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1.
Int J Mol Sci ; 25(13)2024 Jul 04.
Article in English | MEDLINE | ID: mdl-39000445

ABSTRACT

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.


Subject(s)
Aging , Angiotensin II Type 1 Receptor Blockers , Cognitive Dysfunction , Hypertension , Losartan , Maze Learning , Oxidative Stress , Rats, Inbred SHR , Animals , Losartan/pharmacology , Losartan/therapeutic use , Rats , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Male , Aging/drug effects , Oxidative Stress/drug effects , Hypertension/drug therapy , Hypertension/metabolism , Maze Learning/drug effects , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Rats, Wistar , Hippocampus/metabolism , Hippocampus/drug effects , Spatial Memory/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use
2.
Nutrients ; 16(13)2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38999870

ABSTRACT

Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans' lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.


Subject(s)
Caenorhabditis elegans , Capsicum , Collagen , Longevity , Plant Extracts , Caenorhabditis elegans/drug effects , Longevity/drug effects , Animals , Plant Extracts/pharmacology , Collagen/metabolism , Capsicum/chemistry , Aging/drug effects , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism
3.
Int J Mol Sci ; 25(13)2024 Jun 23.
Article in English | MEDLINE | ID: mdl-39000003

ABSTRACT

Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.


Subject(s)
Glutamate Carboxypeptidase II , Peripheral Nerve Injuries , Remyelination , Animals , Mice , Peripheral Nerve Injuries/drug therapy , Peripheral Nerve Injuries/metabolism , Remyelination/drug effects , Glutamate Carboxypeptidase II/antagonists & inhibitors , Glutamate Carboxypeptidase II/metabolism , Myelin Sheath/metabolism , Myelin Sheath/drug effects , Aging/drug effects , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Mice, Inbred C57BL , Nerve Regeneration/drug effects , Sciatic Nerve/injuries , Sciatic Nerve/drug effects , Male , Axons/drug effects , Axons/metabolism
4.
Sci Rep ; 14(1): 16215, 2024 Jul 13.
Article in English | MEDLINE | ID: mdl-39003416

ABSTRACT

The Apple polysaccharides (AP), extracted from the fruit of apple, has been used to treat multiple pathological diseases. In this study, we evaluated the effects of AP on cognitive impairment and intestinal aging in naturally aging mice. As a result, it was found that AP could improve spatial learning and memory impairment in aging mice through the Morris water maze experiment. Additionally, AP intervention can upregulate the expression of nerve growth factor (BDNF), postsynaptic marker (PSD95), and presynaptic marker (SYP) proteins. Moreover, AP can enhance total antioxidant capacity, reduce the level of pro-inflammatory cytokine, and inhibit the activation of the NF-κB signaling pathway, exerting anti-inflammatory and antioxidant functions. And the administration of AP restored intestinal mucosal barrier function, reduced the expression of aging and apoptosis related proteins. The administration of AP also altered the gut microbiota of mice. At the genus level, AP decreased the abundance of Helicobacter and Bilophila, while increased the abundance of Lactobacillus and Bacteroides. In summary, these data demonstrate that AP treatment can alleviate cognitive impairment, oxidative stress, and inflammatory reactions, repair the intestinal mucosal barrier, reduce intestinal aging, and alter specific microbial characteristics, ultimately improving the health of the elderly.


Subject(s)
Aging , Brain-Gut Axis , Cognitive Dysfunction , Gastrointestinal Microbiome , Malus , Polysaccharides , Animals , Polysaccharides/pharmacology , Gastrointestinal Microbiome/drug effects , Malus/chemistry , Mice , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Aging/drug effects , Brain-Gut Axis/drug effects , Male , Oxidative Stress/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Maze Learning/drug effects , Mice, Inbred C57BL , Intestines/drug effects , Intestines/microbiology , Brain/metabolism , Brain/drug effects
5.
Physiol Res ; 73(3): 461-480, 2024 07 15.
Article in English | MEDLINE | ID: mdl-39012176

