Anti-aging Strategies Research Articles

Testosterone in long-term sedentary aging males: Effect of antiaging strategies.

Physical activity can provide health benefits if done regularly and of sufficient duration and intensity. TheWorld Health Organization recommends adults do 150-300 min of moderate-intensity activity per week, 75-150 min of vigorous-intensity activity, or an equivalent combination.Physical inactivity is the fourth leading cause of early death globally, with 31% of the world's population not getting enough physical activity. Aging is defined by rapid decline in physical activity, loss of mobility, and premature morbidity.Low testosterone levels in men decline from 30 to 40 years of age, and this continues until death. Antiaging strategies, such as caloric restriction, balanced diet, regular exercise, weight management, diabetes control, and smoking cessation can prevent and treat aging-related diseases. Exercise significantly boosts testosterone production, with levels varying based on type, frequency, volume, intensity, and duration. It increases muscle steroidogenesis, total testosterone, and free testosterone in the elderly. Testosterone replacement therapy in elderly men improves physical function, strength, protein synthesis, cholesterol, bone density, sexual desire, erectile function, and overall cognition. However, some studies suggest dehydroepiandrosterone supplementation may provide health improvements without negative effects, potentially reversing arterial aging and reducing the risk of cardiovascular diseases. Senolytic therapeutics focus on cellular senescence, and stem cell transplantation investigates the therapeutic potential of older stem cells.

Activation of Nuclear Receptor CAR: A Pathway to Delay Aging through Enhanced Capacity for Xenobiotic Resistance.

Environmental factors are linked to aging and age-related diseases. Emerging evidence suggests that enhancing body's resistance to xenobiotics might be an anti-aging strategy. The constitutive androstane receptor (CAR) regulates drug-metabolizing enzymes and transporters, coordinating metabolism and immune responses to adapt to stress triggered by exogenous exposure. However, the impact of activating CAR on aging remains unknown. In this study, Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice are used as models to explore the effects of CAR activation on lifespan and healthspan, along with the underlying mechanisms. The results showed that hCAR agonist CITCO and mCAR agonist TCPOBOP prolonged the lifespan and healthspan in model organism. The longevity effects of CITCO and TCPOBOP were attenuated in CAR homozygous nhr-8/daf-12 mutant C. elegans as well as CAR-/- mice. In C. elegans, CITCO activated both anti-stress and detoxification genes, and increased the resistance to environmental adversities. Additionally, the lifespan-extending and xenobiotic resistant effects of CITCO might be related to the regulation of age-related pathways. Furthermore, CITCO improved age-related neurodegeneration in C. elegans models. Taken together, the results suggest that the longevity effects of CAR agonists may be related to the enhancement of xenobiotic resistance of animals.

Crassifolin A prolongs lifespan and healthspan in Caenorhabditis elegans via activating autophagy.

The root of Croton crassifolius Geiseler (C. crassifolius), commonly known as "Jiguxiang" in traditional Chinese medicine, is globally recognized for its ethnomedical applications in treating a spectrum of diseases. Crassifolin A (CA), a diterpenoid compound extracted from the roots of C. crassifolius, exhibits anti- herpes simplex virus (HSV), anti-viral and anti-angiogenic properties. This study aimed to explore the effects of CA on aging and the mechanisms involved. Utilizing Caenorhabditis elegans (C. elegans) as a model organism, we conducted a comprehensive survival analysis and evaluated aging-related phenotypes, including the period of fast body movement and body bending rates. To elucidate the molecular mechanisms of CA's impact on aging, we employed a multifaceted approach, including reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, and fluorescence quantification of transgenic reporter strains. Our findings demonstrated that CA significantly prolonged both the lifespan and healthspan of C. elegans. The survival benefits conferred by CA were found to correlate with the activation of several key aging-related signaling pathways, including insulin/insulin-like signaling pathway (IIS), dietary restriction (DR) pathway, and germline signaling pathway. Engagement of these pathways led to the activation of transcription factors DAF-16/FOXO, SKN-1/NRF2, HSF-1 and HLH-30/TFEB, as well as the nuclear receptor DAF-12. Consequently, this activation cascade prompted an upregulation of autophagy, a cellular process associated with the maintenance of cellular homeostasis and longevity. Our study delineates novel mechanisms underlying anti-aging strategies, establishing a conceptual framework for the exploitation and advancement of traditional Chinese medicinal herbs as potential therapeutic agents in the fight against aging and its associated pathologies.

