«Мангиферин и транс-коричная кислота как перспективные модуляторы продолжительности жизни и стрессоустойчивости на примере Caenorhabditis elegans»/ «Mangiferin and trans-cinnamic acid as promising modulators for health span and stress resistance using Caenorhabditis elegans model» тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Салимон Саобан Сунканми

• Салимон Саобан Сунканми
• кандидат наук
• 2025

Оглавление диссертации кандидат наук Салимон Саобан Сунканми

Table of Contents

Title page (English)

Title page (Russian)

Table of Contents

INTRODUCTION

The relevance of the research topic

Aims and objectives of the study

Scientific novelty

Theoretical and practical significance

Methodology and research

Thesis statements submitted for defence

Author's contribution

Structure and scope of the dissertation

Approbation of the work

CHAPTER ONE: Literature Review

1.1 Herbal Medicine Practice - Altai Region, Russian Federation

1.2 Aging Research

1.3 Important Model Organisms used in Aging Research

1.3.1 Yeast (Saccharomyces cerevisiae)

1.3.2 Fruit flies (Drosophila melanogaster)

1.3.3 Zebra fish (Danio rerio)

1.3.4 Mice (Mus musculus)

1.3.5 Albino Rats (Rattus norvegicus)

1.3.6 Nematodes (Caenorhabditis elegans)

1.4 Role of C. elegans in healthy aging

1.4.1 C. elegans assay relevant to healthy aging

1.5 Translational Implications for Human Aging

1.5.1 Conserved Pathways and Mechanisms

1.5.2 Drug Discovery and Therapeutic Development

CHAPTER TWO: Materials and Methods

2.0 Chemical Reagents

2.1 Reagents and Chemicals

2.2 Materials and Equipment

2.3 Preparation of basic stock solutions and buffers

2.4 Nematodes Cultivation on Solid Agar

2.4.1 Preparation of bacterial food for nematodes

2.4.2 Preparation of Nematode Growth Medium Petri Plates

2.4.3 Nematode Growth Conditions

2.4.4 Transferring Frequency

2.5 Preparation of Liquid Cultures

2.5.1 Nematodes Synchronisation

2.5.2 Seeding into Well Plates

2.6 Freezing and Recovery of Nematode Stock

2.7 Preparation of Biologically Active Substances and Crude Extracts

2.8 Intestinal Autofluorescence Accumulation Assay

2.9 Lipid Droplets Accumulation - BODIPY 505/515 Staining

2.9.1 Image Analysis

2.10 Carbonylated Proteins Accumulation

2.11 Heat stress resistance

2.12 Oxidative stress resistance

2.13 Movement Behaviour Analysis

2.14 Intracellular ROS Levels

2.15 Gene Expression Analysis

2.15.1 Isolation of total RNA

2.15.1.1 RNA Quality Assessment

2.15.2 Complementary-DNA Synthesis

2.15.3 Quantitative Polymerase Chain Reaction (PCR) Analysis

2.15.4 Thermal Cycling Conditions

2.15.5 Melt Curve Analysis

2.15.6 Quantitative Analysis

2.16 Molecular Docking

2.17 Statistical Analysis

CHAPTER THREE: Results

3.0 Mitigation of Intestinal Autofluorescence Accumulation

3.1 Dose - Dependent Mode of BASs Influence on IAM Accumulation

3.2 Lowering of IAM Signals in the Presence of Medicinal Plants Extracts

3.3 Comparison of the Inhibitory Effect of the most Effective BASs and Extracts during

C. elegans Adulthood

3.4 Inhibitory Effect of BASs and Extracts on Lipid Accumulation

3.4.1 No Impact on the Rate of Lipid Accumulation

3.4.2 Low Impact on the Rate of Lipid Accumulation

3.4.3 High Impact on the Rate of Lipid Accumulation

3.4.4 Microscopic Imaging

3.5 Protective effect of BASs and extracts on protein carbonyl accumulation

3.5.1 Effect of BASs on carbonyl accumulation

3.5.2 Influence of crude extracts on carbonyl accumulation

3.6 Effect on heat-stress resistance and maximum lifespan

3.7 Movement behavioural changes in heat-shocked nematodes

3.8 H2O2 induced oxidative-stress resistance

3.9 Movement behavioural changes in H2O2-stressed nematodes

3.10 Deposition of intracellular ROS in C. elegans

3.11 Expression of hsp-16.2 and sod-3

3.12 Molecular Docking

CHAPTER FOUR: Discussion

4.0 Rationale for the choice of animal model

4.1 Mitigation of Intestinal Autofluorescence Accumulation

4.2 Reduction of fat accumulation in C. elegans

4.3 Protective effect on protein oxidation

4.4 Modulation of lifespan and fortification of stress resistance in wild type and

mutant strains

4.5 Sustenance of Motor Activity

4.6 Suppression of ROS-production and bioaccumulation

4.7 Modulatory effect on gene expression

4.8 Insights from in silico studies

CONCLUSION

List of abbreviations

References

Введение диссертации (часть автореферата) на тему ««Мангиферин и транс-коричная кислота как перспективные модуляторы продолжительности жизни и стрессоустойчивости на примере Caenorhabditis elegans»/ «Mangiferin and trans-cinnamic acid as promising modulators for health span and stress resistance using Caenorhabditis elegans model»»

INTRODUCTION

The relevance of the research topic

Stress resistance is the cornerstone of aging biology [1]. It can be described as the ability of cells or organisms to cope with physiological, environmental, and metabolic stressors, all of which play a crucial role in aging and longevity [2]. Various studies have shown that enhanced stress resilience at the molecular, cellular, and systemic levels is strongly associated with health span and extended lifespan [2-5]. The capacity of humans and animals to adapt to fluctuating environmental conditions is referred to as stress tolerance. Research has demonstrated that resilience to various stressors peaks during early adulthood and subsequently declines with advancing age [6]. According to the World Health Organization, the demographics of senior citizens (aged over 60 years) are projected to more than double by 2050 [7], which implies that the world is aging.

Aging is a complex phenomenon that is influenced by a myriad of genetic and environmental factors. Consequently, the development of antiaging medicines is often perceived as unrealistic. Nevertheless, recent investigations into the aging process have provided scientific evidence suggesting that pharmacological intervention in aging is indeed feasible [3-5, 8]. Aging is characterized by the accumulation of diverse molecular and cellular damage over time, including, but not limited to, the buildup of intestinal autofluorescence (lipofuscin), lipids, and protein carbonyls, all of which can be intensified by oxidative stress [9].

Furthermore, the general belief that aging is an inevitable natural process was widely held, primarily due to the paucity of scientific information and suitable research instruments [10]. However, recent advances in the knowledge of aging research in C. elegans and later in other model organisms has shown that aging can be modulated via several signaling pathways (Insulin/Insulin-like Signaling, IIS; Target Of Rapamycin Pathway, TOR; Adenosine Monophosphate Kinase, AMPK), metabolic and environment adaptation processes (autophagy, proteostasis, and hormesis), and transcription factor activity (Nrf2, FOXO, Sirt). All of these pathways are still being investigated [11], and manipulation of these important genes greatly extended not only lifespan but also health span from yeast to mammals [12].

Hence, interventions that modulates the aforementioned signalling pathways, prevent and/or slow down the accumulation of metabolic and molecular damage associated with multiple age-related diseases must be implemented. This is to arrest the burgeoning aging crisis owing to the upward trajectory in the prevalence of chronic diseases, such as cancer, diabetes,

obesity, arthritis, and neurodegenerative issues, all of which are common in the aged-population [13].

Previous studies have indicated that an assortment of bioactive compounds and plant extracts can significantly extend the lifespans of both mammals and invertebrates. The delay in aging as well as the onset of age-related diseases, translates into the concept of healthy aging. Healthy aging constitutes a significant health challenge in human societies worldwide, prompting the declaration of the years 2021 - 2030 as the UN Decade of Healthy Aging [14, 15]. This is a worldwide initiative to promote longer and healthier lives, requiring governments, civil societies, corporate sectors, professionals, international organizations, the media and research institutions to join forces over 10 years with the sole aim of achieving this goal [15].

The last few decades have witnessed the emergence of investigations into naturally occurring bioactive compounds as cornerstones in biomedical research [5]. This has been propelled by the increasing recognition of potential therapeutic advantages and their beneficial contributions to human health. These compounds have attracted significant scholarly interest not only because of their efficacy but also because of their comparatively low toxicity profiles compared to their synthetic alternatives [5, 16]. The natural provenance of these compounds frequently corresponds to traditional medicinal practices, thereby substantiating age-old wisdom through contemporary scientific validation. A salient characteristic of natural bioactive compounds is their structural heterogeneity and intricate mechanisms of action, each of which exhibits distinctive chemical architectures that influence their interactions with biological systems. This characteristic facilitates the targeting of specific pathways involved in disease processes, thereby offering customized therapeutic strategies.

