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1. Spermidine is essential for fasting-mediated autophagy and longevity

Author

Hofer, Sebastian J., Daskalaki, Ioanna, Bergmann, Martina, Friščić, Jasna, Zimmermann, Andreas, Mueller, Melanie I., Abdellatif, Mahmoud, Nicastro, Raffaele, Masser, Sarah, Durand, Sylvère, Nartey, Alexander, Waltenstorfer, Mara, Enzenhofer, Sarah, Faimann, Isabella, Gschiel, Verena, Bajaj, Thomas, Niemeyer, Christine, Gkikas, Ilias, Pein, Lukas, Cerrato, Giulia, Pan, Hui, Liang, YongTian, Tadic, Jelena, Jerkovic, Andrea, Aprahamian, Fanny, Robbins, Christine E., Nirmalathasan, Nitharsshini, Habisch, Hansjörg, Annerer, Elisabeth, Dethloff, Frederik, Stumpe, Michael, Grundler, Franziska, Wilhelmi de Toledo, Françoise, Heinz, Daniel E., Koppold, Daniela A., Rajput Khokhar, Anika, Michalsen, Andreas, Tripolt, Norbert J., Sourij, Harald, Pieber, Thomas R., de Cabo, Rafael, McCormick, Mark A., Magnes, Christoph, Kepp, Oliver, Dengjel, Joern, Sigrist, Stephan J., Gassen, Nils C., Sedej, Simon, Madl, Tobias, De Virgilio, Claudio, Stelzl, Ulrich, Hoffmann, Markus H., Eisenberg, Tobias, Tavernarakis, Nektarios, Kroemer, Guido, and Madeo, Frank

Published
2024
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2. A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan

Author

Ortega-Molina, Ana, Lebrero-Fernández, Cristina, Sanz, Alba, Calvo-Rubio, Miguel, Deleyto-Seldas, Nerea, de Prado-Rivas, Lucía, Plata-Gómez, Ana Belén, Fernández-Florido, Elena, González-García, Patricia, Vivas-García, Yurena, Sánchez García, Elena, Graña-Castro, Osvaldo, Price, Nathan L., Aroca-Crevillén, Alejandra, Caleiras, Eduardo, Monleón, Daniel, Borrás, Consuelo, Casanova-Acebes, María, de Cabo, Rafael, and Efeyan, Alejo

Published
2024
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3. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

Author

Occean, James R., Yang, Na, Sun, Yan, Dawkins, Marshall S., Munk, Rachel, Belair, Cedric, Dar, Showkat, Anerillas, Carlos, Wang, Lin, Shi, Changyou, Dunn, Christopher, Bernier, Michel, Price, Nathan L., Kim, Julie S., Cui, Chang-Yi, Fan, Jinshui, Bhattacharyya, Moitrayee, De, Supriyo, Maragkakis, Manolis, de Cabo, Rafael, Sidoli, Simone, and Sen, Payel

Published
2024
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7. International consensus on fasting terminology

Author

Koppold, Daniela A., Breinlinger, Carolin, Hanslian, Etienne, Kessler, Christian, Cramer, Holger, Khokhar, Anika Rajput, Peterson, Courtney M., Tinsley, Grant, Vernieri, Claudio, Bloomer, Richard J., Boschmann, Michael, Bragazzi, Nicola L., Brandhorst, Sebastian, Gabel, Kelsey, Goldhamer, Alan C., Grajower, Martin M., Harvie, Michelle, Heilbronn, Leonie, Horne, Benjamin D., Karras, Spyridon N., Langhorst, Jost, Lischka, Eva, Madeo, Frank, Mitchell, Sarah J., Papagiannopoulos-Vatopaidinos, Ioannis-Eleemon, Papagiannopoulou, Maria, Pijl, Hanno, Ravussin, Eric, Ritzmann-Widderich, Martha, Varady, Krista, Adamidou, Lilian, Chihaoui, Melika, de Cabo, Rafael, Hassanein, Mohamed, Lessan, Nader, Longo, Valter, Manoogian, Emily N.C., Mattson, Mark P., Muhlestein, J. Brent, Panda, Satchidananda, Papadopoulou, Sousana K., Rodopaios, Nikolaos E., Stange, Rainer, and Michalsen, Andreas

Published
2024
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10. Challenges in developing Geroscience trials

Author

Rolland, Yves, Sierra, Felipe, Ferrucci, Luigi, Barzilai, Nir, De Cabo, Rafael, Mannick, Joan, Oliva, Anthony, Evans, William, Angioni, Davide, De Souto Barreto, Philipe, Raffin, Jeremy, Vellas, Bruno, and Kirkland, James L.

