Strain-specific metabolomic diversity of Lactiplantibacillus plantarum under aerobic and anaerobic conditions.

The chemotaxonomic diversity of 20 Lactiplantibacillus plantarum strains was investigated using non-targeted metabolite profiling under different culture conditions. Multivariate and metabolic pathway analyses based on GC-MS and LC-MS/MS datasets showed that amino acid metabolism, especially 2-hydroxy acids, was enriched under aerobic conditions (AE), whereas fatty acid & sugar metabolism was increased under anaerobic conditions (AN). Based on the metabolite profiles, L. plantarum strains were clustered into three main groups (A, B, and C). Overall, 79 and 83 significantly discriminant metabolites were characterized as chemical markers of AE and AN growth conditions, respectively. Notably, alcohols were more abundant in group A whereas amino acids, peptides, purines, and pyrimidines were significantly higher in group C. 2-hydroxy acids and oxylipins biosynthesized through amino acid and fatty acid metabolism, respectively, were more abundant in groups A and B. Furthermore, we observed a strong correlation between the chemical diversity of L. plantarum groups and their antioxidant activity from metabolite extracts. We propose a non-targeted metabolomic workflow to comprehensively characterize the chemodiversity of L. plantarum strain under different culture conditions, which may help reveal specific biomarkers of individual strains depending on the culture conditions.

L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans.

The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.

Kaempferol tetrasaccharides restore skin atrophy via PDK1 inhibition in human skin cells and tissues: Bench and clinical studies.

Skin aging is a major risk factor for the dermal diseases, and interventions to attenuate cellular senescence are expected to reduce the risk for age-related diseases involving skin atrophy. However, blocking cell death or extending proliferation causally results in side effects and an increased cancer risk. For identification of a safer approach, we focused on PDK1 inhibition, which could revert cellular senescence and reduce senescence factors in skin in vitro, in a human skin equivalent model and in an exploratory, placebo-controlled, interventional trial. Natural phytochemical kaempferol tetrasaccharides resulted in a significant reduction in cellular senescence, and an increase in collagen fiber was observed in the skin cell and human skin equivalent. Clinical enhancement in skin appearance was noted in multiple participants, and an immunohistochemical study revealed improvement in the histological appearance of skin tissue and extracellular matrix. This change was associated with relative improvement in histological markers of senescence and clinical appearance of the aged skin and an increase in collagen fiber, an essential factor for preventing skin atrophy and consistency of the basement membrane. These results indicate that PDK1 inhibition is a potentially effective antiaging intervention, suggesting a diagnostic role and preventive actions of PDK1 in senescence-associated skin atrophy.

Intense Pulsed Light Attenuates UV-Induced Hyperimmune Response and Pigmentation in Human Skin Cells.

The skin of an organism is affected by various environmental factors and fights against aging stress via mechanical and biochemical responses. Photoaging induced by ultraviolet B (UVB) irradiation is common and is the most vital factor in the senescence phenotype of skin, and so, suppression of UVB stress-induced damage is critical. To lessen the UVB-induced hyperimmune response and hyperpigmentation, we investigated the ameliorative effects of intense pulsed light (IPL) treatment on the photoaged phenotype of skin cells. Normal human epidermal keratinocytes and human epidermal melanocytes were exposed to 20 mJ/cm2 of UVB. After UVB irradiation, the cells were treated with green (525-530 nm) and yellow (585-592 nm) IPL at various time points prior to the harvest step. Subsequently, various signs of excessive immune response, including expression of proinflammatory and melanogenic genes and proteins, cellular oxidative stress level, and antioxidative enzyme activity, were examined. We found that IPL treatment reduced excessive cutaneous immune reactions by suppressing UVB-induced proinflammatory cytokine expression. IPL treatment prevented hyperpigmentation, and combined treatment with green and yellow IPL synergistically attenuated both processes. IPL treatment may exert protective effects against UVB injury in skin cells by attenuating inflammatory cytokine and melanogenic gene overexpression, possibly by reducing intracellular oxidative stress. IPL treatment also preserves antioxidative enzyme activity under UVB irradiation. This study suggests that IPL treatment is a useful strategy against photoaging, and provides evidence supporting clinical approaches with non-invasive light therapy.