Mangiferin and trans-cinnamic acid (Figure 1) are two bioactive compounds that have gained attention in aging research due to their antioxidant properties, which could help delay the onset of age-related diseases and promote healthy aging. By mitigating oxidative stress, antioxidants fundamentally impact aging and several chronic illnesses, and their anti-inflammatory qualities help adjust immune responses and reduce inflammation markers that are related to conditions such as arthritis, cardiac issues, and disorders affecting the nervous system [17]. Consequently, the consumption of these natural compounds as supplements or through diet may aid in the prevention of chronic disease pathogenesis and contribute to the deceleration of aging, thereby enhancing the health span of organisms.

A B

Figure 1. Structures of (A) mangiferin and (B) trans-cinnamic acid

Mangiferin is a natural polyphenol primarily found in mangoes (Mangifera indica), as well as in other plants like Anemarrhena asphodeloides, Hedysarum neglectum and Cyclopia species [18, 19]. It is known for its strong antioxidant, anti-inflammatory, and anti-apoptotic properties, all of which are crucial for combating age-related oxidative stress, metabolic syndrome, and inflammation [20-22]. Mangiferin has been shown to activate various cellular pathways involved in longevity and stress resistance, such as the Nrf2 signalling pathway, which enhances the expression of antioxidant enzymes [23, 24]. Additionally, it has been linked to modulating mitochondrial function and promoting autophagy, processes that are key in maintaining cellular health during aging. By reducing oxidative damage and supporting cellular repair mechanisms, mangiferin helps to preserve tissue integrity and function as organisms age [24].

Trans-cinnamic acid is a naturally occurring organic compound found in cinnamon and other plants. It exhibits a range of biological activities that make it relevant for aging research, including its antioxidant, anti-inflammatory, and antimicrobial properties [25, 26]. Like mangiferin, trans-cinnamic helps neutralize reactive oxygen species (ROS), thus protecting cells from oxidative damage, which is a hallmark of aging. Furthermore, trans-cinnamic has been shown to influence metabolic pathways involved in glucose and lipid metabolism, which are crucial for maintaining metabolic health during aging [27, 28]. It has also been associated with modulating the activity of enzymes that regulate cellular stress responses and inflammation, helping to mitigate the chronic low-grade inflammation often observed in aging, known as "inflammaging" [29].

Thus, both mangiferin and trans-cinnamic acid, through their antioxidant and anti-inflammatory actions, offer promising geroprotective effects, making them valuable compounds for further investigation in the field of aging research. Their potential to enhance

cellular resilience and mitigate the effects of aging-related damage may contribute to the development of novel therapeutic strategies for age-associated diseases.

Aims and objectives of the study

The aim of this study is to provide scientific validation for the age long use of Altai medicinal plants in the management of aging and age-relate diseases, identify the bioactive compounds responsible and propose a probable mechanism of action especially in relation to health span and stress resistance, using C. elegans model.

To achieve this, the following objectives were laid out:

1. To screen the crude extracts and their bioactive substances (BAS) for their influence on the mitigation of intestinal autofluorescence accumulation.

2. To evaluate the anti-aging effect of the crude extracts and BAS on the rate lipid droplets accumulation.

3. To evaluate the protective effect of the crude extracts and BAS on protein oxidation by quantifying the carbonylated proteins in both treated and untreated C. elegans.

4. Study the overall effect of the BAS across different hallmarks of aging monitored for the identification of the most promising prospects.

5. An investigation of the role of mangiferin (MF) and trans-cinnamic acid (tCA) in stress resistance in wildtype N2 strains and aak-2 knockdown mutant strains, as it relates to;

a) Heat stress

b) H2O2-induced oxidative stress

6. An analysis of the different movement behaviours exhibited by the wildtype and mutant strains exposed to heat shock and H2O2-induced oxidative stress.

7. Study the effect of MF and tCA on ROS accumulation.

8. mRNA level quantification of the influence of MF and tCA on the expression of heat shock protein (hsp-16.2) and superoxide dismutase (sod-3).

9. Molecular docking analysis of the interactions between ligands (MF and tCA) and their key target receptors.

Scientific novelty

1. This dissertation was set out to explore the anti-aging potentials of medicinal herbs from the Altai Region, Russian Federation by providing scientific credence and establishing their probable mechanisms. H. neglectum, a medicinal herb that is rarely investigated and less known outside of the Altai region, was brought to light by this initiative.

2. While the accretion of intestinal autofluorescence, lipid droplets, carbonylated proteins, ROS are standard procedures for the evaluation of anti-aging compounds, the establishment of the role of mangiferin and trans-cinnamic acid in the mitigation of these processes are previously unreported.

3. Furthermore, a novel methodology has been developed to evaluate the protective effect of bioactive compounds against environmental stressors. It involves the classification of movement behaviour to correctly reflect the functional and physiological changes facilitated by motor neurons at different stages of development in C. elegans.

4. Our molecular docking analysis has unearthed the potential interplay of CCNA2 (a receptor popular for its role in cell cycle regulation) with the modulation of health span and stress response possibly through senescent cell targets and/or autophagic processes.

5. The findings of this dissertation suggests that MF and tCA improved not only lifespan, but health span and stress resistance. These claims were validated by the mitigation of the accretion of intestinal autofluorescence, ROS, lipid droplets and carbonylated proteins; enhanced thermotolerance, modulation of the HSF, AMPK and IlS-signalling pathways; as well as their strong binding affinities with peroxisome proliferator-activated receptor-a (a versatile transcription factor that plays a significant role in peroxisomal fatty acid oxidation, release of apo-lipoproteins, energy balance, and other metabolic processes), and fatty acid synthase (de novo fatty acid synthesis and immunoregulation).

Theoretical and practical significance

The present study explores MF and tCA isolated from medical plants of the Altai Region, Russian federation as potential modulators of health span and stress resistance, contributing valuable insights to the fields of aging research and natural product pharmacology. The accretion of intestinal autofluorescence (also known as age pigment), lipid droplets, carbonylated proteins, impaired locomotive activities as some of the major hallmarks of aging in both vertebrates and invertebrates. Theoretically, this research enhances our understanding of the molecular mechanisms by which our phytochemicals influence aging and stress-response pathways, such as oxidative stress modulation, hormesis, and cellular signaling cascades such as the HSF, IIS, and AMPK. By elucidating the bioactivity of these compounds, the study deepens existing scientific models on how natural molecules can mitigate the bioaccumulation of diverse molecular and cellular damage in our aging population.

Practically, this thesis identifies MF and tCA as promising, accessible candidates for health span-enhancing interventions. Given their natural abundance in food and medicinal

plants, these compounds offer potential for the development of cost-effective, low-risk nutraceuticals or dietary supplements aimed at promoting health span and resilience against environmental stressors. This has implications not only for individual health optimization but also for public health strategies such as the United Nation's Decade of Healthy Aging Declaration, addressing age-related diseases and the growing aging population. The findings provide a scientific basis for future preclinical and clinical studies, potentially translating into cost effective, non-invasive and easily accessible solutions for age-associated health challenges.

Methodology and research

The totality of the methods adopted in this study incorporated various aspects of analytical chemistry, biochemistry, bioinformatics, cell and molecular biology, complementary and alternative medicine, genetics, microbiology, and physiology. As part of the study, some selected plants recommended by the local herbal medicine practitioners were harvested from the flora and fauna of the Altai region from which our crude extracts were prepared and bioactive compounds were isolated. The model C. elegans was adopted for our anti-aging studies due to its numerous benefits, especially for their ease of breeding, age synchronization, short lifespan, and transparency for image analysis. The investigation of intestinal autofluorescence accumulation was conducted using spectrofluorimetric technique to evaluate the influence of our biomolecules on the rate of accumulation over time. Using specific fluorescent molecular probes - 2',7'-dichlorofluorescein diacetate, BODIPY505/515, and cyanine N-hydroxy-succimide, the respective accumulations of reactive oxygen species, lipid droplets and carbonylated proteins were evaluated. Stress tolerance study was implemented by subjecting the nematodes to heat shock and H2O2-induced oxidative stress while their physiological adaptation as it relates to lifespan and motility were simultaneously documented. Through RT-qPCR (expression of hsp-16.2 and sod-3), stress sensitive transgenic mutant strains (aak-2) and molecular docking analysis, the probable mechanism of action of MF and tCA on the aging process was postulated. Various programs such as Microsoft Office Professional Plus 2021, GraphPad Prism 9.3, AutoDock Vina v1.2.3, and CellProfiler 4.2 were adopted at various stages for the statistical data analysis.

Thesis statements submitted for defence

1. The influence of 10 biologically active substances isolated from 5 crude extracts used for managing various age-related diseases in Altai folklore were scientifically validated.

2. Of all the compounds studied, MF and tCA were identified as the most efficacious.

3. Both MF and tCA exhibited strong inhibitory effects on crucial aging parameters such as intestinal autofluorescence accumulation, protein carbonyl accumulation and lipid-drops deposition, which is indicative of their role in modulating metabolic processes associated with aging in C. elegans.

4. C. elegans pre-treated with MF and tCA were subjected to heat (37 °C) and oxidative stress (H2O2) conditions. These compounds markedly improved stress resistance in C. elegans by increasing survival rates and maximum lifespan when compared to the untreated control, thus highlighting their antioxidant potential as an important mechanism for promoting longevity.