ABSTRACT

Aging is an inevitable and complex biological process that is associated with a gradual decline in physiological functions and a higher disease susceptibility. Omega-3 fatty acids, particularly docosahexaenoic acid, play a crucial role in maintaining brain health and their deficiency is linked to age-related cognitive decline. Combining omega-3-rich diets with exercise may enhance cognitive function more effectively, as both share overlapping neurobiological and physiological effects. This study aimed to evaluate the effect of exercise and omega-3 fatty acid (FA) supplementation in two different doses (160 mg/kg and 320 mg/kg) on anxiety-like behavior and cognitive abilities in both adult and aged rats. Male Wistar rats (4-5- and 23-24-month-old) were randomly divided into seven groups: 3-week control supplemented with placebo without exercise, low-dose omega-3 FAs, high-dose omega-3 FAs, 7-week control supplemented with placebo without exercise, exercise-only, low-dose omega-3 FAs with exercise, and high-dose omega-3 FAs with exercise. The administered oil contained omega-3 FAs with DHA:EPA in a ratio of 1.5:1. Our results indicate that aging negatively impacts the locomotor and exploratory activity of rats. In adult rats, a low dose of omega-3 FAs reduces locomotor activity when combined with exercise while high dose of omega-3 FAs reduces anxiety-like behavior and improves recognition memory when combined with exercise. The combination of omega-3 FAs and exercise had varying impacts on behavior, suggesting a need for further research in this area to fully understand their therapeutic efficacy in the context of cognitive changes associated with aging.


Subject(s)
Aging , Anxiety , Dietary Supplements , Exploratory Behavior , Fatty Acids, Omega-3 , Physical Conditioning, Animal , Rats, Wistar , Animals , Male , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/pharmacology , Anxiety/prevention & control , Physical Conditioning, Animal/physiology , Aging/psychology , Aging/drug effects , Rats , Exploratory Behavior/drug effects , Locomotion/drug effects , Locomotion/physiology , Behavior, Animal/drug effects , Cognition/drug effects
6.
Genome Med ; 16(1): 85, 2024 07 02.
Article in English | MEDLINE | ID: mdl-38956711

ABSTRACT

BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.


Subject(s)
Aging , DNA Methylation , Longevity , Humans , Animals , DNA Methylation/drug effects , Longevity/drug effects , Aging/drug effects , Epigenesis, Genetic/drug effects , Drug Discovery/methods , Cellular Senescence/drug effects , Drug Evaluation, Preclinical/methods , Drosophila , Cells, Cultured , Sirolimus/pharmacology
8.
J Nutr Sci Vitaminol (Tokyo) ; 70(3): 210-218, 2024.
Article in English | MEDLINE | ID: mdl-38945886

ABSTRACT

L-Theanine is contained in green tea at 1-3% per dry matter as an amino acid with an umami taste, and the antidepressant effect and protective effect against stress-induced brain atrophy in mice, as well as the related mechanism have been reported. However, effects of theanine on the hippocampus from the proteome analysis and the action mechanism have not been examined. In this study, we mainly investigated the possibility of theanine's cognitive impairment-preventing function and the action mechanism by proteomics in the hippocampus of SAMP8 administered with theanine. In addition to improvement in the aging score with theanine administration, in proteomics, significant suppressions in the expressions of synapsin 2, α-synuclein, ß-synuclein, and protein tau were observed by theanine administration, and the expression of CAM kinase II beta and alpha exhibited a significant increase and increasing tendency with theanine administration, respectively. The expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein tended to increase by theanine administration. On the other hand, serotonin/tryptophan, GABA/glutamic acid and glutamine/glutamic acid ratios in the hippocampus showed an increasing tendency, a significant increase, and an increasing tendency with theanine administration, respectively. These results suggested that theanine might have been involved in the improvement of neurodegeneration or cognitive impairment by suppressing the productions of synapsin, synuclein and protein tau which are considered to be produced along with aging and oxidation, and by enhancing the production of serotonin by increasing the expression of CAM kinase II, and further by affecting the metabolism of glutamate.