Natural anti-aging strategies: mechanisms and role of phytoextracts in combating skin aging.

Natural anti-aging strategies: mechanisms and role of phytoextracts in combating skin aging.

Anti-skin aging effects of Gosori liquor lees extract by regulating interactions between senescent fibroblasts and adipose-derived stem cells.

When cellular ageing is accelerated by various extrinsic/endogenous stimuli, regenerative function deteriorates, and enriched secretomes, such as the senescence-associated secretory phenotype (SASP), contribute to chronic inflammation and cause matrix degeneration. SASPs from senescent fibroblasts exacerbate cellular senescence via autocrine signalling and also accelerate skin ageing through the induction of neighbouring cell senescence via paracrine signalling. The interaction between dermis fibroblasts and their neighbours, adipose-derived stem cells (ADSCs) in the hypodermis, which lies deep in the dermis, is a potential target for skin ageing. In this study, we observed that an extract of the lees of Gosori liquor (GLE), a traditional Korean liquor made by fermenting millet and rice, suppressed the senescence of fibroblasts, including SASP production, in a replicative senescent model. We further examined whether the anti-ageing effects of GLE on fibroblasts affected the cellular senescence of their surrounding cells, ADSCs. The results showed that senescence factors in ADSCs were suppressed by culture medium from senescent fibroblasts (SF-CM) treated with GLE compared to the SF-CM-only treated group. Furthermore, the regenerative ability of ADSCs was promoted in the GLE-treated SF-CM group. ADSC migration was stimulated by upregulating the levels of α-smooth muscle actin, collagen type I alpha 2, and vascular endothelial growth factor expression through the PI3K/AKT pathway. Those results indicate that GLE can exert regenerative ability by regulating fibroblasts, and adipocyte interactions, improving cellular senescence. We conducted a clinical trial of subjects over 45 years of age to confirm the anti-ageing effects of GLE invivo and observed changes in ageing parameters, such as skin wrinkles and volume on the face (IRB No. DM-IRB-2023-809-01-T1). The results showed that GLE-containing cream was more effective in improving skin wrinkles, elasticity, density, thickness, and volume around sunken eyes after 4 weeks of use than placebo. In conclusion, GLE plays an important role in inhibiting the ageing transition to ADSCs by inhibiting the senescence of fibroblasts and can be a promising anti-ageing strategy.

Alternative Splicing: Emerging Roles in Anti-Aging Strategies.

Alternative splicing plays a fundamental role in gene expression and protein complexity. Aberrant splicing impairs cell homeostasis and is closely associated with aging and cellular senescence. Significant changes to alternative splicing, including dysregulated splicing events and the abnormal expression of splicing factors, have been detected during the aging process or in age-related disorders. Here, we highlight the possibility of suppressing aging and cellular senescence by controlling alternative splicing. In this review, we will summarize the latest research progress on alternative splicing in aging and cellular senescence, discuss the roles and regulatory mechanisms of alternative splicing during aging, and then excavate existing and potential approaches to anti-aging by controlling alternative splicing. Novel therapeutic breakthroughs concerning aging and senescence entail a further understanding of regulating alternative splicing mechanically and accurately.

L-Theanine Extends the Lifespan of Caenorhabditis elegans by Reducing the End Products of Advanced Glycosylation.