5. In C. elegans, aak-2 is involved in stress responses, Dauer formation and maintenance of longevity, the absence of which leads to increased sensitivity to oxidative stress. However, MF significantly extended the lifespan of not only wild-type but also aak-2 knockdown mutant strains subjected to oxidative stress conditions. The highest increase in survival ratio in the H2O2-treated aak-2 knockdown mutant strains was 51.85 %.

6. The influence of MF and tCA were not limited to survival ratio and lifespan, as the loss of motility function resulting from the exposure of nematodes to heat and oxidative stressors were mitigated.

7. Gene expression analysis of important longevity-related genes hsp-16.2 and sod-3 that are respectively involved in response to heat stress and redox homeostasis in C. elegans revealed an upregulation in the expression of these genes.

8. Molecular docking analysis of MF and tCA exhibited a strong ligand-receptor interaction with retinoic acid receptor-a (RARA), retinoic acid receptor-y (RARG), peroxisome proliferator-activated receptor-a (PPARA), fatty acid synthase (FASN) and cyclin-A2 (CCNA2) that play integral roles on aging in C. elegans.

9. AAK-2 is a well-established activator of DAF-16 which is a crucial intermediary within the insulin/IGF-1 signalling (IIS) pathway of C. elegans. It is responsible for enhancing the transcriptional activity of numerous genes whose resultant proteins confer protection against diverse stressors, including oxidative stress mediated by sod-3, thermotolerance, and proteotoxicity facilitated by small heat shock proteins (hsp-16.2). The entirety of our results suggests that MF and tCA might have acted through the

modulation of the hsf-1, and IIS-signalling pathway as evidenced by the upregulation of hsp-16.2 and sod-3 expression, rejuvenation of aak-2 knockdown mutant strains function, increased lifespan and stress resistance.

Author's contribution

The study was conducted on territory of the Federal State Autonomous Educational Institution of Higher Education "Moscow Institute of Physics and Technology (National Research University)" within the time period of 2021 - 2025. The author conducted an in-depth review of contemporary local and international literature, relevant to the research topic independently. Further unbiased research was done to design and improve the entire study, with the guidance of the supervisors. The author participated in all experimental investigations, both in vivo, in vitro, and in silico studies. The candidate actively participated in data analysis, grant applications, compiled and obtained results, authored manuscripts, and contributed to the writing and publication of scientific articles and conference proceedings. The findings presented in this dissertation are the result of four years of research conducted by the author as a Laboratory Assistant in the Laboratory for Personalised Chemo-radiotherapy, Institute of Future Biophysics and a PhD student of the School of Biological and Medical Physics, Moscow Institute of Physics and Technology.

Structure and scope of the dissertation

The dissertation is 125 pages long text, type written using the Times New Roman font, font size 12, line spacing - 1.5, and organised into several sections: introduction, literature review, materials and methods, results, discussion, conclusion and references. It includes 8 tables and 40 figures, and the reference list is made up of 206 references.

Approbation of the work

The findings of this dissertation served as the basis for six conference abstracts. The following conferences hosted presentations of the research:

1. 67th All-Russian Scientific Conference of the Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia, 1 - 5 Apr., 2025.

2. Biomembranes'24 International Conference, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Moscow Region, Russia, 7 - 11 Oct., 2024.

3. XI Russian Biotechnology Forum - OPENBIO International Scientific Conference of Young Scientists 2024, Science City of Koltsovo, Russia, 24 - 27 Sept., 2024.

4. 66th All-Russian Scientific Conference of the Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia, 1 - 6 Apr., 2024.

5. 65th All-Russian Scientific Conference of the Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia, 3 - 8 Apr., 2023.

6. 6th International Conference, Society for Medicinal Plants and Economic Development, Cape-Peninsula University, Cape-Town, South Africa, 23 - 26 Aug., 2022.

In addition, 4 works related to the theme of the research have been published in journals indexed in RSCI, Scopus and Web of Science and 1 review in a book chapter.

1. Salimon, S.S., Leonov S.V., Marusich E.I. (2025). The protective role of mangiferin and trans-cinnamic acid against oxidative stress in wild type and aak-2 knockout Caenorhabditis elegans strains. Biochemistry (Moscow), Suppl. Series A: Membrane and Cell Biology 19(3): 363 - 371. https://doi.org/10.1134/S1990747825700321.

2. Salimon, S. S., Marusich E. I., Leonov S. V., and Pustovalova, M. V. Mitigation of intestinal autofluorescence accumulation in Caenorhabditis elegans treated with plant-based natural products. Acta Biomedica Scientifica 2024, 9(6): 67 - 77. https://doi.org/10.29413/ABS.2024-9.6.19

3. Nurudeen, Q.O., Yusuf, Z.M., Salimon, S.S., Falana, M.B., Ayinla, A.A., Asinmi, MR., Oweh, O.T. and Dikwa, M.A. (2024). Hydroethanolic extract of Piliostigma thonningii leaves extenuates the severity of diarrhoea in female Wistar rats. Journal of Complementary and Integrative Medicine, 21(1): 26-37. https://doi.org/10.1515/jcim-2023-0205

4. Salimon, S.S., Marusich E.I., Leonov S.V. The impact of mangiferin and trans-cinnamic acid on the survival and lifespan of wildtype N2 Bristol and aak-2 Caenorhabditis elegans mutant strains under oxidative stress. OPENBIO Conference proceedings 2024, p. 586-587. https://doi .org/10.25205/978-5-4437-1691 -6-290

5. Izah, S.C., Ogidi, O. I., Ogwu, M.C., Salimon, S.S., Yusuf, Z.M., Akram, M., Raimi, O.M. and Iyingiala, A. Historical Perspectives and Overview of the Value of Herbal Medicine. In: Izah, S.C., (eds) Herbal Medicine Phytochemistry. Reference Series in Phytochemistry 2023, pp. 1-33. Springer. https://doi.org/10.1007/978-3-031-21973-3 1-1

Заключение диссертации по теме «Другие cпециальности», Салимон Саобан Сунканми

CONCLUSION

The study scientifically validated the efficacy of 10 biologically active substances derived from Altai folklore medicinal plants in managing age-related diseases, with mangiferin and trans-cinnamic acid emerging as the most potent compounds. This was achieved through the evaluation of the influence of these plants and their bioactive compounds on various physiological, molecular and cellular hallmarks of aging. Both mangiferin and trans-cinnamic acid demonstrated robust inhibitory effects on key aging biomarkers in C. elegans, including intestinal autofluorescence, protein carbonyl accumulation, and lipid droplet deposition, underscoring their role in modulating metabolic processes linked to aging. These compounds significantly enhanced stress resistance, improving survival rates and maximum lifespan under oxidative (H2O2) and thermal (37 °C) stress conditions. Notably, mangiferin restored longevity and stress resilience even in aak-2 knockdown mutants, with a 51.85% increase in survival under oxidative stress, suggesting a mechanism unlimited by the canonical AMPK (aak-2)-mediated pathway. Furthermore, mangiferin and trans-cinnamic acid mitigated age-related motility decline and upregulated longevity-associated genes (hsp-16.2 and sod-3), which are critical for heat shock response and redox homeostasis. Molecular docking revealed strong interactions between these compounds and aging-related targets (e.g., RARA, PPARA, FASN), implicating their potential to modulate pathways such as insulin/IGF-1 signalling, HSF-1 and AMPK. The collective findings propose that mangiferin and trans-cinnamic acid exert anti-aging effects via multifaceted mechanisms, including antioxidant activity, stress resistance enhancement, and gene expression modulation, positioning them as promising candidates for health span and lifespan therapeutics. However, the need for future research to explore their translational potential in higher organisms is hugely recommended.

Список литературы диссертационного исследования кандидат наук Салимон Саобан Сунканми, 2025 год

References

1. Musi, N., & Hornsby, P. (Eds.). (2021). Handbook of the Biology of Aging (Ninth Edition). Academic Press, ISBN 9780128159620.

2. Badial, K., Lacayo, P., & Murakami, S. (2024). Biology of healthy aging: biological hallmarks of stress resistance related and unrelated to longevity in humans. International Journal of Molecular Sciences, 25(19), 10493.

3. Ogawa, T., Kodera, Y., Hirata, D., Blackwell, T. K., & Mizunuma, M. (2016). Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf. Scientific Reports, 6(1), 21611.

4. Fan, H., Wang, C., Liu, S., Li, Y., & Xu, Z. (2025). Therapeutic potential of natural products in stress granules: underlying molecular mechanisms and future perspectives. Current Pharmaceutical Analysis, 21(2), 88 - 99.

5. Narayanankutty, A., Famurewa, A.C., & Oprea, E. (2024). Natural bioactive compounds and human health. Molecules. 29(14): 3372.

6. Dues, D. J., Andrews, E. K., Schaar, C. E., Bergsma, A. L., Senchuk, M. M., & Van Raamsdonk, J. M. (2016). Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways. Aging (Albany NY), 5(4), 777.

7. WHO (2024). Ageing and health. Available online: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health Accessed on - 12/05/2025.

8. Faskhutdinova, E. R., Sukhikh, A. S., Le Violeta, M., Minina, V. I., Khelef, M. E. A., & Loseva, A. I. (2022). Effects of bioactive substances isolated from Siberian medicinal plants on the lifespan of Caenorhabditis elegans. Foods and Raw Materials, 10(2), 340-352.

