the flight autostabilizer of fruit flies by inducing aerial stumbles

Just as the Wright brothers implemented controls to achieve stable airplane flight, flying insects have evolved behavioral strategies that ensure recovery from flight disturbances. Pioneering studies performed on tethered and dissected insects demonstrate that the sensory, neurological, and musculoskeletal systems play important roles in flight control. Such studies, however, cannot produce an integrative model of insect flight stability because they do not incorporate the interaction of these systems with free-flight aerodynamics. We directly investigate control and stability through the application of torque impulses to freely flying fruit flies (Drosophila melanogaster) and measurement of their behavioral response. High-speed video and a new motion tracking method capture the aerial “stumble,” and we discover that flies respond to gentle disturbances by accurately returning to their original orientation. These insects take advantage of a stabilizing aerodynamic influence and active torque generation to recover their heading to within 2° in < 60 ms. To explain this recovery behavior, we form a feedback control model that includes the fly’s ability to sense body rotations, process this information, and actuate the wing motions that generate corrective aerodynamic torque. Thus, like early man-made aircraft and modern fighter jets, the fruit fly employs an automatic stabilization scheme that reacts to short time-scale disturbances.     

Parkin overexpression during aging reduces proteotoxicity,alters mitochondrial dynamics,and extends lifespan

Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin–proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.     

Resveratrol extends lifespan and preserves glia but not neurons of the Nothobranchius guentheri optic tectum

Resveratrol is reported as having neuroprotective properties, however, much of this reputation has come from research using disease and injury models of neurodegeneration and not neurodegenerative-ageing. The results published here pertain to the affect resveratrol has on neurodegenerative-ageing. Resveratrol had previously been used to extend the lifespan of Nothobranchius furzeri wherein it preserved cognition and reduced ageing-associated neurodegeneration. No cell-type specific antibodies were then identified which could be used to investigate the nature of the neurodegeneration or resveratrols effect on CNS cells. Using wholemounts stained with SMI31 anti-phospho-neurolament, GA-5 and DAKO Z0334 anti-GFAP antibodies, E587 antiserum against NCAMs and anti-Tenascin-R antibodies we determined what cellular changes occurred with age in the optic tectum of Nothobranchius guentheri. We show that resveratrol-treatment extended the lifespan of N. guentheri but did not preserve neuron density of the optic tectum stratum griseum superciale even though it did reduce the proportion of degenerate (SMI31 antigen accumulating) neurons in the optic tectum. Resveratrol-treatment did prevent the ageing-dependent loss of radial glia lining the optic tectum of N. guentheri. The ageing-related loss of NCAM expression and Tenascin-R expressing perineuronal nets was also prevented by resveratrol-treatment. Glial and perineuronal density as well as NCAM expression appear to correlate well with age. These results suggest that the anti-ageing properties of resveratrol in vertebrates may be unrelated to the protection of neurons.     

Changes in taurine in aging fruit flies and mice

The whole-body concentration of the amino acid taurine was found to be more than 1000% higher during the adult stage of Drosophila melanogaster than during the larval stage. Drosophila larvae were killed by adding taurine (0.01 to 0.10 M) to their food medium. Adult Drosophila failed to produce progeny when fed 0.2 M taurine for one week. Lifetime feeding of taurine (0.05 to 0.20 M) produced no change in life span. Feeding the taurine precursor, hypotaurine, and the taurine mobilizing agent, beta-alanine, to Drosophila did not change life span at low concentrations but both decreased life span at higher concentrations. Taurine concentration in male C57BL/6J mice increased with aging in the heart, decreased in leg muscle and remained unchanged in brain, liver, kidney, and blood. We suggest that an as yet undefined developmental process is altered in Drosophila by taurine and that this process may be unique to insects.