Subject(s)
Aging , Glutamates , Hippocampus , Animals , Glutamates/pharmacology , Hippocampus/metabolism , Hippocampus/drug effects , Mice , Male , Aging/drug effects , Synapsins/metabolism , Glutamic Acid/metabolism , alpha-Synuclein/metabolism , tau Proteins/metabolism , Proteomics/methods , Dietary Supplements , Serotonin/metabolism , Diet/methods , gamma-Aminobutyric Acid/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cognitive Dysfunction/prevention & control , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism
9.
Physiol Rep ; 12(12): e16094, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38924381

ABSTRACT

The renin-angiotensin system (RAS)-a classical blood pressure regulator-largely contributes to healthy organ development and function. Besides, RAS activation promotes age-related changes and age-associated diseases, which are attenuated/abolished by RAS-blockade in several mammalian species. RAS-blockers also increase rodent lifespan. In previous work, we discussed how RAS-blockade downregulates mTOR and growth hormone/IGF-1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D-receptor upregulation), and proposed that at least some of RAS-blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS-blockade's impact on other aging regulatory pathways, that is, TGF-ß, NF-kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS-blockade-aging regulatory pathway-mitochondria interactions. However, existing results allow to conjecture that RAS-blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)-even at subclinical doses-offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well-tolerated anti-hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement.


Subject(s)
Aging , Angiotensin-Converting Enzyme Inhibitors , Renin-Angiotensin System , Humans , Renin-Angiotensin System/drug effects , Aging/drug effects , Aging/metabolism , Aging/physiology , Animals , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Signal Transduction/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use
10.
J Ethnopharmacol ; 333: 118505, 2024 Oct 28.
Article in English | MEDLINE | ID: mdl-38945466

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Zuogui Pill (ZGP) is a traditional herbal formula of Chinese Medicine with a long history of use in alleviating ovarian aging. AIM OF THE STUDY: To examine the impact of ZGP on oxidative stress and the stemness of oogonial stem cells (OSCs) in cyclophosphamide (CTX)-induced ovarian aging, as well as its molecular mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2)/heme oxygenase-1 (HO-1, Hmox1) pathway. MATERIALS AND METHODS: Female Sprague-Dawley (SD) rats were randomly divided into seven groups: control, model (CTX), estradiol valerate (EV, 0.103 mg/kg), ZGP-L (low dose Zuogui Pill, 1.851 g/kg), ZGP-H (high dose Zuogui Pill, 3.702 g/kg), ML385 (30 mg/kg), and ML385+ZGP-L. After CTX modeling, the EV, ZGP-L, ZGP-H, and ML385+ZGP-L groups were treated by gavage for 8 weeks, while the ML385 and ML385+ZGP-L groups were administered the Nrf2 antagonist ML385 twice a week. OSCs were isolated after modeling and then treated with drug serum containing 10% ZGP or 10 µM ML385. The general conditions of the rats, including body weight, ovarian weight/body weight ratio, and estrous cycle, were observed. Ovarian ultrastructure, follicle and corpus luteum counts were assessed via hematoxylin and eosin (H&E) staining. Serum hormone levels were measured using enzyme-linked immunosorbent assay (ELISA). Nrf2/HO-1 pathway, stem cell, germ cell, and cell cycle biomarkers were analyzed by qPCR and Western blot. Cell viability was assessed by cell counting kit-8 (CCK-8) assay. Oxidative stress biomarkers were evaluated using flow cytometry and assay kits. Immunofluorescence was employed to detect and locate OSCs in the ovary, quantify the average fluorescence intensity, and identify OSCs. RESULTS: After ZGP treatment, rats with CTX-induced ovarian aging exhibited improved general condition, increased body weight, higher total ovarian weight to body weight ratio, and a restoration of the estrous cycle similar to the control group. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH), two sex hormones, were also improved. Ovarian ultrastructure and follicle count at all stages showed improvement. Moreover, the viability and proliferation capacity of OSCs were enhanced following ZGP intervention. The Nrf2/HO-1 pathway was found to be down-regulated in CTX-induced aging ovarian OSCs. However, ZGP reversed this effect by activating the expression of Nrf2, HO-1, and NAD(P)H oxidoreductase 1 (NQO1), increasing the activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reducing the accumulation of malonaldehyde (MDA) and reactive oxygen species (ROS), thus restoring resistance to oxidative stress. Additionally, ZGP improved the cell cycle of OSCs, up-regulated the expression of Cyclin D1 and Cyclin E1, restored cell stemness, promoted proliferation, enhanced the expression of cell stemness markers octamer-binding transcription factor 4 (Oct4) and mouse VASA homolog (MVH), and down-regulated the expression of P21, thereby inhibiting apoptosis. The therapeutic effects of ZGP against oxidative stress and restoration of cell stemness were attenuated following inhibition of the Nrf2 signaling pathway using ML385. CONCLUSIONS: ZGP protected against CTX-induced ovarian aging by restoring normal ovarian function, alleviating oxidative stress in aging OSCs, promoting OSCs proliferation, and restoring their stemness in rats, possibly through regulating the Nrf2/HO-1 pathway.