9. da Silva, P. F., & Schumacher, B. (2021). Principles of the molecular and cellular mechanisms of aging. Journal of Investigative Dermatology, 141(4), 951-960.

10. Vaiserman, A., & Lushchak, O. (2017). Implementation of longevity-promoting supplements and medications in public health practice: achievements, challenges and future perspectives. Journal of translational medicine, 15, 1-9.

11. Ma, S., & Gladyshev, V. N. (2017). Molecular signatures of longevity: Insights from cross-species comparative studies. In Seminars in Cell & Developmental Biology, 70, 190-203.

12. Carretero, M., Gomez-Amaro, R. L., & Petrascheck, M. (2015). Pharmacological classes that extend lifespan of Caenorhabditis elegans. Frontiers in genetics, 6, 77.

13. Atella, V., Piano Mortari, A., Kopinska, J., Belotti, F., Lapi, F., Cricelli, C., & Fontana,

L. (2019). Trends in age-related disease burden and healthcare utilization. Aging cell, 15(1), e12861.

14. Keating, N. (2022). A research framework for the United Nations Decade of Healthy Ageing (2021-2030). European Journal of Ageing, 19(3), 775-787.

15. WHO (2022). Decade of healthy ageing. Available online: https://www.who.int/initiatives/decade-of-healthy-ageing Accessed on - 25/04/2023

16. Abubakar, U.S., Osodi, F.A., Aliyu, I., Jamila, G.A., Saidu, S.R., Fatima, S.S., Sani, S.I., Ahmad, S.A. and Tsoken, B.G. (2016). The use of traditional medicine among Bayero University community, Kano. Journal of Medicinal Plants Studies. 4(6): 23-25.

17. Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., & Supuran, C. T. (2021). Natural products in drug discovery: advances and opportunities. Nature reviews Drug discovery, 20(3), 200-216.

18. Matkowski, A., Kus, P., Goralska, E., & Wozniak, D. (2013). Mangiferin-a bioactive xanthonoid, not only from mango and not just antioxidant. Mini reviews in medicinal chemistry, 13(3), 439-455.

19. Mei, S., Perumal, M., Battino, M., Kitts, D. D., Xiao, J., Ma, H., & Chen, X. (2023). Mangiferin: a review of dietary sources, absorption, metabolism, bioavailability, and safety. Critical Reviews in Food Science and Nutrition, 63(18), 3046-3064.

20. Imran, M., Arshad, M. S., Butt, M. S., Kwon, J. H., Arshad, M. U., & Sultan, M. T. (2017). Mangiferin: a natural miracle bioactive compound against lifestyle related disorders. Lipids in health and disease, 16, 1-17.

21. Jangra, A., Arora, M. K., Kisku, A., & Sharma, S. (2021). The multifaceted role of mangiferin in health and diseases: A review. Advances in Traditional Medicine, 21, 619-643.

22. Xiang, G., Guo, S., Xing, N., Du, Q., Qin, J., Gao, H., ... & Wang, S. (2024). Mangiferin, a potential supplement to improve metabolic syndrome: current status and future opportunities. The American Journal of Chinese Medicine, 52(02), 355-386.

23. Salehi, B., Azzini, E., Zucca, P., Maria Varoni, E., V. Anil Kumar, N., Dini, L., ... & Sharifi-Rad, J. (2020). Plant-derived bioactives and oxidative stress-related disorders: a key trend towards healthy aging and longevity promotion. Applied Sciences, 10(3), 947.

24. Rahmani, A. H., Almatroudi, A., Allemailem, K. S., Alharbi, H. O. A., Alwanian, W. M., Alhunayhani, B. A., ... & Khan, A. A. (2023). Role of mangiferin in management of cancers through modulation of signal transduction

pathways. Biomedicines, 11(12), 3205.

25. Walkowiak, J., Lisowska, A., & Blaszczynski, M. (2008). The changing face of the exocrine pancreas in cystic fibrosis: pancreatic sufficiency, pancreatitis and genotype. European journal of gastroenterology & hepatology, 20(3), 157-160.

26. Ju, J., Santana de Oliveira, M., & Qiao, Y. (2023). Pharmacological Effects of Cinnamon in Functional Foods. In Cinnamon: A Medicinal Plant and A Functional Food Systems Springer p. 57-68.

27. Alam, M. A., Subhan, N., Hossain, H., Hossain, M., Reza, H. M., Rahman, M. M., & Ullah, M. O. (2016). Hydroxycinnamic acid derivatives: a potential class of natural compounds for the management of lipid metabolism and obesity. Nutrition & metabolism, 13, 1-13.

28. Wu, L., Zhou, B., Oshiro-Rapley, N., Li, M., Paulo, J. A., Webster, C. M., ... & Soukas, A. A. (2016). An ancient, unified mechanism for metformin growth inhibition in C. elegans and cancer. Cell, 167(7), 1705-1718.

29. Leyane, T. S., Jere, S. W., & Houreld, N. N. (2022). Oxidative stress in ageing and chronic degenerative pathologies: molecular mechanisms involved in counteracting oxidative stress and chronic inflammation. International journal of molecular sciences, 23(13), 7273.

30. Jamshidi-Kia, F., Lorigooini, Z. & Amini-Khoei, H. (2018). Medicinal plants: Past history and future perspective. Journal of HerbmedPharmacology. 7(1).

31. Astana (2019). Global conference on primary health care. Available online https://www.who.int/docs/default-source/primary-health/declaration/gcphc-declaration.pdf?ua=1 Accessed on 28th February 2023.

32. World Health Organization. (2018). Antimicrobial resistance and primary health care. World Health Organization.

33. Daniyal, M., Akram, M., Zainab, R., Munir, N., Shah, S.M., Liu, B., Wang, W., Riaz, M. & Jabeen, F. (2019). Progress and prospects in the management of psoriasis and developments in phyto-therapeutic modalities. Dermatologic Therapy. 32(3):e12866.

34. Che, C. T., George, V., Ijinu, T. P., Pushpangadan, P., & Andrae-Marobela, K. (2017). Traditional medicine. In Pharmacognosy (pp. 15-30). Academic Press.

35. Mukherjee, P. K. (2001). Evaluation of Indian traditional medicine. Drug Information Journal, 35(2), 623-632.

36. Izah, S.C., Ogidi, O.I., Ogwu, M.C., Salimon, S.S., Yusuf, Z.M., Akram, M., et al. (2023). Historical Perspectives and Overview of the Value of Herbal Medicine. In: Izah,

S.C., Ogwu, M.C. and Akram, M., Eds., Herbal Medicine Phytochemistry, Springer International Publishing, 1-33.

37. Gu, S., & Pei, J. (2017). Innovating Chinese herbal medicine: from traditional health practice to scientific drug discovery. Frontiers in pharmacology, 8, 381.

38. World Health Organization (WHO). (2005). National Policy on Traditional Medicine and Regulation of Herbal Medicines. Geneva. Report of WHO global survey.

39. Xu, J., & Yang, Y. (2009). Traditional Chinese medicine in the Chinese health care system. Health policy, 90(2-3), 133-139.

40. Heinrich, M., Sharma, S. K., Suetterle, U., & Bhamra, S. K. (2023). Herbal medicine use in the UK and Germany and pharmacy practice-A commentary. Research in Social and Administrative Pharmacy 19(3): 535-540.

41. Fortune Business Insights (2021). The global herbal medicine market is projected to grow from $165.66 billion in 2022 to $347.50 billion by 2029, at a CAGR of 11.16% in forecast period. Available online: https://www.fortunebusinessinsights.com/herbal-medicine-market-106320 (Accessed on 28/02/2023)

42. Niazi, P., & Monib, A. W. (2024). The role of plants in traditional and modern medicine. Journal of Pharmacognosy and Phytochemistry.

43. Rashrash, M., Schommer, J. C., & Brown, L. M. (2017). Prevalence and predictors of herbal medicine use among adults in the United States. Journal of Patient Experience 4(3): 108-113.

44. Barnes, P. M., Bloom, B. and Nahin, R. (2007). Complementary and alternative medicine use among adults and children: United States. CDC National Health Statistics Report.

45. Luczaj, L. (2008). Archival data on wild food plants used in Poland in 1948. J. Ethnobiol. Ethnomed. 4:4.

46. Shikov, A. N., Tsitsilin, A. N., Pozharitskaya, O. N., Makarov, V. G., & Heinrich, M. (2017). Traditional and current food use of wild plants listed in the Russian Pharmacopoeia. Frontiers in pharmacology, 8, 841.

47. Nekratova, N. A., & Shurupova, M. N. (2015). Medicinal plants in the Altai Mountains: reserves of raw materials and annual possible volumes of harvesting. International Journal of Environmental Studies, 72(3), 490-500.

48. Altaiskiy Krai (2025). Brief profile of the Altai Territory. Available online https://altairegion22.ru/en/region/brief-profile/ Accessed on 13 April 2025

49. Kurbonbekova, S. S. (2022). Ethnobotany and traditional medicine in the Pamir.

Problems of botany of Southern Siberia and Mongolia, 21(2), 98-100.