Application of green tea catechins, polysaccharides, and flavonol prevent fine dust induced bronchial damage by modulating inflammation and airway cilia.

Airborne fine dust particles (FDPs) have been identified as major toxins in air pollution that threaten human respiratory health. While searching for an anti-FDP reagent, we found that green tea extract (GTE) and fractions rich in flavonol glycosides (FLGs) and crude tea polysaccharides (CTPs) had protective effects against FDP-stimulated cellular damage in the BEAS-2B airway epithelial cell line. The GTE, FLGs, and CTPs significantly increased viability and lowered oxidative stress levels in FDP-treated cells. Combined treatment with GTE, FLGs, and CTPs also exerted synergistic protective effects on cells and attenuated FDP-induced elevations in inflammatory gene expression. Moreover, the green tea components increased the proportion of ciliated cells and upregulated ciliogenesis in the airway in FDP-stimulated BEAS-2B cells. Our findings provide insights into how natural phytochemicals protect the airway and suggest that green tea could be used to reduce FDP-induced airway damage as an ingredient in pharmaceutical, nutraceutical, and also cosmeceutical products.

Isolindleyin exerts anti-melanogenic effects in human epidermal melanocytes via direct binding to tyrosinase.

To overcome dermatological concerns causing abnormally excessive melanin synthesis, highly effective and safe skin depigmentation compounds have been identified in the cosmetic and pharmaceutical industries. Among several methods used to achieve skin depigmentation, inhibition of tyrosinase is one of the most effective, since tyrosinase is a crucial enzyme in melanogenesis. Herein, isolindleyin, a novel inhibitor of human tyrosinase, was introduced and evaluated for its anti-melanogenic effects in human epidermal melanocytes. The results revealed that isolindleyin was directly bound to tyrosinase and it suppressed melanin synthesis. The binding mode between isolindleyin and the active sites of human tyrosinase was investigated using computational molecular docking at the atomic level. Isolindleyin binding was found to be stabilized by hydrophobic interactions between His 367 and Val 377 and by hydrogen bonds between Ser 380 and Asn 364. The results of this study revealed the anti-melanogenic effects of isolindleyin that could contribute toward overcoming dermatological concerns that cause abnormally excessive melanin synthesis.

Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming.

Many studies utilizing animal models have revealed the genetic and pharmacogenetic modulators of the rate of organismal aging. However, finding routes for healthy aging during extended life remains one of the largest questions. With regards to an antiaging reagent, it has been shown that natural phytochemical syringaresinol (SYR) delays cellular senescence by activating sirtuin1 (SIRT1). Here, it is found that SYR treatment results in metabolic changes similar to those observed during dietary restriction (DR). The DR mimetic effects are mediated by FoxO3a-dependent SIRT1 activation and insulin/insuline growth factor-1 signaling modulation. The direct binding of SYR-FoxO3a is identified and this could partially explain the DR-like phenotype. The report gives a clue as to how the longevity gene involves the DR pathway and suggests that natural phytochemicals applied as a geroprotector mimics DR effects.

Tyrosinase-Targeting Gallacetophenone Inhibits Melanogenesis in Melanocytes and Human Skin-Equivalents.

Demands for safe depigmentation compounds are constantly increasing in the pharmaceutical and cosmetic industry, since the numerous relevant compounds reported to date have shown undesirable side effects or low anti-melanogenic effects. In this study, we reported three novel inhibitors of tyrosinase, which is the key enzyme in melanogenesis, identified using docking-based high throughput virtual screening of an in-house natural compound library followed by mushroom tyrosinase inhibition assay. Of the three compounds, gallacetophenone showed high anti-melanogenic effect in both human epidermal melanocytes and a 3D human skin model, MelanoDerm. The inhibitory effect of gallacetophenone on tyrosinase was elucidated by computational molecular modeling at the atomic level. Binding of gallacetophenone to the active site of tyrosinase was found to be stabilized by hydrophobic interactions with His367, Ile368, and Val377; hydrogen bonding with Ser380 and a water molecule bridging the copper ions. Thus, our results strongly suggested gallacetophenone as an anti-melanogenic ingredient that inhibits tyrosinase.