Subject(s)
Cyclophosphamide , Drugs, Chinese Herbal , NF-E2-Related Factor 2 , Oogonial Stem Cells , Ovary , Oxidative Stress , Rats, Sprague-Dawley , Signal Transduction , Animals , Female , Oxidative Stress/drug effects , Cyclophosphamide/toxicity , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Drugs, Chinese Herbal/pharmacology , Ovary/drug effects , Ovary/metabolism , Ovary/pathology , Rats , Oogonial Stem Cells/drug effects , Heme Oxygenase-1/metabolism , Aging/drug effects , Heme Oxygenase (Decyclizing)/metabolism
11.
Nutrients ; 16(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38892482

ABSTRACT

Skin problems caused by aging have attracted much attention, and marine collagen peptides have been proved to improve these problems, while mammalian collagen peptides are rarely reported. In this study, fermented deer bone collagen peptide (FCP) and non-fermented deer bone collagen peptide (NCP) were extracted from fermented and non-fermented deer bone, respectively, and their peptide sequences and differential proteins were analyzed using LC-MS/MS technology. After they were applied to aging mice induced with D-gal, the skin hydration ability, antioxidant ability, collagen synthesis, and degradation ability of the mice were studied. The results show that FCP and NCP are mainly peptides that constitute type Ⅰ collagen, and their peptide segments are different. In vivo experiments show that FCP and NCP can improve the richness of collagen fibers in the skin of aging mice; improve the hydration ability of skin; promote the activity of antioxidant-related enzymes; and also show that through the TGF-ß and MAPK pathways, the synthesis and degradation of collagen in skin are regulated. These results show that deer bone collagen peptide can improve skin problems caused by aging, promote skin hydration and antioxidant capacity of aging mice, and regulate collagen synthesis and degradation through the MAPK pathway.


Subject(s)
Aging , Antioxidants , Bone and Bones , Collagen , Deer , Skin , Animals , Antioxidants/pharmacology , Mice , Skin/metabolism , Skin/drug effects , Bone and Bones/drug effects , Bone and Bones/metabolism , Collagen/metabolism , Aging/drug effects , Administration, Oral , Peptides/pharmacology , Skin Aging/drug effects , Male , Fermentation , Collagen Type I/metabolism
13.
Nat Aging ; 4(6): 839-853, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38858606

ABSTRACT

Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.