Published
2023
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11. Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts

Author

Rowan, Sheldon, Jiang, Shuhong, Francisco, Sarah G, Pomatto, Laura CD, Ma, Zhiwei, Jiao, Xiaodong, Campos, Maria M, Aryal, Sandeep, Patel, Shaili D, Mahaling, Binapani, Riazuddin, S Amer, Duh, Elia J, Lachke, Salil A, Hejtmancik, J Fielding, de Cabo, Rafael, FitzGerald, Paul G, and Taylor, Allen

Subjects
Aging, Prevention, Nutrition, Genetics, Eye Disease and Disorders of Vision, Animals, Cataract, Cell Differentiation, Diet, Disease Models, Animal, Female, Glucose, Glycemic Index, Lens, Crystalline, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Phenotype, Slit Lamp Microscopy, age-related cataract, antioxidant, nutrition, glycemic index, caloric restriction, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

PurposeAge-related cataracts affect the majority of older adults and are a leading cause of blindness worldwide. Treatments that delay cataract onset or severity have the potential to delay cataract surgery, but require relevant animal models that recapitulate the major types of cataracts for their development. Unfortunately, few such models are available. Here, we report the lens phenotypes of aged mice lacking the critical antioxidant transcription factor Nfe2l2 (designated as Nrf2 -/-).MethodsThree independent cohorts of Nrf2 -/- and wild-type C57BL/6J mice were evaluated for cataracts using combinations of slit lamp imaging, photography of freshly dissected lenses, and histology. Mice were fed high glycemic diets, low glycemic diets, regular chow ad libitum, or regular chow with 30% caloric restriction.ResultsNrf2 -/- mice developed significant opacities between 11 and 15 months and developed advanced cortical, posterior subcapsular, anterior subcapsular, and nuclear cataracts. Cataracts occurred similarly in male mice fed high or low glycemic diets, and were also observed in 21-month male and female Nrf2 -/- mice fed ad libitum or 30% caloric restriction. Histological observation of 18-month cataractous lenses revealed significant disruption to fiber cell architecture and the retention of nuclei throughout the cortical region of the lens. However, fiber cell denucleation and initiation of lens differentiation was normal at birth, with the first abnormalities observed at 3 months.ConclusionsNrf2 -/- mice offer a tool to understand how defective antioxidant signaling causes multiple forms of cataract and may be useful for screening drugs to prevent or delay cataractogenesis in susceptible adults.

Published
2021

12. The carbohydrate-insulin model: a physiological perspective on the obesity pandemic

Author

Ludwig, David S, Aronne, Louis J, Astrup, Arne, de Cabo, Rafael, Cantley, Lewis C, Friedman, Mark I, Heymsfield, Steven B, Johnson, James D, King, Janet C, Krauss, Ronald M, Lieberman, Daniel E, Taubes, Gary, Volek, Jeff S, Westman, Eric C, Willett, Walter C, Yancy, William S, and Ebbeling, Cara B

Subjects
Prevention, Obesity, Nutrition, Cancer, Cardiovascular, Oral and gastrointestinal, Metabolic and endocrine, Stroke, Affordable and Clean Energy, Carbohydrates, Dietary Carbohydrates, Dietary Fats, Energy Intake, Energy Metabolism, Humans, Insulin, Pandemics, obesity, weight loss, dietary carbohydrate, energy balance, macronutrients, endocrinology, insulin, glucagon, incretins, scholarly discourse, Engineering, Medical and Health Sciences, Nutrition & Dietetics
Abstract

According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body-resulting from the hormonal responses to a high-glycemic-load diet-drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.