50. Jha, S.K., Chauhan, S.S., Shamim, K., Lal, G. and Suman, S. (2024). Medicinal properties of plants used in traditional medicinal systems. Futuristic Trends in Herbal Medicines and Food Products, IIP Series, 3: 13-56.

51. Wang, X., Gong, X., Zhang, H., Zhu, W., Jiang, Z., Shi, Y., & Li, L. (2020). In vitro anti-aging activities of ginkgo biloba leaf extract and its chemical constituents. Food Science and Technology, 40, 476-482.

52. Zuo, W., Yan, F., Zhang, B., Li, J., & Mei, D. (2017). Advances in the studies of Ginkgo biloba leaves extract on aging-related diseases. Aging and disease, 8(6), 812.

53. Yang, J. H., Shin, B. Y., Han, J. Y., Kim, M. G., Wi, J. E., Kim, Y. W., ... & Ki, S. H. (2014). Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. Toxicology and applied pharmacology, 274(2), 293301.

54. Pan, X., Liu, X., Zhao, H., Wu, B., & Liu, G. (2020). Antioxidant, anti-inflammatory and neuroprotective effect of kaempferol on rotenone-induced Parkinson's disease model of rats and SH-S5Y5 cells by preventing loss of tyrosine hydroxylase. Journal of Functional Foods, 74, 104140.

55. Barbalho, S. M., Direito, R., Laurindo, L. F., Marton, L. T., Guiguer, E. L., Goulart, R. D. A., ... & Araujo, A. C. (2022). Ginkgo biloba in the aging process: A narrative review. Antioxidants, 11(3), 525.

56. Olonova, M. V., Zhang, D., Duan, S., Yin, L., & Pan, B. (2010). Rare and endangered plant species of the Chinese Altai Mountains. Journal of Arid Land 2(3): 222-230.

57. Zhao, F., Chang, Y., Gao, L., Qin, X., Du, G., Zhang, X., & Zhou, Y. (2018). Protective effects of Scutellaria baicalensis Georgi extract on D-galactose induced aging rats. Metabolic Brain Disease, 33, 1401-1412.

58. Sun, G., Dang, Y., Lin, Y., Zeng, W., Wu, Z., Zhang, X., ... & Wu, B. (2022). Scutellaria baicalensis Georgi regulates REV-ERBa/BMAL1 to protect against skin aging in mice. Frontiers in Pharmacology, 13, 991917.

59. Vesnina, A., Milentyeva, I., Minina, V., Kozlova, O., & Asyakina, L. (2023). Evaluation of the In Vivo Anti-Atherosclerotic Activity of Quercetin Isolated from the Hairy Roots of Hedysarum neglectum Ledeb. Life, 13(8), 1706.

60. Lang, T., Pan, L., Liu, B., Guo, T., & Hou, X. (2020). Vegetation characteristics and response to the soil properties of three medicinal plant communities in Altay Prefecture, China. Sustainability, 12(24), 10306.

61. Peng, X., Hao, M., Zhao, Y., Cai, Y., Chen, X., Chen, H., ... & Luo, Y. (2021). Red ginseng has stronger anti-aging effects compared to ginseng possibly due to its regulation of oxidative stress and the gut microbiota. Phytomedicine, 93, 153772.

62. Wurchaih, Huar, Menggenqiqig and Khasbagan (2019). Medicinal wild plants used by the Mongol herdsmen in Bairin Area of Inner Mongolia and its comparative study between TMM and TCM. J Ethnobiology Ethnomedicine 15, 32: 1-18.

63. Chauhan, S., Jaiswal, V., Cho, Y. I., & Lee, H. J. (2022). Biological activities and phytochemicals of lungworts (genus Pulmonaria) focusing on Pulmonaria officinalis. Applied Sciences, 12(13), 6678.

64. Dyshlyuk, L. S., Fotina, N. V., Milentyeva, I. S., Ivanova, S. A., Izgarysheva, N. V., & Golubtsova, Y. V. (2022). Antimicrobial and antioxidant activity of Panax ginseng and Hedysarum neglectum root crop extracts. Brazilian Journal of Biology, 84, e256944.

65. Faskhutdinova, E. R., Sukhikh, A. S., Le Violeta, M., Minina, V. I., Khelef, M. E. A., & Loseva, A. I. (2022). Effects of bioactive substances isolated from Siberian medicinal plants on the lifespan of Caenorhabditis elegans. Foods and Raw Materials, 10(2), 340-352.

66. Fedorova A.M., Dyshlyuk L.S., Milentyeva I.S., Loseva A.I., Neverova O.A., Khelef M.E.A. Geroprotective activity of trans-cinnamic acid isolated from the Baikal skullcap (Scutellaria baicalensis). Food Processing: Techniques and Technology. 2022; 52(3): 582-591.

67. Salimon S.S., Marusich E.I., Leonov S.V., Pustovalova M.V. Mitigation of intestinal autofluoresceance accumulation in Caenorhabditis elegans treated with plantbased natural products. Acta biomedica scientifica. 2024; 9(6): 184-194.

68. United Nations (2021). World Population Prospects 2019 Highlights. Available online https://population.un.org/wpp/Publications/Files/WPP2019_Highlights.pdf Accessed 18 April 2023.

69. Rudnicka E, Napierala P, Podfigurna A, M^czekalski B, Smolarczyk R, Grymowicz M. (2020). The World Health Organization (WHO) approach to healthy ageing. Maturitas 139:6-11.

70. Gómez-Linton, D. R., Alavez, S., Alarcón-Aguilar, A., López-Diazguerrero, N. E., Konigsberg, M., & Pérez-Flores, L. J. (2019). Some naturally occurring compounds that increase longevity and stress resistance in model organisms of aging. Biogerontology, 20, 583-603.

71. Pant, A., & Pandey, R. (2015). Bioactive phytomolecules and aging in

Caenorhabditis elegans. Healthy Aging Research, 4, 19.

72. Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016). Epigenetic mechanisms of longevity and aging. Cell, 166, 822-839.

73. Zhou, J., Zheng, Y., Zeng, Y., Wang, J., Pei, Z., & Pang, J. (2018). Marine derived xyloketal derivatives exhibit anti-stress and anti-ageing effects through HSF pathway in Caenorhabditis elegans. European Journal of Medicinal Chemistry, 148, 63-72.

74. Ye, Y., Gu, Q., & Sun, X. (2020). Potential of Caenorhabditis elegans as an antiaging evaluation model for dietary phytochemicals: A review. Compr Rev FoodSci FoodSaf. 19:3084-3105.

75. Martorell, P., Forment, J. V., de Llanos, R., Monton, F., Llopis, S., Gonzalez, N., ... Ramon, D. (2011). Use of Saccharomyces cerevisiae and Caenorhabditis elegans as model organisms to study the effect of cocoa polyphenols in the resistance to oxidative stress. Journal of Agricultural Food Chemistry, 59, 2077-2085.

76. Urits, I., Borchart, M., Hasegawa, M., Kochanski, J., Orhurhu, V., & Viswanath, O. (2019). An update of current cannabis-based pharmaceuticals in pain medicine. Pain and Therapy, 8, 41-51.

77. Gershon, H., & Gershon, D. (2000). The budding yeast, Saccharomyces cerevisiae, as a model for aging research: a critical review. Mechanisms of ageing and development, 120(1-3), 1-22.

78. Zimmermann, A., Hofer, S., Pendl, T., Kainz, K., Madeo, F., & Carmona-Gutierrez, D. (2018). Yeast as a tool to identify anti-aging compounds. FEMSyeast research, 18(6), foy020.

79. Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. Science, 328(5976), 321-326.

80. Lee, S. H., & Min, K. J. (2019). Drosophila melanogaster as a model system in the study of pharmacological interventions in aging. Translational Medicine of Aging, 3, 98-103.

81. Li, H., & Jasper, H. (2016). Gastrointestinal stem cells in health and disease: from flies to humans. Disease models & mechanisms, 9(5), 487-499.

82. Wolf, M. J., & Rockman, H. A. (2011). Drosophila, genetic screens, and cardiac function. Circulation research, 109(7), 794-806.

83. Gutierrez, E., Wiggins, D., Fielding, B., & Gould, A. P. (2007). Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature, 445(7125), 275-280.

84. Ong, C., Yung, L. Y. L., Cai, Y., Bay, B. H., & Baeg, G. H. (2015). Drosophila

melanogaster as a model organism to study nanotoxicity. Nanotoxicology, 9(3), 396-403.

85. Keller, J. M., & Keller, E. T. (2018). The use of mature zebrafish (Danio rerio) as a model for human aging and disease. Conn's handbook of models for human aging, 351359.

86. Cayuela, M. L., Claes, K. B., Ferreira, M. G., Henriques, C. M., van Eeden, F., Varga, M., ... & Mione, M. C. (2019). The zebrafish as an emerging model to study DNA damage in aging, cancer and other diseases. Frontiers in cell and developmental biology, 6, 178.

87. Willemsen, R., Padje, S. V. T., van Swieten, J. C., & Oostra, B. A. (2011). Zebrafish (Danio rerio) as a model organism for dementia. Animal Models of Dementia, 255-269.