Subject(s)
Adipocytes, Beige , Adipogenesis , Aging , Endoplasmic Reticulum Stress , Estrogens , Nicotinamide Phosphoribosyltransferase , Nicotinamide Phosphoribosyltransferase/metabolism , Animals , Adipogenesis/drug effects , Endoplasmic Reticulum Stress/drug effects , Mice , Aging/drug effects , Aging/physiology , Estrogens/metabolism , Estrogens/pharmacology , Adipocytes, Beige/drug effects , Adipocytes, Beige/metabolism , Cytokines/metabolism , Signal Transduction/drug effects , Female , Mice, Inbred C57BL , Energy Metabolism/drug effects
14.
Neuroreport ; 35(12): 805-812, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-38935067

ABSTRACT

Neuromuscular junctions are innervated by motor and sympathetic nerves. The sympathetic modulation of motor innervation shows functional decline during aging, but the cellular and molecular mechanism of this change is not fully known. This study aimed to evaluate the effect of aging on sympathetic nerves and synaptic proteins at mouse neuromuscular junctions. Sympathetic nerves, presynaptic, and postsynaptic proteins of sympathetic nerves at neuromuscular junctions were visualized using immunohistochemistry, and aging-related changes were compared between adult-, aged-, and nicotinamide mononucleotide (NMN) administered aged mice. Sympathetic nerves were detected by anti-tyrosine hydroxylase antibody, and presynaptic protein vesicular monoamine transporter 2 colocalized with the sympathetic nerves. These two signals surrounded motor nerve terminals and acetylcholine receptor clusters. Postsynaptic neurotransmitter receptor ß2-adrenergic receptors colocalized with motor nerve terminals and resided in reduced density at extrasynaptic sarcolemma. The signal intensity of the sympathetic nerve marker did not show a significant difference at neuromuscular junctions between 8.5-month-old adult mice and 25-month-old aged mice. However, the signal intensity of vesicular monoamine transporter 2 and ß2-adrenergic receptors showed age-related decline at neuromuscular junctions. Interestingly, both age-related declines reverted to the adult level after 1 month of oral administration of NMN by drinking water. In contrast, NMN administration did not alter the expression level of sympathetic marker tyrosine hydroxylase at neuromuscular junctions. The results suggest a functional decline of sympathetic nerves at aged neuromuscular junctions due to decreases in presynaptic and postsynaptic proteins, which can be reverted to the adult level by NMN administration.


Subject(s)
Aging , Neuromuscular Junction , Nicotinamide Mononucleotide , Animals , Neuromuscular Junction/drug effects , Neuromuscular Junction/metabolism , Aging/metabolism , Aging/drug effects , Mice , Nicotinamide Mononucleotide/pharmacology , Nicotinamide Mononucleotide/administration & dosage , Male , Presynaptic Terminals/metabolism , Presynaptic Terminals/drug effects , Mice, Inbred C57BL , Vesicular Monoamine Transport Proteins/metabolism , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolism , Receptors, Adrenergic, beta-2/metabolism
15.
Nutrients ; 16(12)2024 Jun 09.
Article in English | MEDLINE | ID: mdl-38931170

ABSTRACT

Androgen production primarily occurs in Leydig cells located in the interstitial compartment of the testis. In aging males, testosterone is crucial for maintaining muscle mass and strength, bone density, sexual function, metabolic health, energy levels, cognitive function, as well as overall well-being. As men age, testosterone production by Leydig cells of the testes begins to decline at a rate of approximately 1% per year starting from their 30s. This review highlights recent findings concerning the use of natural polyphenolics compounds, such as flavonoids, resveratrol, and phenolic acids, to enhance testosterone production, thereby preventing age-related degenerative conditions associated with testosterone insufficiency. Interestingly, most of the natural polyphenolic antioxidants having beneficial effects on testosterone production tend to enhance the expression of the steroidogenic acute regulatory protein (Star) gene in Leydig cells. The STAR protein facilitates the entry of the steroid precursor cholesterol inside mitochondria, a rate-limiting step for androgen biosynthesis. Natural polyphenolic compounds can also improve the activities of steroidogenic enzymes, hypothalamus-pituitary gland axis signaling, and testosterone bioavailability. Thus, many polyphenolic compounds such as luteolin, quercetin, resveratrol, ferulic acid phenethyl ester or gigantol may be promising in delaying the initiation of late-onset hypogonadism accompanying aging in males.