The natural phytochemical trans-communic acid inhibits cellular senescence and pigmentation through FoxO3a activation.

Ageing is characterized by the accumulation of chronic and irreversible oxidative damage, chronic inflammation and organ dysfunction. To attenuate these ageing-related changes, various natural phytochemicals are often applied. Trans-communic acid (TCA), an active component of brown pine leaf extract, has antimicrobial and cancer chemopreventive activity and inhibits ultraviolet B (UVB)-induced MMP-1 expression. To determine whether the phytochemical TCA could affect the lifespan of an ageing model, Caenorhabditis elegans prevent ageing-related phenotypes of the skin. Caenorhabditis elegans (C. elegans) wild-type N2 and mutant strains were used in this study to explore the lifespan extension effect of TCA and its mechanism. We estimated lipofuscin accumulation and melanin levels, which are closely associated with skin senescence. Moreover, we explored the mechanism of action associated with ageing attenuation. We performed oxidative stress resistance and thermotolerance assays in C. elegans and surface plasmon resonance analysis of TCA binding with the forkhead box-O3a (FoxO3a) protein. TCA, which is the active component in Korean red pine (Pinus densiflora), attenuated ageing-related changes in skin cells. TCA lowered lipofuscin accumulation in fibroblasts and decreased melanin levels in melanocytes. These protective effects were mediated by activation of the representative longevity gene FoxO3a, which was induced by direct binding with TCA. Interestingly, TCA extended the lifespan of C. elegans, although it did not affect stress resistance, oxidative stress or thermotolerance. These results strongly suggest that TCA prevents the senescent phenotype of model organisms and exhibits beneficial effects on ageing-related skin phenotypes through direct FoxO3a activation.

Dietary supplementation of a high-temperature-processed green tea extract attenuates cognitive impairment in PS2 and Tg2576 mice.

Green tea intake is generally recognized as an effective supplement that promotes mental clarity and cognitive function. These health benefits of green tea have been attributed mainly to its effective component, epigallocatechin gallate (EGCG). Because various catechin derivatives potently enhance these health benefits, we manipulated the extraction process with a high-temperature intervention. High-temperature-processed green tea extract (HTP-GTE) showed an elevated proportion of gallocatechin gallate (GCG) content. To investigate the preventive effects of HTP-GTE on cognitive decline, we found its neuroprotective effects against amyloid ß (Aß)-induced neurotoxicity in neurons and clarified that GCG significantly inhibited Aß aggregation in vitro. Moreover, we showed that HTP-GTE intake attenuated several cognitive-decline phenotypes in a model mouse of Alzheimer's disease. These beneficial effects of HTP-GTE against cognitive decline were due to the distinctive composition of the extract and suggest the possibility that HTP-GTE supplementation could attenuate cognitive decline of Alzheimer's disease.

Syringaresinol Reverses Age-Related Skin Atrophy by Suppressing FoxO3a-Mediated Matrix Metalloproteinase-2 Activation in Copper/Zinc Superoxide Dismutase-Deficient Mice.

Aging is characterized by accumulation of chronic and irreversible oxidative damage, chronic inflammation, and organ dysfunction. Superoxide dismutase (SOD) serves as a major enzyme for cellular superoxide radical metabolism and physiologically regulates cellular redox balance throughout the body. Copper/zinc superoxide dismutase-deficient (SOD1-/-) mice showed diverse phenotypes associated with enhanced oxidative damage in whole organs. Here, we found that oral treatment with syringaresinol (also known as lirioresinol B), which is the active component in the berries of Korean ginseng (Panax ginseng C.A. Meyer), attenuated the age-related changes in Sod1-/- skin. Interestingly, syringaresinol morphologically normalized skin atrophy in Sod1-/- mice and promoted fibroblast outgrowth from Sod1-/- skin in vitro. These protective effects were mediated by the suppression of matrix metalloproteinase-2 overproduction in Sod1-/- skin, but not by increased collagen expression. Syringaresinol also decreased the oxidative damage and the phosphorylation of FoxO3a protein, which was a transcriptional factor of matrix metalloproteinase-2, in Sod1-/- skin. These results strongly suggest that syringaresinol regulates the FoxO3-matrix metalloproteinase-2 axis in oxidative damaged skin and exhibits beneficial effects on age-related skin involution in Sod1-/- mice.