Published
2021

14. ARDD 2020: from aging mechanisms to interventions

Author

Mkrtchyan, Garik V, Abdelmohsen, Kotb, Andreux, Pénélope, Bagdonaite, Ieva, Barzilai, Nir, Brunak, Søren, Cabreiro, Filipe, de Cabo, Rafael, Campisi, Judith, Cuervo, Ana Maria, Demaria, Marco, Ewald, Collin Y, Fang, Evandro Fei, Faragher, Richard, Ferrucci, Luigi, Freund, Adam, Silva-García, Carlos G, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David J, Gorbunova, Vera, de Grey, Aubrey, He, Wei-Wu, Hoeijmakers, Jan, Hoffmann, Eva, Horvath, Steve, Houtkooper, Riekelt H, Jensen, Majken K, Jensen, Martin Borch, Kane, Alice, Kassem, Moustapha, de Keizer, Peter, Kennedy, Brian, Karsenty, Gerard, Lamming, Dudley W, Lee, Kai-Fu, MacAulay, Nanna, Mamoshina, Polina, Mellon, Jim, Molenaars, Marte, Moskalev, Alexey, Mund, Andreas, Niedernhofer, Laura, Osborne, Brenna, Pak, Heidi H, Parkhitko, Andrey, Raimundo, Nuno, Rando, Thomas A, Rasmussen, Lene Juel, Reis, Carolina, Riedel, Christian G, Franco-Romero, Anais, Schumacher, Björn, Sinclair, David A, Suh, Yousin, Taub, Pam R, Toiber, Debra, Treebak, Jonas T, Valenzano, Dario Riccardo, Verdin, Eric, Vijg, Jan, Young, Sergey, Zhang, Lei, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, Prevention, Good Health and Well Being, Artificial Intelligence, Biomedical Research, Cellular Senescence, Congresses as Topic, Drug Discovery, Humans, Life Style, Longevity, Pharmaceutical Preparations, aging, interventions, drug discovery, artificial intelligence, Physiology, Oncology and Carcinogenesis, Developmental Biology
Abstract

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.

Published
2020

15. A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin.

Author

Levine, Morgan, McDevitt, Ross A, Meer, Margarita, Perdue, Kathy, Di Francesco, Andrea, Meade, Theresa, Farrell, Colin, Thrush, Kyra, Wang, Meng, Dunn, Christopher, Pellegrini, Matteo, de Cabo, Rafael, and Ferrucci, Luigi

Subjects
Heterochromatin, Animals, Mice, Inbred C57BL, Rats, Inbred F344, Rats, DNA Methylation, Epigenesis, Genetic, Biological Clocks, Aging, Phenotype, Male, Biomarkers, Unsupervised Machine Learning, DNA methylation, biological age, caloric restriction, computational biology, epigenetic clock, genetics, genomics, mouse, rat, systems biology, Behavioral and Social Science, Human Genome, Genetics, Basic Behavioral and Social Science, 1.1 Normal biological development and functioning, Generic health relevance, Biochemistry and Cell Biology
Abstract

Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats-a model with unique physical, physiological, and biochemical advantages-by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.

Published
2020

17. Prolonged fasting times reap greater geroprotective effects when combined with caloric restriction in adult female mice

Author

Duregon, Eleonora, Fernandez, Maria Emilia, Martinez Romero, Jorge, Di Germanio, Clara, Cabassa, Meaghan, Voloshchuk, Romaniya, Ehrlich-Mora, Margaux R., Moats, Jacqueline M., Wong, Sarah, Bosompra, Oye, Rudderow, Annamaria, Morrell, Christopher H., Camandola, Simonetta, Price, Nathan L., Aon, Miguel A., Bernier, Michel, and de Cabo, Rafael

Published
2023
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20. Correction: The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Author

Firestein, Ron, primary, Blander, Gil, additional, Michan, Shaday, additional, Oberdoerffer, Philipp, additional, Ogino, Shuji, additional, Campbell, Jennifer, additional, Bhimavarapu, Anupama, additional, Luikenhuis, Sandra, additional, de Cabo, Rafael, additional, Fuchs, Charles, additional, Hahn, William C., additional, Guarente, Leonard P., additional, and Sinclair, David A., additional