L-theanine, a non-protein amino acid naturally occurring in tea leaves, is recognized for its antioxidant, anti-inflammatory, and neuroprotective properties. Despite its known benefits, the mechanisms by which L-theanine influences lifespan extension remain poorly understood. This study investigated the effects of L-theanine on the lifespan of Caenorhabditis elegans and explored the underlying mechanisms. Our findings indicate that L-theanine significantly diminishes the accumulation of advanced glycation end products (AGEs), which are biomarkers closely linked to aging and age-related diseases. Through an AGE-level analysis, we observed that L-theanine, when administered during early adulthood, notably extended the lifespan of Caenorhabditis elegans under both normal and high-glucose-induced stress conditions. L-theanine enhanced the lifespan under typical conditions and provided protective effects against high-glucose-induced stress. A further analysis demonstrated that L-theanine extends the lifespan of Caenorhabditis elegans by modulating the DAF-2/DAF-16 insulin-like signaling pathway and reducing the accumulation of advanced glycation end products (AGEs). In summary, this study identified L-theanine as a potential anti-aging intervention that extends the lifespan by reducing AGE accumulation and regulating insulin-like signaling pathways. These findings provide new insights for developing anti-aging strategies and lay the groundwork for further research on the potential benefits of L-theanine in mammals. Future studies could explore the molecular mechanisms, test L-theanine in mammalian models, and assess the long-term side effects.

Lipidomic and Instrumental Evaluation of a Melatonin-Based In & Out Strategy Versus Topical Treatment in Skin Aging: A Randomized Prospective Trial.

This study aimed to evaluate the efficacy of a novel "In & Out" strategy, combining topical and oral melatonin supplementation, in managing skin aging compared to topical treatment alone. A randomized, prospective study was conducted on 39 healthy females aged 55-69 years. Participants were divided into two groups: one received both the topical formula and oral melatonin supplementation (Group A), while the other received a topical melatonin-based formula (Group B). Clinical evaluations included lipidomic analysis, skin moisturization, and wrinkle depth analysis at baseline and after 84 days. The addition of oral melatonin supplementation to the topical regimen led to improvements in the skin's lipid profile and moisturization levels. These findings suggest that combining topical and oral melatonin may provide a more comprehensive approach to managing skin aging by addressing both local and systemic factors. Background/Objectives: With age, the endogenous antioxidant capacity of the skin decreases, including melatonin (Mel) synthesis. Skin aging is also associated with alterations in epidermal lipids, particularly a reduction in triglycerides and ceramides, which are essential for maintaining skin structure and hydration. The administration of exogenous melatonin could, therefore, be an effective anti-aging strategy. While some data suggest that melatonin may positively influence the lipid profile, specific data on its effects on skin aging are lacking. This study aimed to evaluate the anti-aging effects of an "In & Out" regimen consisting of a Mel-based cream and dietary supplement in comparison with topical treatment alone, focusing on clinical and lipidomic changes involved in skin homeostasis. Results: A statistically significant variation was observed in both groups compared to baseline (T0) in terms of moisturization (+23.6% in Group A, +18.3% in Group B) and wrinkle depth (-18.5% in Group A, -9.4% in Group B, p < 0.05). Both groups showed improvements in the lipid content of the skin, which typically decreases with age. The "In & Out" strategy resulted in a statistically significant increase in triacylglycerols and ceramides, key lipids that exhibit water-holding properties. Conclusions: The "In & Out" melatonin-based regimen demonstrated greater efficacy in clinical improvement and positive lipid profile modifications compared to topical treatment alone, highlighting its potential as a comprehensive anti-aging strategy.

Gut microbial composition associated with risk of premature aging in women with Yin-deficiency constitution.

Yin-deficiency constitution (YinDC) refers to a traditional Chinese medicine concept, characterized by an imbalance state that includes an imbalance in the gut microbiota, resulting from a relative deficiency of Yin fluids within the body. In recent years, it has become apparent that the composition and structure of the gut microbiota play a significant role in the aging process. The imbalance of gut microbiota in YinDC may accelerate the aging process. However, the specific gut microbiota compositions involved in the YinDC premature aging process remain unknown. In this study, we conducted a cohort study including 60 women with YinDC and BC to analyze their gut microbiota composition. We integrated 16S rDNA sequencing with machine learning methods to reveal the association between gut microbiota and premature aging in YinDC women. We found a significant difference in the composition of gut microbiota between the YinDC and the BC group. At the phylum level, Cyanobacteria and Synerobacteria only emerged in the YinDC group. At the genus level, Bacteroides, Bifidobacterium, Haemophilus, Alistipes, and Dialister showed higher abundance in the YinDC group. Bilophila, Eubacterium, and Aeromonas were the most significant indicators influencing the YinDC premature aging. The YinDC group had the most functional gene pathways associated with the metabolism. Our study demonstrated that the gut microbiota was associated with premature aging in women with YinDC, potentially providing preliminary evidence and guidance for personalized anti-aging strategies.