Effect of polysaccharides from a Korean ginseng berry on the immunosenescence of aged mice.

BACKGROUND: Korean ginseng has been widely evaluated to treat human diseases; however, most studies on Korean ginseng have focused on its root. In this study, polysaccharides [acidic-polysaccharide-linked glycopeptide (APGP) extracted with 90% ethanol and hot water] were prepared from Korean ginseng berries, and their effect on immunosenescence was explored. METHODS: The effect of APGP on thymic involution was evaluated by measuring the size of thymi dissected from aged mice. The effect of APGP on populations of immune cells, including natural killer (NK) cells, dendritic cells, age-correlated CD11c-positive B cells, and several subtypes of T cells [CD4-positive, CD8-positive, and regulatory (Treg) T cells] in the thymi and spleens of aged mice was analyzed by fluorescence-activated cell sorting analysis. Serum levels of interleukin (IL)-2 and IL-6 were evaluated by enzyme-linked immunosorbent assay analysis. Profiles of APGP components were evaluated by high-performance liquid chromatography (HPLC) analysis. RESULTS: APGP suppressed thymic involution by increasing the weight and areas of thymi in aged mice. APGP increased the population of NK cells, but showed no effect on the population of dendritic cells in the thymi and spleens of aged mice. APGP decreased the population of age-correlated CD11c-positive B cells in the spleens of aged mice. APGP showed no effect on the populations of CD4- and CD8-positive T cells in the thymi of aged mice, whereas it increased the population of Treg cells in the spleens of aged mice. APGP further decreased the reduced serum levels of IL-2 in aged mice, but serum levels of IL-6 were not statistically changed by APGP in aged mice. Finally, HPLC analysis showed that APGP had one major peak at 15 min (a main type of polysaccharide) and a long tail up to 35 min (a mixture of a variety of types of polysaccharides). CONCLUSION: These results suggested that APGP exerted an anti-immunosenescent effect by suppressing thymic involution and modulating several types of immune cells.

AKT-targeted anti-inflammatory activity of Panax ginseng calyx ethanolic extract.

BACKGROUND: Korean ginseng (Panax ginseng) plays an anti-inflammatory role in a variety of inflammatory diseases such as gastritis, hepatitis, and colitis. However, inflammation-regulatory activity of the calyx of the P. ginseng berry has not been thoroughly evaluated. To understand whether the calyx portion of the P. ginseng berry is able to ameliorate inflammatory processes, an ethanolic extract of P. ginseng berry calyx (Pg-C-EE) was prepared, and lipopolysaccharide-activated macrophages and HEK293 cells transfected with inflammation-regulatory proteins were used to test the anti-inflammatory action of Pg-C-EE. METHODS: The ginsenoside contents of Pg-C-EE were analyzed by HPLC. Suppressive activity of Pg-C-EE on NO production, inflammatory gene expression, transcriptional activation, and inflammation signaling events were examined using the Griess assay, reverse transcription-polymerization chain reaction, luciferase activity reporter gene assay, and immunoblotting analysis. RESULTS: Pg-C-EE reduced NO production and diminished mRNA expression of inflammatory genes such as cyclooxygenase-2, inducible NO synthase, and tumor necrosis factor-α in a dose-dependent manner. This extract suppressed luciferase activity induced only by nuclear factor-κB. Interestingly, immunoblotting analysis results demonstrated that Pg-C-EE reduced the activities of protein kinase B (AKT)1 and AKT2. CONCLUSION: These results suggest that Pg-C-EE may have nuclear-factor-κB-targeted anti-inflammatory properties through suppression of AKT. The calyx of the P. ginseng berry is an underused part of the ginseng plant, and development of calyx-derived extracts may be useful for treatment of inflammatory diseases.