88. Zhang, M. J., Pisco, A. O., Darmanis, S., & Zou, J. (2021). Mouse aging cell atlas analysis reveals global and cell type-specific aging signatures. elife, 10, e62293.

89. Jones, E. P., Kooij, J. V. D., Solheim, R., & Searle, J. B. (2010). Norwegian house mice (Mus musculus musculus/domesticus): distributions, routes of colonization and patterns of hybridization. Molecular Ecology, 19(23), 5252-5264.

90. Salnikov, L., Goldberg, S., Rijhwani, H., Shi, Y., & Pinsky, E. (2023). The RNA-Seq data analysis shows how the ontogenesis defines aging. Frontiers in Aging, 4, 1143334.

91. Salnikov, L. (2024). Aging mechanisms and their relationship with the ontogenesis program: a narrative review. Aging Advances, 1(2), 112-117.

92. Bitto, A., Wang, A. M., Bennett, C. F., & Kaeberlein, M. (2015). Biochemical genetic pathways that modulate aging in multiple species. Cold Spring Harbor perspectives in medicine, 5(11), a025114.

93. McQuail, J. A., Johnson, S. A., Burke, S. N., & Bizon, J. L. (2018). Rat Models of Cognitive Aging (pp. 211-230). Academic Press.

94. Krubaa, P., & Yogitha, P. S. (2024). Albino Wistar Rats: Advantages and Limitations in Biomedical Research. SBV Journal of Basic, Clinical and Applied Health Science, 7(2), 61-65.

95. Nadon, N. L. (2006). Aged Rodents for Biogerontology Research. In Handbook of models for human aging, pp. 393-401. Academic Press

96. Schulenburg, H., & Félix, M. A. (2017). The natural biotic environment of Caenorhabditis elegans. Genetics, 206(1), 55-86.

97. Giunti, S., Andersen, N., Rayes, D., & De Rosa, M. J. (2021). Drug discovery: Insights from the invertebrate Caenorhabditis elegans. Pharmacology Research &

Perspectives, 9(2), e00721.

98. Corsi, A. K., Wightman, B., & Chalfie, M. (2015). A transparent window into biology: a primer on Caenorhabditis elegans. Genetics, 200(2), 387-407.

99. Wang, C., Xia, C., Zhu, Y., & Zhang, H. (2021). Innovative fluorescent probes for in vivo visualization of biomolecules in living Caenorhabditis elegans. Cytometry Part A, 99(6), 560-574.

100. Altun, Z. F., & Hall, D. H. (2024). Handbook of C. elegans Anatomy. In WormAtlas http://www.wormatlas.org/hermaphrodite/hermaphroditehomepage.htm

101. Beard, J. R., Officer, A., De Carvalho, I. A., Sadana, R., Pot, A. M., Michel, J. P., ... & Chatterji, S. (2016). The World report on ageing and health: a policy framework for healthy ageing. The Lancet, 387(10033), 2145-2154.

102. Kirchweger, B., Zwirchmayr, J., Grienke, U., & Rollinger, J. M. (2023). The role of Caenorhabditis elegans in the discovery of natural products for healthy aging. Natural Product Reports, 40(12), 1849-1873.

103. Zhang, S., Li, F., Zhou, T., Wang, G., & Li, Z. (2020). Caenorhabditis elegans as a Useful Model for Studying Aging Mutations. Frontiers in Endocrinology, 11, 554994.

104. Lattice, I. (2023). Living the best of your life, the rest of your life. Available online: https://www.bangor.ac.uk/news/2023-09-25-09-23-bangor-university-fitness-gym-membership-winner-continues-journey Access on 18/05/2025

105. Klug, J., Christensen, S., Imai, D. M., Snider, T. A., & Ladiges, W. (2021). The geropathology of organ-specific aging. Journal of translational science, 7(1), 458.

106. Lithgow, G. J., Driscoll, M., & Phillips, P. (2017). A long journey to reproducible results. Nature, 548(7668), 387-388.

107. Lin, C., Su, Z., Luo, J., Jiang, L., Shen, S., Zheng, W., ... & Chen, Y. (2020). Polysaccharide extracted from the leaves of Cyclocarya paliurus (Batal.) Iljinskaja enhanced stress resistance in Caenorhabditis elegans via skn-1 and hsf-1. International journal of biological macromolecules, 143, 243-254.

108. Lin, C., Lin, Y., Chen, Y., Xu, J., Li, J., Cao, Y., ... & Chen, Y. (2019). Effects of Momordica saponin extract on alleviating fat accumulation in Caenorhabditis elegans. Food & Function, 10(6), 3237-3251.

109. Lin, C., Lin, Y., Xiao, J., Lan, Y., Cao, Y., & Chen, Y. (2021). Effect of Momordica saponin-and Cyclocarya paliurus polysaccharide-enriched beverages on oxidative stress and fat accumulation in Caenorhabditis elegans. Journal of the Science of Food and Agriculture, 101(8), 3366-3375.

110. Yang, H. C., Yu, H., Liu, Y. C., Chen, T. L., Stern, A., Lo, S. J., & Chiu, D. T. Y.

(2019). IDH-1 deficiency induces growth defects and metabolic alterations in GSPD-1-deficient Caenorhabditis elegans. Journal of Molecular Medicine, 97, 385-396.

111. Lu, Q., Bu, Y., Ma, L., & Liu, R. (2020). Transgenerational reproductive and developmental toxicity of tebuconazole in Caenorhabditis elegans. Journal of Applied Toxicology, 40(5), 578-591.

112. Chen, Y., Qin, Q., Luo, J., Dong, Y., Lin, C., Chen, H., ... & Su, Z. (2022). Litchi flower essential oil balanced lipid metabolism through the regulation of DAF-2/IIS, MDT-15/SBP-1, and MDT- 15/NHR-49 pathway. Frontiers in Nutrition, 9, 934518.

113. Maklakov, A. A., Carlsson, H., Denbaum, P., Lind, M. I., Mautz, B., Hinas, A., & Immler, S. (2017). Antagonistically pleiotropic allele increases lifespan and late-life reproduction at the cost of early-life reproduction and individual fitness. Proceedings of the Royal Society B: Biological Sciences, 284(1856), 20170376.

114. Lin, Y., Lin, C., Cao, Y., & Chen, Y. (2023). Caenorhabditis elegans as an in vivo model for the identification of natural antioxidants with anti-aging actions. Biomedicine & Pharmacotherapy, 167, 115594.

115. Macedo, F., Romanatto, T., Gomes de Assis, C., Buis, A., Kowaltowski, A. J., Aguilaniu, H., & Marques da Cunha, F. (2020). Lifespan-extending interventions enhance lipid-supported mitochondrial respiration in Caenorhabditis elegans. The FASEB Journal, 34(8), 9972-9981.

116. Cho, J., Lu, J., Kim, D., & Park, Y. (2025). Determination of health status during aging using bending and pumping rates at various survival rates in Caenorhabditis elegans. Scientific Reports, 15(1), 9057.

117. Zhang, X., Zhong, H. Q., Chu, Z. W., Zuo, X., Wang, L., Ren, X. L., ... & Wu, H. M.

(2020). Arsenic induces transgenerational behavior disorders in Caenorhabditis elegans and its underlying mechanisms. Chemosphere, 252, 126510.

118. Komura, T., Yamanaka, M., Nishimura, K., Hara, K., & Nishikawa, Y. (2021). Autofluorescence as a noninvasive biomarker of senescence and advanced glycation end products in Caenorhabditis elegans. Aging and Mechanisms of Disease, 7(1), 12.

119. Kushwaha, S. S., Patro, N., & Patro, I. K. (2019). A sequential study of age-related lipofuscin accumulation in hippocampus and striate cortex of rats. Annals of Neurosciences, 25(4), 223-233.

120. Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144.

121. Pincus, Z., Mazer, T. C., & Slack, F. J. (2016). Autofluorescence as a measure of senescence in C. elegans: look to red, not blue or green. Aging (Albany NY), 5(5), 889.

122. Fam, T. K., Klymchenko, A. S., & Collot, M. (2018). Recent advances in fluorescent probes for lipid droplets. Materials, 11(9), 1768.

123. Zhao, Y., Shi, W., Li, X., & Ma, H. (2022). Recent advances in fluorescent probes for lipid droplets. Chemical Communications, 55(10), 1495-1509.

124. Okoro, N. O., Odiba, A. S., Osadebe, P. O., Omeje, E. O., Liao, G., Fang, W., ... & Wang, B. (2021). Bioactive phytochemicals with anti-aging and lifespan extending potentials in Caenorhabditis elegans. Molecules, 26(23), 7323.

125. Denzel, M. S., Lapierre, L. R., & Mack, H. I. (2019). Emerging topics in C. elegans aging research: Transcriptional regulation, stress response and epigenetics. Mechanisms of ageing and development, 177, 4-21.

126. Kumsta, C., Chang, J. T., Schmalz, J., & Hansen, M. (2017). Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nature communications, 5(1), 14337.

127. Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European journal of medicinal chemistry, 97, 55-74.

128. Ha, N. M., Tran, S. H., Shim, Y. H., & Kang, K. (2022). Caenorhabditis elegans as a powerful tool in natural product bioactivity research. Applied Biological Chemistry, 65(1), 18.

