Abstract:Quercetin is a flavonoid that is ubiquitously found in vegetables and fruits. Like other flavonoids, it is active in balancing cellular reactive oxygen species (ROS) levels and has a cyto-protective function. Previously, a link between ROS balancing, aging, and the activity of O-methyltransferases was reported in different organisms including the aging model Podospora anserina. Here we describe a role of the S-adenosylmethionine-dependent O-methyltransferase PaMTH1 in quercetin-induced lifespan extension. We f… Show more
“…Quercetin (300 μM) was found to have a moderate effect on growth, while DMSO (as a control) had no effect on longevity or growth rate. In Podospora anserina WT treatment, the mean life expectancy increased by 10.2% and the maximum lifespan increased by 16.6% [ 96 ]. Scheme 3 The structures of natural products as antiaging agents …”
Section: Natural Products As Antiaging Agentsmentioning
Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.
“…Quercetin (300 μM) was found to have a moderate effect on growth, while DMSO (as a control) had no effect on longevity or growth rate. In Podospora anserina WT treatment, the mean life expectancy increased by 10.2% and the maximum lifespan increased by 16.6% [ 96 ]. Scheme 3 The structures of natural products as antiaging agents …”
Section: Natural Products As Antiaging Agentsmentioning
Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.
“…Most metal-dependent plant COMTs strictly target caffeoyl-CoA, a key intermediate in lignin biosynthesis. Other cation-dependent OMTs in eukaryotes display promiscuous substrate specificity; examples include phenylpropanoid and flavonoid O-methyltransferase (PFOMT) from the ice plant Mesembryanthemum crystallinum acting on phenylpropanoid and flavonoid conjugates 1 and Podospora anserina O-methyltransferase (PaOMT or PaMTH1), which methylates flavonoids containing vicinal hydroxyl groups such as myricetin or quercetin 2–4 . Cellular targets of bacterial COMTs appear to be more diverse and often unknown, in contrast to the targets of their eukaryotic homologs.…”
Catechol O-methyltransferase (COMT) is widely distributed in nature and installs a methyl group onto one of the vicinal hydroxyl groups of a catechol derivative. Enzymes belonging to this family require two cofactors for methyl transfer: S-adenosyl-l-methionine as a methyl donor and a divalent metal cation for regiospecific binding and activation of a substrate. We have determined two high-resolution crystal structures of Rv0187, one of three COMT paralogs from
Mycobacterium tuberculosis
, in the presence and absence of cofactors. The cofactor-bound structure clearly locates strontium ions and S-adenosyl-l-homocysteine in the active site, and together with the complementary structure of the ligand-free form, it suggests conformational dynamics induced by the binding of cofactors. Examination of
in vitro
activities revealed promiscuous substrate specificity and relaxed regioselectivity against various catechol-like compounds. Unexpectedly, mutation of the proposed catalytic lysine residue did not abolish activity but altered the overall landscape of regiospecific methylation.
“…For qualitative determination of superoxide anion release from mycelia a histochemical nitro blue tetrazolium (NBT, Sigma-Aldrich, N6876) staining was performed as previously described (Warnsmann et al, 2018a). Analogously, for hydrogen peroxide release a histochemical diaminobenzidine (DAB, Sigma-Aldrich, D-8001) staining was performed as previously described (Warnsmann et al, 2018a) 2.12 Fluorescence microscopy P. anserina strains were cultivated on glass slides with a central depression containing 130 µl M2 medium for 1 day under standard conditions. Fluorescence microscopic analyses were performed with the confocal spinning disc microscope Zeiss Cell Observer SD and a 63x/1.4 oil objective lens (Carl Zeiss Microscopy, Jena, Germany) using a 488 nm laser line.…”
Section: Superoxide and Hydrogen Peroxide Release Measurementsmentioning
Mitochondria are dynamic eukaryotic organelles involved in a variety of essential cellular processes including the generation of adenosine triphosphate (ATP) and reactive oxygen species (ROS) as well as in the control of apoptosis and autophagy. Impairments of mitochondrial functions lead to aging and disease. Previous works with the ascomycete Podospora anserina demonstrated that mitochondrial morphotype as well as mitochondrial ultrastructure change during aging. The latter goes along with an age-dependent reorganization of the inner mitochondrial membrane leading to a change from lamellar cristae to vesicular structures. Especially from studies with yeast it is known that beside the F1Fo-ATP-synthase and the phospholipid cardiolipin also the ‘mitochondrial contact site and cristae organizing system’ (MICOS) complex, existing of the Mic60- and Mic10-subcomplex, is essential for proper cristae formation. In the present study, we aimed to understand the mechanistic basis of age-related changes of the mitochondrial ultrastructure. We observed that MICOS subunits are co-regulated at the posttranscriptional level. This regulation partially depends on the mitochondrial iAAA-protease PaIAP. Most surprisingly, we made the counterintuitive observation that, despite the loss of lamellar cristae and of mitochondrial impairments, the ablation of MICOS subunits (except of PaMIC12) leads to a pronounced lifespan extension. Moreover, simultaneous ablation of subunits of both MICOS subcomplexes synergistically increases lifespan, providing formal genetic evidence that both subcomplexes affect lifespan by different and at least partially independent pathways. At the molecular level we found that ablation of Mic10-subcomplex components leads to a mitohormesis-induced lifespan extension, while lifespan extension of Mic60-subcomplex mutants seems to be controlled by another pathway. Overall, our data demonstrate that both MICOS subcomplexes have different functions and play distinct roles in the aging process of P. anserina.
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