Beyond the Hayflick limit: How microbes influence cellular aging.

Cellular senescence, a complex biological process resulting in permanent cell-cycle arrest, is central to aging and age-related diseases. A key concept in understanding cellular senescence is the Hayflick Limit, which refers to the limited capacity of normal human cells to divide, after which they become senescent. Senescent cells (SC) accumulate with age, releasing pro-inflammatory and tissue-remodeling factors collectively known as the senescence-associated secretory phenotype (SASP). The causes of senescence are multifaceted, including telomere attrition, oxidative stress, and genotoxic damage, and they extend to influences from microbial sources. Research increasingly emphasizes the role of the microbiome, especially gut microbiota (GM), in modulating host senescence processes. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), support host health by maintaining antioxidant defenses and reducing inflammation, potentially mitigating senescence onset. Conversely, pathogenic bacteria like Pseudomonas aeruginosa and Helicobacter pylori introduce factors that damage host DNA or increase ROS, accelerating senescence via pathways such as NF-κB and p53-p21. This review explores the impact of bacterial factors on cellular senescence, highlighting the role of specific bacterial toxins in promoting senescence. Additionally, it discusses how dysbiosis and the loss of beneficial microbial species further contribute to age-related cellular deterioration. Modulating the gut microbiome to delay cellular senescence opens a path toward targeted anti-aging strategies. This work underscores the need for deeper investigation into microbial influence on aging, supporting innovative interventions to manage and potentially reverse cellular senescence.

Multi Characteristic Analysis of Vascular Cambium Cells in Populus euphratica Reveals Its Anti-Aging Strategy.

All multicellular organisms undergo senescence, but the continuous division of the vascular cambium in plants enables certain tree species to survive for hundreds or even thousands of years. Previous studies have focused on the development of the vascular cambium, but the mechanisms regulating age-related changes remain poorly understood. This study investigated age-related changes in the vascular cambium of P. euphratica trees aged 50 to 350 years. The number of cambium cells in the 50-year-old tree group was 10 ± 2, while the number of cambium cells in the 200-year-old and 350-year-old tree groups significantly decreased. The thickness of the cambium cells exhibited a similar trend. In addition, the net photosynthetic and transpiration rates continue to increase with age, but no notable differences were found in factors like average leaf area, palisade tissue thickness, and stomatal density. A total of 6491 differentially expressed genes (DEGs) were identified in the vascular cambium of P. euphratica at three distinct ages using RNA sequencing. The expression patterns of DEGs associated with cell division and differentiation, lignin biosynthesis, plant hormones, and transcription factors were analyzed. DEGs related to XTH, EXP, PAL, C4H, ABA, Br, GA, and others are highly expressed in older trees, whilst those encoding expansins, kinases, cyclins, 4CL, Auxin, Eth, SA, and others are more prevalent in younger trees. Gene family members, such as NAC, MYB, HD-ZIP III, WRKY, and GRF, have various regulatory functions in the vascular cambium. The findings offer insights into how ancient P. euphratica trees maintain vitality by balancing growth and aging, providing a foundation for future research on their longevity mechanisms.

Immune aging and infectious diseases.

The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.

Polygonum multiflorum Extracellular Vesicle-Like Nanovesicle for Skin Photoaging Therapy.