129. de Almeida, A. J. P. O., de Oliveira, J. C. P. L., da Silva Pontes, L. V., de Souza Júnior, J. F., Gonçalves, T. A. F., Dantas, S. H., ... & de Medeiros, I. A. (2022). ROS: Basic concepts, sources, cellular signaling, and its implications in aging pathways. Oxidative medicine and cellular longevity, 2022(1), 1225578.

130. Jovic, K., Sterken, M. G., Grilli, J., Bevers, R. P., Rodriguez, M., Riksen, J. A., ... & Snoek, L. B. (2017). Temporal dynamics of gene expression in heat-stressed Caenorhabditis elegans. PloS one, 12(12), e0189445.

131. Zevian, S. C., & Yanowitz, J. L. (2014). Methodological considerations for heat shock of the nematode Caenorhabditis elegans. Methods, 65(3), 450-457.

132. Kyriakou, E., Taouktsi, E., & Syntichaki, P. (2022). The thermal stress coping network of the nematode Caenorhabditis elegans. International Journal of Molecular Sciences, 23(23), 14907.

133. Zhang, H., Zhou, Q., Yang, Y., Chen, X., Yan, B., & Du, A. (2013). Characterization of heat shock protein 70 gene from Haemonchus contortus and its expression and

promoter analysis in Caenorhabditis elegans. Parasitology, 140(6), 683-694.

134. Keith, S. A., Amrit, F. R. G., Ratnappan, R., & Ghazi, A. (2014). The C. elegans healthspan and stress-resistance assay toolkit. Methods, 68(3), 476-486.

135. Fischer, N., Buchter, C., Koch, K., Albert, S., Csuk, R., & Watjen, W. (2017). The resveratrol derivatives trans-3, 5-dimethoxy-4-fluoro-4'-hydroxystilbene and trans-2, 4', 5-trihydroxystilbene decrease oxidative stress and prolong lifespan in Caenorhabditis elegans. Journal of Pharmacy and Pharmacology, 69(1), 73-81.

136. Senchuk, M. M., Dues, D. J., & Van Raamsdonk, J. M. (2017). Measuring oxidative stress in Caenorhabditis elegans: paraquat and juglone sensitivity assays. Bioprotocol, 7(1), e2086-e2086.

137. Lennicke, C., & Cocheme, H. M. (2021). Redox metabolism: ROS as specific molecular regulators of cell signaling and function. Molecular cell, 81(18), 3691-3707.

138. Kuzmic, M., Javot, H., Bonzom, J. M., Lecomte-Pradines, C., Radman, M., Garnier-Laplace, J., & Frelon, S. (2016). In situ visualization of carbonylation and its co-localization with proteins, lipids, DNA and RNA in Caenorhabditis elegans. Free Radical Biology and Medicine, 101, 465-474.

139. Lee, H., & Lee, S.-J. (2022). Recent Progress in Regulation of Aging by Insulin/IGF-1 Signaling in Caenorhabditis elegans. Molecules and Cells, 45(11), 763-770.

140. Son, H. G., Altintas, O., Kim, E. J. E., Kwon, S., & Lee, S. J. V. (2019). Age-dependent changes and biomarkers of aging in Caenorhabditis elegans. Aging cell, 18(2), e12853.

141. Murphy, C. T., & Hu, P. J. (2018). Insulin/insulin-like growth factor signaling in C. elegans. WormBook: The online review of C. elegans biology [Internet]. Available online: https://doi.org/10.1895/wormbook.1.164.1 Accessed on 10/09/2023

142. Herzig, S., & Shaw, R. J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nature reviews Molecular cell biology, 19(2), 121-135.

143. Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 168(6), 960-976.

144. Saoudaoui, S., Bernard, M., Cardin, G. B., Malaquin, N., Christopoulos, A., & Rodier, F. (2021). mTOR as a senescence manipulation target: A forked road. Advances in cancer research, 150, 335-363.

145. Holtze, S., Gorshkova, E., Braude, S., Cellerino, A., Dammann, P., Hildebrandt, T. B., ... & Sahm, A. (2021). Alternative animal models of aging research. Frontiers in Molecular Biosciences, 8, 660959.

146. Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics, 77(1), 71-94.

147. Wahlby, C., Kamentsky, L., Liu, Z. H., Riklin-Raviv, T., Conery, A. L., O'rourke, E. J., ... & Carpenter, A. E. (2012). An image analysis toolbox for high-throughput C. elegans assays. Nature methods, 9(7), 714-716.

148. McQuin, C., Goodman, A., Chernyshev, V., Kamentsky, L., Cimini, B. A., Karhohs, K. W., ... & Carpenter, A. E. (2018). CellProfiler 3.0: Next-generation image processing for biology. PLoS biology, 16(7), e2005970.

149. Daina, A., & Zoete, V. (2024). Testing the predictive power of reverse screening to infer drug targets, with the help of machine learning. Communications Chemistry, 7(1), 105.

150. Kolberg, L., Raudvere, U., Kuzmin, I., Adler, P., Vilo, J., & Peterson, H. (2023). g: Profiler—interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic acids research, 51(W1), W207-W212.

151. Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2. 0: New docking methods, expanded force field, and python bindings. Journal of chemical information and modeling, 61(8), 3891-3898.

152. Jiang, S., Deng, N., Zheng, B., Li, T., & Liu, R. H. (2021). Rhodiola extract promotes longevity and stress resistance of Caenorhabditis elegans via DAF-16 and SKN-1. Food & Function, 12(10), 4471-4483.

153. Liu, Y., Zhou, Z., Yin, L., Zhu, M., Wang, F., Zhang, L., ... & Fan, S. (2022). Tangeretin promotes lifespan associated with insulin/insulin-like growth factor-1 signaling pathway and heat resistance in Caenorhabditis elegans. BioFactors, 48(2), 442-453.

154. Sugawara, T., & Sakamoto, K. (2020). Quercetin enhances motility in aged and heat-stressed Caenorhabditis elegans nematodes by modulating both HSF-1 activity, and insulin-like and p38-MAPK signalling. PloSone, 15(9), e0238528.ku

155. Ayuda-Durán, B., González-Manzano, S., González-Paramás, A. M., & Santos-Buelga, C. (2020). Caenorhabditis elegans as a model organism to evaluate the antioxidant effects of phytochemicals. Molecules, 25(14), 3194.

156. Havermann, S., Humpf, H. U., & Watjen, W. (2016). Baicalein modulates stressresistance and life span in C. elegans via SKN-1 but not DAF-16. Fitoterapia, 113, 123-127.

157. Zheng, S. Q., Huang, X. B., Xing, T. K., Ding, A. J., Wu, G. S., & Luo, H. R. (2017). Chlorogenic acid extends the lifespan of Caenorhabditis elegans via insulin/IGF-1 signaling pathway. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(4), 464-472.

158. Wang, J., Chen, X., Bai, W., Wang, Z., Xiao, W., & Zhu, J. (2021). Study on mechanism of Ginkgo biloba L. leaves for the treatment of neurodegenerative diseases based on network pharmacology. Neurochemical Research, 46(7), 1881-1894.

159. Sun, J., Zhong, X., Sun, D., Xu, L., Shi, L., Sui, J., & Liu, Y. (2023). Anti-aging effects of polysaccharides from ginseng extract residues in Caenorhabditis elegans. International Journal of BiologicalMacromolecules, 225, 1072-1084.

160. Moreno-García, A., Kun, A., Calero, O., Medina, M., & Calero, M. (2018). An overview of the role of lipofuscin in age-related neurodegeneration. Frontiers in neuroscience, 12, 464.

161. Rauthan, M., & Pilon, M. (2011). The mevalonate pathway in C. elegans. Lipids in health and disease, 10, 1-12.

162. Koch, K., Havermann, S., Büchter, C., & Watjen, W. (2014). Caenorhabditis elegans as model system in pharmacology and toxicology: Effects of flavonoids on redox-sensitive signalling pathways and ageing. The Scientific World Journal, 1, 920398.

163. Kampkotter, A., Nkwonkam, C. G., Zurawski, R. F., Timpel, C., Chovolou, Y., Watjen, W., & Kahl, R. (2007). Investigations of protective effects of the flavonoids quercetin and rutin on stress resistance in the model organism Caenorhabditis elegans. Toxicology, 234(1-2), 113-123.

164. Ayoub, I. M., Eldahshan, O. A., Roxo, M., Zhang, S., Wink, M., & Singab, A. N. B. (2024). Stress resistance, antiaging, and neuroprotective activities of baicalein 5, 6-dimethyl ether and Alnus rugosa extract in Caenorhabditis elegans model. Archiv der Pharmazie, 357(12), 2400464.

165. Mukherjee, P. K., & Houghton, P. J. (Eds.). (2009). Evaluation of Herbal Medicinal Products: perspectives on quality, safety and efficacy (pp. 399-401). London: Pharmaceutical press.

166. Escorcia, W., Ruter, D. L., Nhan, J., & Curran, S. P. (2018). Quantification of lipid abundance and evaluation of lipid distribution in Caenorhabditis elegans by nile red and oil red O staining. Journal of visualized experiments: JoVE, (133), 57352.