Subject(s)
Antioxidants , Hypogonadism , Polyphenols , Testosterone , Male , Humans , Hypogonadism/drug therapy , Antioxidants/pharmacology , Polyphenols/pharmacology , Testosterone/metabolism , Leydig Cells/drug effects , Leydig Cells/metabolism , Animals , Aging/drug effects , Phosphoproteins/metabolism , Resveratrol/pharmacology
16.
Pharmacol Res ; 205: 107257, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38866264

ABSTRACT

Global aging is a tendency of the world, as is the increasing prevalence of diabetes, and the two are closely linked. In our early research, Enteromorpha prolifera oligosaccharide (EPO) possesses the excellent ability of anti-oxidative, anti-inflammatory, and anti-diabetic. We aim to further explore the deeper mechanism of how EPO delays aging and regulates glycometabolism. EPO effectively impacts crotonylation procession to enhance glucose metabolism and reduce cell senescence in aging diabetic rats. Crotonylation modification of XPO1 influences the expression of critical genes, including p53, CDK1, and CCNB1, which affect cell cycle regulation and aging. Additionally, EPO improves glucose metabolism by inhibiting the crotonylation modification of HSPA8-K126 and activating the AKT pathway. EPO promotes crotonylation of histones in intestinal cells, influencing the aging process by increasing the butyric acid-producing bacteria Ruminococcaceae. The observed enhancement in pyrimidine metabolism underscores EPO's potential role in regulating intestinal health, presenting a promising avenue for delaying aging. In summary, our findings affirm EPO as a naturally bioactive ingredient with significant potential for anti-aging and antidiabetic interventions.


Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Oligosaccharides , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Oligosaccharides/pharmacology , Oligosaccharides/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/drug therapy , Aging/metabolism , Aging/drug effects , Cellular Senescence/drug effects , Rats, Sprague-Dawley , Rats , Humans , Gastrointestinal Microbiome/drug effects
17.
Int J Biol Macromol ; 272(Pt 1): 132833, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38834112

ABSTRACT

Chicken meat processing generates a substantial number of byproducts, which are either underutilized or improperly disposed. In this study, we employed in silico approaches to identify antioxidant peptides in chicken liver byproducts. Notably, the peptide WYR exhibited remarkable 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging activity with an IC50 of 0.13 ± 0.01 mg/mL and demonstrated stability under various conditions, including thermal, pH, NaCl, and simulated gastrointestinal digestion. Molecular docking analysis revealed significant hydrogen bonding interactions, while molecular dynamics showed differential stability with ABTS and 2,2-Diphenyl-1-picrylhydrazyl (DPPH). WYR exhibited improved stress resistance, decreased levels of reactive oxygen species (ROS), elevated the activities of superoxide dismutase (SOD) and catalase (CAT), and modulated the expression of crucial genes through the insulin/insulin-like growth factor (IIS) signaling pathway, mitogen-activated protein kinase (MAPK), and heat shock transcription factor-1 (HSF-1) pathways. These effects collectively contributed to the extension of Caenorhabditis elegans' lifespan. This study not only provides an effective method for antioxidant peptide analysis but also highlights the potential for enhancing the utilization of poultry byproducts.


Subject(s)
Antioxidants , Caenorhabditis elegans , Chickens , Liver , Molecular Docking Simulation , Peptides , Animals , Caenorhabditis elegans/drug effects , Antioxidants/pharmacology , Antioxidants/chemistry , Peptides/chemistry , Peptides/pharmacology , Liver/drug effects , Liver/metabolism , Reactive Oxygen Species/metabolism , Aging/drug effects , Computer Simulation , Superoxide Dismutase/metabolism , Oxidative Stress/drug effects , Catalase/metabolism
18.
J Agric Food Chem ; 72(25): 14315-14325, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38847877

ABSTRACT

This study aimed to investigate the mitigation effect of epigallocatechin gallate (EGCG) on aging induced by 3-monochloropropane-1,2-diol (3-MCPD) in Caenorhabditis elegans, evaluate health indicators during the process, and reveal the underlying mechanism through transcriptomics and identification of mutants. The results showed that EGCG alleviated the declined fertility, shortened lifespan, reduced body size, weakened movement, increased reactive oxygen species and lipofuscin, and damaged antioxidative stress response and excessive heat shock proteins caused by 3-MCPD. Transcriptomics study indicated that treatment with 3-MCPD and EGCG altered gene expression, and gene mutants confirmed the involvement of insulin/IGF-1 signaling pathway in mediating the process that EGCG alleviated the aging toxicity induced by 3-MCPD. The study showed that EGCG alleviated the aging toxicity induced by 3-MCPD.