Ultraviolet (UV) irradiation leads to the degradation of the extracellular matrix and collagen, thereby accelerating skin aging and imposing substantial psychological burden on patients. Current anti-aging strategies are limited and often associated with high costs or strong side effects. Plant-derived extracellular vesicle-like nanovesicles, with advantages such as natural availability and cost-effectiveness, show potential in anti-aging interventions. This study extracted extracellular vesicle-like nanovesicle from Polygonum multiflorum (PMELNVs) and systematically investigated their composition and metabolic pathways, further examining their efficacy and underlying mechanisms in combating photoaging. Results revealed the excellent antioxidative properties of PMELNVs, alleviating UV-induced oxidative stress, inhibiting matrix metalloproteinase production, reducing extracellular matrix degradation, promoting collagen synthesis, and ultimately exerting anti-photoaging effects. Additionally, safety assessments demonstrated favorable biocompatibility of PMELNVs. This study provides novel evidence supporting PMELNVs' ability to resist photoaging by reducing oxidative stress and enhancing collagen expression, thereby offering potential as a new natural therapeutic agent against skin photoaging and promising a safer and more effective local anti-aging strategy.

The role of anti-aging approaches in managing hypogonadism in sedentary older males.

With thirty percent of the world's population not getting enough exercise, Worldwide, physical inactivity ranks as one of the most common causes of premature mortality. Rapid drops in physical activity, decreased mobility, and early morbidity are aging characteristics. As the population over 80 continues to rise, aging raises the danger of age-related illnesses and changes in hormone release. Understanding the aging process is useful in developing pharmacological therapies and identifying therapeutic targets for age-related testosterone deficiency. Therefore, this study's purpose is to present a thorough evaluation of the effects of anti-aging strategies on testosterone levels in older, inactive men. A literature search was completed for clinical and preclinical studies published in English between 2014 and 2024 related to age, sedentary life, testosterone, and anti-aging strategies. A sedentary lifestyle and low testosterone are linked to a vicious cycle. A sedentary lifestyle lowers testosterone levels, which leads to depression, exhaustion, low energy, and weakened bone and muscle strength. These effects exacerbate the detrimental consequences of aging and physical inactivity. Anti-aging techniques can prevent and treat age-related diseases, including calorie restriction, a balanced diet, regular exercise, weight control, diabetes management, and quitting smoking. Regular exercise raises total testosterone, free testosterone, and muscle steroidogenesis. In older men, testosterone replacement treatment increases bone density, cholesterol, protein synthesis, strength, erectile function, sexual desire, and general cognitive performance. However, some studies suggest dehydroepiandrosterone supplementation may provide health improvements without negative effects, potentially reversing arterial aging and reducing cardiovascular disease risk. This article evaluates the prospects for anti-aging procedures to assist in reducing the adverse effects of aging and physical inactivity in men.

IGFBP7 is a key component of the senescence-associated secretory phenotype (SASP) that induces senescence in healthy cells by modulating the insulin, IGF, and activin A pathways

Senescent cells exert their effects through the release of various factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The SASP can induce senescence in healthy cells (secondary senescence), modulate immune system function, reshape the extracellular matrix, and facilitate cancer progression.Among SASP components, certain factors act as key regulators in the induction of secondary senescence. In this study, we evaluated the role of IGFBP7, a crucial SASP component. Our results demonstrated that ROS-prostaglandin signaling is involved in the release of IGFBP7. Furthermore, neutralizing antibodies targeting IGFBP7 attenuated the SASP’s pro-senescence activity. Cells incubated with IGFBP7 also entered a state of senescence.The senescence induced by IGFBP7 appears to be mediated through three primary pathways. First, IGFBP7 can bind to insulin, thereby inhibiting its anti-senescence and pro-growth effects. In addition to this inhibitory effect on the insulin pathway, IGFBP7 may enhance IGFII pro-senescence signaling by promoting its interaction with IGF2R while blocking IGF1R. These activities are dependent on ERK and AKT signaling pathways. Finally, IGFBP7 and Activin A, both of which can induce cellular senescence, appear to regulate and inhibit each other, suggesting a compensatory mechanism to prevent excessive senescence. Notably, our preliminary data indicate that IGFBP7, in addition to blocking Activin A, may interact with its receptors and induce senescence via SMAD pathways.Our findings highlight that IGFBP7, along with other members of the IGFBP family, plays a pivotal role in senescence-related signaling pathways. Therefore, IGFBP7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence on tissues and organs.