167. Zhao, Y., Shi, W., Li, X., & Ma, H. (2022). Recent advances in fluorescent probes for lipid droplets. Chemical Communications, 58(10), 1495-1509.

168. Palikaras, K., Mari, M., Ploumi, C., Princz, A., Filippidis, G., & Tavernarakis, N. (2023). Age-dependent nuclear lipid droplet deposition is a cellular hallmark of aging in Caenorhabditis elegans. Aging Cell, 22(4), e13788.

169. Lin, Y., Yang, N., Bao, B., Wang, L., Chen, J., & Liu, J. (2020). Luteolin reduces fat

storage in Caenorhabditis elegans by promoting the central serotonin pathway. Food & function, 11(1), 730-740.

170. Guerrero-Rubio, M. A., Hernández-García, S., García-Carmona, F., & Gandía-Herrero, F. (2021). Flavonoids' effects on Caenorhabditis elegans' longevity, fat accumulation, stress resistance and gene modulation involve mTOR, SKN-1 and DAF-16. Antioxidants, 10(3), 438.

171. Sies, H., Belousov, V. V., Chandel, N. S., Davies, M. J., Jones, D. P., Mann, G. E., ... & Winterbourn, C. (2022). Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nature reviews Molecular cell biology, 23(7), 499-515.

172. Forman, H. J., & Zhang, H. (2021). Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery, 20(9), 689-709.

173. Cheng, J., Liu, Y., Liu, Y., Liu, D., Liu, Y., Guo, Y., ... & Wang, H. (2020). Ursolic acid alleviates lipid accumulation by activating the AMPK signaling pathway in vivo and in vitro. Journal of food science, 85(11), 3998-4008.

174. Wang, Z., Ge, S., Li, S., Lin, H., & Lin, S. (2020). Anti-obesity effect of trans-cinnamic acid on HepG2 cells and HFD-fed mice. Food and Chemical Toxicology, 137, 111148.

175. Geng, L., Liu, K., & Zhang, H. (2023). Lipid oxidation in foods and its implications on proteins. Frontiers in Nutrition, 10, 1192199.

176. Hematyar, N., Rustad, T., Sampels, S., & Kastrup Dalsgaard, T. (2019). Relationship between lipid and protein oxidation in fish. Aquaculture Research, 50(5), 1393-1403.

177. Wang, Y., Xu, E., Musich, P. R., & Lin, F. (2019). Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure. CNS neuroscience & therapeutics, 25(7), 816-824.

178. Harlow, P. H., Perry, S. J., Stevens, A. J., & Flemming, A. J. (2018). Comparative metabolism of xenobiotic chemicals by cytochrome P450s in the nematode Caenorhabditis elegans. Scientific reports, 8(1), 13333.

179. Shin, H., Lee, H., Fejes, A. P., Baillie, D. L., Koo, H. S., & Jones, S. J. (2011). Gene expression profiling of oxidative stress response of C. elegans aging defective AMPK mutants using massively parallel transcriptome sequencing. BMC research notes, 4, 116.

180. Leyane, T. S., Jere, S. W., & Houreld, N. N. (2022). Oxidative stress in ageing and chronic degenerative pathologies: molecular mechanisms involved in counteracting oxidative stress and chronic inflammation. International journal of molecular sciences, 23(13), 7273.

181. Salmon, A. B., Richardson, A., & Pérez, V. I. (2010). Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging?. Free Radical Biology and Medicine, 48(5), 642-655.

182. Aranda-Rivera, A. K., Cruz-Gregorio, A., Arancibia-Hernández, Y. L., Hernández-Cruz, E. Y., & Pedraza-Chaverri, J. (2022). RONS and oxidative stress: an overview of basic concepts. Oxygen, 2(4), 437-478.

183. Glenn, C. F., Chow, D. K., David, L., Cooke, C. A., Gami, M. S., Iser, W. B., ... & Wolkow, C. A. (2004). Behavioral deficits during early stages of aging in Caenorhabditis elegans result from locomotory deficits possibly linked to muscle frailty. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 59(12), 1251-1260.

184. Stein, G. M., & Murphy, C. T. (2012). The intersection of aging, longevity pathways, and learning and memory in C. elegans. Frontiers in Genetics, 3, 259.

185. Kerr, R. A., Roux, A. E., Goudeau, J., & Kenyon, C. (2022). The C. elegans Observatory: High-throughput exploration of behavioral aging. Frontiers in Aging, 3, 932656.

186. Toth, M. L., Melentijevic, I., Shah, L., Bhatia, A., Lu, K., Talwar, A., ... & Driscoll, M. (2012). Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. Journal of Neuroscience, 32(26), 8778-8790.

187. Lee, H., Cho, J. S., Lambacher, N., Lee, J., Lee, S. J., Lee, T. H., ... & Koo, H. S. (2008). The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. Journal of biological chemistry, 283(22), 14988-14993.

188. Escoubas-Güney, C. (2018). Role of AMPK in Aging and Age-related Loss of Behavioral Plasticity in C. elegans (Doctoral dissertation, COMUE Université Côte d'Azur (2015-2019).

189. Morbidoni, V. (2019). C. elegans as model to study neurometabolic conditions. Doctoral thesis submitted to Università degli studi di Padova. https://www.research.unipd.it/handle/11577/3422830

190. Murphy, C. T., & Hu, P. J. (2018). Insulin/insulin-like growth factor signaling in C. elegans. WormBook: The online review of C. elegans biology [Internet].

191. Greer, E. L., Dowlatshahi, D., Banko, M. R., Villen, J., Hoang, K., Blanchard, D., ... & Brunet, A. (2007). An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Current biology, 17(19), 1646-1656.

192. Di Meo, S., Venditti, P., Victor, V. M., & Napolitano, G. (2022). Harmful and beneficial role of ROS 2020. Oxidative medicine and cellular longevity, 2022, 9873652.

193. Murphy, C. T., McCarroll, S. A., Bargmann, C. I., Fraser, A., Kamath, R. S., Ahringer, J., ... & Kenyon, C. (2003). Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature, 424(6946), 277-283.

194. Rousakis, A., Vlanti, A., Borbolis, F., Roumelioti, F., Kapetanou, M., & Syntichaki, P. (2014). Diverse functions of mRNA metabolism factors in stress defense and aging of Caenorhabditis elegans. PLoS One, 9(7), e103365.

195. Elbouzidi, A., Taibi, M., & Addi, M. (2024). Exploring the Potential of Molecular Docking and In Silico Studies in Secondary Metabolite and Bioactive Compound Discovery for Plant Research. Bioinformatics for Plant Research and Crop Breeding, 413-434.

196. Le Maire, A., Germain, P., & Bourguet, W. (2020). Protein-protein interactions in the regulation of RAR-RXR heterodimers transcriptional activity. In Methods in enzymology 637, 175-207.

197. Piskunov, A., Al Tanoury, Z., & Rochette-Egly, C. (2014). Nuclear and extra-nuclear effects of retinoid acid receptors: how they are interconnected. The biochemistry of retinoic acid receptors I: Structure, activation, and function at the molecular level, 103127.

198. Tang, S., Wu, F., Lin, X., Gui, W., Zheng, F., & Li, H. (2020). The effects of new selective PPARa agonist CP775146 on systematic lipid metabolism in obese mice and its potential mechanism. Journal of Diabetes Research, 2020(1), 4179852.

199. Janssen, A. W., Betzel, B., Stoopen, G., Berends, F. J., Janssen, I. M., Peijnenburg, A. A., & Kersten, S. (2015). The impact of PPARa activation on whole genome gene expression in human precision cut liver slices. BMC genomics, 16, 1-13.

200. Navidshad, B., & Royan, M. (2016). Peroxisome proliferator-activated receptor alpha (PPARa), a key regulator of lipid metabolism in Avians. Critical Reviews™ in Eukaryotic Gene Expression, 26(4), 303-308.

201. Lin, H. P., Cheng, Z. L., He, R. Y., Song, L., Tian, M. X., Zhou, L. S., ... & Xiong, Y. (2016). Destabilization of fatty acid synthase by acetylation inhibits de novo lipogenesis and tumor cell growth. Cancer research, 76(23), 6924-6936.

202. Zhao, R., Kou, H., Jiang, D., & Wang, F. (2023). Exploring the anti-aging effects of fisetin in telomerase-deficient progeria mouse model. PeerJ, 11, e16463.

203. Brandt, A., Petrovsky, R., Kriebel, M., & Großhans, J. (2023). Use of Farnesyl Transferase Inhibitors in an Ageing Model in Drosophila. Journal of Developmental Biology, 77(4), 40.

204. Cassano, T., Calcagnini, S., Pace, L., De Marco, F., Romano, A., & Gaetani, S. (2017). Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Frontiers in neuroscience, 77, 30.

205. Naylor, R. M., Baker, D. J., & Van Deursen, J. M. (2013). Senescent cells: a novel therapeutic target for aging and age-related diseases. Clinical Pharmacology & Therapeutics, 93(1), 105-116.

206. Manastireanu, D. M., Salazar, N. A., Bejarano, E., & Nieto-Torres, J. L. (2024). Selective autophagy: a therapeutic target for healthy aging?. Aging Advances, 7(1), 222.