Subject(s)
Aging , Caenorhabditis elegans Proteins , Caenorhabditis elegans , Catechin , Heat-Shock Proteins , Reproduction , alpha-Chlorohydrin , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Catechin/analogs & derivatives , Catechin/pharmacology , Reproduction/drug effects , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Aging/drug effects , alpha-Chlorohydrin/toxicity , Signal Transduction/drug effects , Reactive Oxygen Species/metabolism , Oxidative Stress/drug effects , Longevity/drug effects
19.
Neuroscience ; 551: 177-184, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38823551

ABSTRACT

Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.


Subject(s)
Aging , Dopamine Agonists , Receptors, Dopamine D1 , Animals , Receptors, Dopamine D1/agonists , Receptors, Dopamine D1/metabolism , Male , Aging/drug effects , Aging/physiology , Dopamine Agonists/pharmacology , Rats , Phenanthridines/pharmacology , Dose-Response Relationship, Drug , Recognition, Psychology/drug effects , Rats, Sprague-Dawley , Rats, Inbred F344 , Cyclic AMP/metabolism
20.
Arch Gerontol Geriatr ; 125: 105517, 2024 Oct.
Article in English | MEDLINE | ID: mdl-38851091

ABSTRACT

This investigation explores the combined influence of SCD Probiotics and tauroursodeoxycholic acid (TUDCA) on liver health in elderly male Sprague-Dawley rats. Through the administration of intravenous TUDCA (300 mg/kg) and oral SCD Probiotics (3 mL at 1 × 10^8 CFU) daily for one week, this study evaluates the biomolecular composition, histopathological alterations, and inflammasome activity in the liver. Analytical methods encompassed ATR-FTIR spectroscopy integrated with machine learning for the assessment of biomolecular structures, RT-qPCR for quantifying inflammasome markers (NLRP3, ASC, Caspase-1, IL18, IL1ß), and histological examinations to assess liver pathology. The findings reveal that TUDCA prominently enhanced lipid metabolism by reducing cholesterol esters, while SCD Probiotics modulated both lipid and protein profiles, notably affecting fatty acid chain lengths and protein configurations. Histological analysis showed significant reductions in cellular degeneration, lymphatic infiltration, and hepatic fibrosis. Furthermore, the study noted a decrease in the immunoreactivity for NLRP3 and ASC, suggesting suppressed inflammasome activity. While SCD Probiotics reduced the expression of certain inflammasome-related genes, they also paradoxically increased AST and LDH levels. Conversely, an exclusive elevation in albumin levels was observed in the group treated with SCD Probiotics, implying a protective role against liver damage. These results underscore the therapeutic potential of TUDCA and SCD Probiotics for managing age-associated liver disorders, illustrating their individual and synergistic effects on liver health and pathology. This study provides insights into the complex interactions of these agents, advocating for customized therapeutic approaches to combat liver fibrosis, enhance liver functionality, and decrease inflammation in aging populations.


Subject(s)
Inflammasomes , Liver , NLR Family, Pyrin Domain-Containing 3 Protein , Probiotics , Rats, Sprague-Dawley , Taurochenodeoxycholic Acid , Animals , Taurochenodeoxycholic Acid/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Probiotics/pharmacology , Probiotics/therapeutic use , Male , Rats , Inflammasomes/metabolism , Inflammasomes/drug effects , Liver/pathology , Liver/drug effects , Liver/metabolism , Longevity/drug effects , Lipid Metabolism/drug effects , Aging/drug effects
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