Anti-aging potential of Cephalotaxus harringtonia extracts: the role of harringtonine and homoharringtonine in skin protection

Photoaging damages the skin layers. The tumor necrosis factor-alpha (TNF-α) plays a crucial role in the central mechanism of photoaging. TNF-α production leads to direct damage to skin cells and facilitates the degradation of vital extracellular matrix (ECM) proteins. TNF-α stimulates matrix metalloproteinase-1 (MMP-1) activation This accelerates the loss of skin elasticity and wrinkle formation. Thus, preventing photoaging and delaying the skin aging process are important research objectives, and the development of new anti-aging substances that target the TNF-α and MMP-1 pathways is promising. In this context, the efficacies of four extracts derived from two types of Cephalotaxus harringtonia (CH) buds (CH-10Y-buds, CH-200Y-buds) and leaves (CH-10Y-leaves, CH-200Y-leaves) were investigated, exhibiting a significant reduction in reactive oxygen species (ROS). Among the four extracts, CH-10Y-buds was the most effective in reducing ROS and exhibited the highest amounts of harringtonine and homoharringtonine. The activities of harringtonine, homoharringtonine, and ginkgetin were evaluated; harringtonine exhibited a high efficacy in inhibiting TNF-α-induced inflammatory responses and MMP-1 activation, thereby reducing collagen degradation. These findings suggest that CH-10Y-buds and their components herringtonin are promising candidates for preventing damage caused by photoaging. Our results can facilitate the development of new methods for maintaining skin health and inhibiting the skin aging process. Further research is necessary to comprehensively evaluate the potential efficacy of these candidate substances and investigate their applicability to actual skin. Such studies will aid in the development of more effective anti-aging strategies in the future.

Lycium barbarum Extract Enhanced Neuroplasticity and Functional Recovery in 5xFAD Mice via Modulating Microglial Status of the Central Nervous System.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with limited treatment options. This study aimed to investigate the effects of Lycium barbarum extract (LBE), a Chinese herb, on the central nervous system (CNS)-including the retina, brain, and spinal cord-in 5xFAD transgenic mice after the onset of AD. Starting at 6 months of age, 5xFAD mice received daily intragastric gavage of LBE (2 g/kg) for 2 months. At 8 months, behavioral tests were conducted to assess cognition, motor function, and visual function. These included the Morris water maze, novel object recognition, and Y-maze tests for cognition; the beam walking balance and clasping tests for motor function; and electroretinogram (ERG) for visual function. Immunohistochemistry, western blotting, and ELISA were used to evaluate Aβ deposition, microglial morphology, neuroinflammation, and neuroprotective signaling pathways. Primary microglia and the IMG cell line were used to study LBE's effects on Aβ uptake and degradation invitro. After 2 months of LBE treatment, the decline in cognition, motor, and visual functions in 5xFAD mice was significantly slowed. Microglia in the brain, spinal cord, and retina exhibited a neuroprotective state, with reduced Aβ deposition, decreased inflammatory cytokine levels (e.g., TNF-α, IL-1β, IL-6), increased Arg-1/iNOS ratio, and enhanced phagocytic capacity. LBE also promoted Aβ uptake and degradation in primary microglia and the IMG cell line. Neuroprotective signals such as p-Akt, p-Erk1/2, and p-CREB were elevated. Additionally, LBE treatment restored synaptic protein expression and enhanced neuroplasticity. The findings suggest that LBE treatment can enhance neuroplasticity, reduce systemic inflammation, and improve phagocyte clearance of Aβ deposition via inducing a neuroprotective microglial phenotype throughout CNS. As an upper-class Chinese medicine, appropriate intake of LBE may serve as a beneficial antiaging strategy for AD.

Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting.