Antimelanogenesis and skin-protective activities of Panax ginseng calyx ethanol extract.

BACKGROUND: The antioxidant effects of Panax ginseng have been reported in several articles; however, little is known about the antimelanogenesis effect, skin-protective effect, and cellular mechanism of Panax ginseng, especially of P. ginseng calyx. To understand how an ethanol extract of P. ginseng berry calyx (Pg-C-EE) exerts skin-protective effects, we studied its activities in activated melanocytes and reactive oxygen species (ROS)-induced keratinocytes. METHODS: To confirm the antimelanogenesis effect of Pg-C-EE, we analyzed melanin synthesis and secretion and messenger RNA and protein expression levels of related genes. Ultraviolet B (UVB) and hydrogen peroxide (H2O2) were used to induce cell damage by ROS generation. To examine whether this damage is inhibited by Pg-C-EE, we performed cell viability assays and gene expression and transcriptional activation analyses. RESULTS: Pg-C-EE inhibited melanin synthesis and secretion by blocking activator protein 1 regulatory enzymes such as p38, extracellular signal-regulated kinases (ERKs), and cyclic adenosine monophosphate response element-binding protein. Pg-C-EE also suppressed ROS generation induced by H2O2 and UVB. Treatment with Pg-C-EE decreased the expression of matrix metalloproteinases, mitogen-activated protein kinases, and hyaluronidases and increased the cell survival rate. CONCLUSION: These results suggest that Pg-C-EE may have antimelanogenesis properties and skin-protective properties through regulation of activator protein 1 and cyclic adenosine monophosphate response element-binding protein signaling. Pg-C-EE may be used as a skin-improving agent, with moisture retention and whitening effects.

Efficacy and safety of Panax ginseng berry extract on glycemic control: A 12-wk randomized, double-blind, and placebo-controlled clinical trial.

BACKGROUND: Antihyperglycemic effects of Panax ginseng berry have never been explored in humans. The aims of this study were to assess the efficacy and safety of a 12-wk treatment with ginseng berry extract in participants with a fasting glucose level between 100 mg/dL and 140 mg/dL. METHODS: This study was a 12-wk, randomized, double-blind, placebo-controlled clinical trial. A total of 72 participants were randomly allocated to two groups of either ginseng berry extract or placebo, and 63 participants completed the study. The parameters related to glucose metabolism were assessed. RESULTS: Although the present study failed to show significant antihyperglycemic effects of ginseng berry extract on the parameters related to blood glucose and lipid metabolism in the total study population, it demonstrated that ginseng berry extract could significantly decrease serum concentration of fasting glucose by 3.7% (p = 0.035), postprandial glucose at 60 min during 75 g oral glucose tolerance test by 10.7% (p = 0.006), and the area under the curve for glucose by 7.7% (p = 0.024) in those with fasting glucose level of 110 mg/dL or higher, while the placebo group did not exhibit a statistically significant decrease. Safety profiles were not different between the two groups. CONCLUSION: The present study suggests that ginseng berry extract has the potential to improve glucose metabolism in human, especially in those with fasting glucose level of 110 mg/dL or higher. For a more meaningful benefit, further research in people with higher blood glucose levels is required.

Effects of Korean ginseng berry on skin antipigmentation and antiaging via FoxO3a activation.

BACKGROUND: The ginseng berry has various bioactivities, including antidiabetic, anticancer, antiinflammatory, and antioxidative properties. Moreover, we have revealed that the active antiaging component of the ginseng berry, syringaresinol, has the ability to stimulate longevity via gene activation. Despite the many known beneficial effects of ginseng, its effects on skin aging are poorly understood. In this study, we investigated the effects of ginseng and the ginseng berry on one of the skin aging processes, melanogenesis, and age-related pigment lipofuscin accumulation, to elucidate the mechanism of action with respect to antiaging. METHODS: The human melanoma MNT1 cell line was treated with ginseng root extract, ginseng berry extract, or syringaresinol. Then, the cells were analyzed using a melanin assay, and the tyrosinase activity was estimated. The Caenorhabditis elegans wild type N2 strain was used for the life span assay to analyze the antiaging effects of the samples. A lipofuscin fluorescence assay was performed during 10 passages with the syringaresinol treatment. RESULTS: A 7-d treatment with ginseng berry extract reduced melanin accumulation and tyrosinase activity more than ginseng root extract. These results may be due to the active compound of the ginseng berry, syringaresinol. The antimelanogenic activity was strongly coordinated with the activation of the longevity gene foxo3a. Moreover, the ginseng berry extract had more potent antiaging effects, caused a life span extension, and reduced lipofuscin accumulation. CONCLUSION: Taken together, our results suggest that these antimelanogenic effects and antiaging effects of ginseng berry mediate the activation of antioxidation-FoxO3a signaling.