Drug development for Alzheimer's disease (AD) treatment is challenging due to its complex pathogenesis. Tetradecyl 2,3-dihydroxybenzoate (ABG-001), a leading compound identified in our prior research, has shown promising NGF-mimicking activity and anti-aging properties. In the present study, both high-fat diet (HFD)-induced AD mice and naturally aging AD mice were used to evaluate anti-AD effects. Meanwhile, RNA-sequences, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), drug affinity-responsive target stability (DARTS) assay, construction of expression plasmid and protein purification, surface plasmon resonance (SPR) analysis, and 16S rRNA sequence analysis were used to identify the target protein of ABG-001 and clarify the mechanism of action for this molecule. ABG-001 effectively mitigates the memory dysfunction in both HFD-induced AD mice and naturally aging AD mice. The therapeutic effect of ABG-001 is attributed to its ability to promote neurogenesis, activate chaperone-mediated autophagy (CMA), and reduce neuronal inflammation. Additionally, ABG-001 positively influenced the gut microbiota, enhancing the production of indole-3-propionic acid (IPA), which is capable of crossing the blood-brain barrier (BBB) and contributes to neuronal regeneration. Furthermore, our research revealed that IPA, linked to the anti-AD properties of ABG-001, targets the heat shock cognate 70 kDa protein (Hsc70) and regulates the Hsc70/PKM2/HK2/LC3 and FOXO3a/SIRT1 signaling pathways. ABG-001 improves the memory dysfunction of AD mice by modulating autophagy and inflammation through IPA and Hsc70 targeting. These findings offer a novel approach for treating neurodegenerative diseases, focusing on the modification of the gut microbiota and metabolites coupled with anti-aging strategies.

Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster.

Various dietary supplements have been shown to extend the life span of Drosophila melanogaster, including several that promote autophagy, such as rapamycin and spermidine. The goal of the study presented here was to test numerous additional potential anti-aging supplements, primarily inhibitors of the target of rapamycin (TOR) and/or phosphatidylinositol 3-kinase (PI3K). Using a single, comparatively long-lived y w test strain, screening was performed in male flies supplemented either throughout adulthood or, in a few cases, beginning in middle or late adult life, with concentrations spanning 4-6 orders of magnitude in most cases. Supplementation with PP242 and deferiprone, an iron chelator, beginning in late adult life had no positive effect on life span. Lifelong supplementation with Ku-0063794, LY294002, PX-866-17OH, Torin2 and WYE-28 had no effect at any dose. Rapamycin, spermidine and wortmannin all had significant life-shortening effects at the highest doses tested. AZD8055, PI-103 hydrochloride and WYE-132 yielded slight beneficial effects at 1-2 doses, but only 100 nM AZD8055 was confirmed to have a minor (1.3%) effect in a replicate experiment, which was encompassed by other control groups within the same study. These compounds had no effect on fly fecundity (egg laying) or fertility (development of progeny to adulthood), but equivalent high doses of rapamycin abolished fertility. The solvent DMSO had no significant effect on life span at the concentrations used to solubilize most compounds in the fly medium, but it drastically curtailed both survival and fertility at higher concentrations. 2-Hydroxypropyl-β-cyclodextrin also failed to extend the life span when provided throughout adulthood or beginning in mid-adult life. Collectively, the results suggest that inhibition of the TOR/PI3K pathway and autophagy through dietary intervention is not a straightforward anti-aging strategy in Drosophila and that further extension of life is difficult in comparatively long-lived flies.

Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.

Impaired redox homeostasis is an important hallmark of aging. Among various anti-aging interventions, caloric restriction mimetics (CRMs) are the most effective inpromoting health and longevity. The potential role of spermidine (SPD) as a CRM in modulating oxidative stress and redox homeostasis during aging remains unclear. Thisstudy aimed to investigate the protective effect of SPD inD-galactose (D-gal) accelerated induced senescence model and naturally aged rats. Young male rats (4months), D-gal induced (500 mg/kg b. w., subcutaneously) aging model and naturally aged (22months) rats were supplemented with SPD (10 mg/kg b. w., orally) for 6weeks. The results showed that SPD supplementation suppresses the age induced increase in reactive oxygen species, lipid peroxidation andprotein oxidation. Additionally, it increases the level ofantioxidants, plasma membrane redox system in erythrocytes and membrane. These results also indicate that membrane transporter activity is correlated with the susceptibility of the erythrocyte towards oxidative damage. We therefore present evidence that SPD improves redox status and membrane impairments in erythrocytes in experimental and naturally aging rat models, however, more research is required to recommend a potential therapeutic role for SPD as an anti-aging intervention strategy.