Oxidative Stress & FoxO Transcription Factors in Cardiovascular Aging.

BACKGROUND: Aging is a phenomenon in which the functions, adaptability and resistance of an organism decrease over time. With the global population aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to many diseases, and the cardiovascular system is no exception. Indeed, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. METHODS: We attempted an organized search of bibliographic databases for peer-reviewed research papers by searching featured reviews using inclusion/exclusion criteria. The collected papers were assessed by standard tools for quality control. RESULTS: Forty-six papers were admitted to the review, and most papers featured recent research results (44) and reviewed the research field (8). We discuss these papers along with the recent progress of our work. In this review, we examine the relationship of oxidative stress with aging and the FoxO proteins, which are essential anti-aging factors in the cardiovascular system. CONCLUSION: The observations of this review suggest that anti-aging signaling mediated by FoxO proteins is important for understanding cardiovascular aging and the design of medicinal approaches.

Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice.

Age-associated immunological dysfunction (immunosenescence) is closely linked to perturbation of the gut microbiota. Here, we investigated whether syringaresinol (SYR), a polyphenolic lignan, modulates immune aging and the gut microbiota associated with this effect in middle-aged mice. Compared with age-matched control mice, SYR treatment delayed immunosenescence by enhancing the numbers of total CD3+ T cells and naïve T cells. SYR treatment induced the expression of Bim as well as activation of FOXO3 in Foxp3+ regulatory T cells (Tregs). Furthermore, SYR treatment significantly enhanced the Firmicutes/Bacteroidetes ratio compared with that in age-matched controls by increasing beneficial bacteria, Lactobacillus and Bifidobacterium, while reducing the opportunistic pathogenic genus, Akkermansia. In addition, SYR treatment reduced the serum level of lipopolysaccharide-binding protein, an inflammatory marker, and enhanced humoral immunity against influenza vaccination to the level of young control mice. Taken together, these findings suggest that SYR may rejuvenate the immune system through modulation of gut integrity and microbiota diversity as well as composition in middle-aged mice, which may delay the immunosenescence associated with aging.

The natural phytochemical dehydroabietic acid is an anti-aging reagent that mediates the direct activation of SIRT1.

Dehydroabietic acid (DAA) is a naturally occurring diterpene resin acid of confers, such as pinus species (P. densiflora, P. sylvestris) and grand fir (Abies grandis), and it induces various biological actions including antimicrobial, antiulcer, and cardiovascular activities. The cellular targets that mediate these actions are largely unknown yet. In this report, we suggest that DAA is an anti-aging reagent. DAA has lifespan extension effects in Caenorhabditis elegans, prevents lipofuscin accumulation, and prevents collagen secretion in human dermal fibroblasts. We found that these anti-aging effects are primarily mediated by SIRT1 activation. Lifespan extension effects by DAA were ameliorated in sir-2.1 mutants and SIRT1 protein expression was increased, resulting in the deacetylation of SIRT1 target protein PGC-1α. Moreover, DAA binds directly to the SIRT1 protein independent of the SIRT1 substrate NAD(+) levels. Through a molecular docking study, we also propose a binding model for DAA-SIRT1. Taken together, our results demonstrate that the anti-aging effects are the first identified biological property of DAA and that the direct activation of SIRT1 enzymatic activity suggests the potential use of this natural diterpene, or related compounds, in age-related diseases or as a preventive reagent against the aging process.