Published
2024
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22. The Impact of Aging, Calorie Restriction and Dietary Fat on Autophagy Markers and Mitochondrial Ultrastructure and Dynamics in Mouse Skeletal Muscle

Author

Gutiérrez-Casado, Elena, Khraiwesh, Husam, López-Domínguez, José A, Montero-Guisado, Jesús, López-Lluch, Guillermo, Navas, Plácido, de Cabo, Rafael, Ramsey, Jon J, González-Reyes, José A, and Villalba, José M

Subjects
Biomedical and Clinical Sciences, Health Sciences, Nutrition, Aging, Underpinning research, 1.1 Normal biological development and functioning, Musculoskeletal, Animals, Autophagy, Beclin-1, Biomarkers, Caloric Restriction, Dietary Fats, Dynamins, Fish Oils, GTP Phosphohydrolases, Longevity, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Mitochondria, Muscle, Models, Animal, Muscle Fibers, Skeletal, Protein Kinases, RNA-Binding Proteins, Sarcopenia, Soybean Oil, Ubiquitin-Protein Ligases, Caloric restriction, Dietary fat, Mitochondria, Mice, Muscles, Clinical Sciences, Gerontology, Biomedical and clinical sciences, Health sciences
Abstract

Loss of skeletal muscle mass and function is a hallmark of aging. This phenomenon has been related to a dysregulation of mitochondrial function and proteostasis. Calorie restriction (CR) has been demonstrated to delay aging and preserve function until late in life, particularly in muscle. Recently, we reported the type of dietary fat plays an important role in determining life span extension with 40% CR in male mice. In these conditions, lard fed mice showed an increased longevity compared to mice fed soybean or fish oils. In this article, we analyze the effect of 40% CR on muscle mitochondrial mass, autophagy, and mitochondrial dynamics markers in mice fed these diets. In CR fed animals, lard preserved muscle fibers structure, mitochondrial ultrastructure, and fission/fusion dynamics and autophagy, not only compared to control animals, but also compared with CR mice fed soybean and fish oils as dietary fat. We focus our discussion on dietary fatty acid saturation degree as an essential predictor of life span extension in CR mice.

Published
2019

23. Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice

Author

Bernier, Michel, Enamorado, Ignacio Navas, Gómez-Cabrera, Mari Carmen, Calvo-Rubio, Miguel, González-Reyes, Jose Antonio, Price, Nathan L., Cortés-Rodríguez, Ana Belén, Rodríguez-Aguilera, Juan Carlos, Rodríguez-López, Sandra, Mitchell, Sarah J., Murt, Kelsey N., Kalafut, Krystle, Williams, Katrina M., Ward, Christopher W., Stains, Joseph P., Brea-Calvo, Gloria, Villalba, Jose M., Cortassa, Sonia, Aon, Miguel A., and de Cabo, Rafael

Published
2022
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25. A BDNF-TrkB autocrine loop enhances senescent cell viability

Author

Anerillas, Carlos, Herman, Allison B., Munk, Rachel, Garrido, Amanda, Lam, Kwan-Wood Gabriel, Payea, Matthew J., Rossi, Martina, Tsitsipatis, Dimitrios, Martindale, Jennifer L., Piao, Yulan, Mazan-Mamczarz, Krystyna, Fan, Jinshui, Cui, Chang-Yi, De, Supriyo, Abdelmohsen, Kotb, de Cabo, Rafael, and Gorospe, Myriam

Published
2022
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26. DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice

Author

Herman, Allison B., Tsitsipatis, Dimitrios, Anerillas, Carlos, Mazan-Mamczarz, Krystyna, Carr, Angelica E., Gregg, Jordan M., Wang, Mingyi, Zhang, Jing, Michel, Marc, Henry-Smith, Charnae A., Harris, Sophia C., Munk, Rachel, Martindale, Jennifer L., Piao, Yulan, Fan, Jinshui, Mattison, Julie A., De, Supriyo, Abdelmohsen, Kotb, Maul, Robert W., Tanaka, Toshiko, Moore, Ann Zenobia, DeMouth, Megan E., Sidoli, Simone, Ferrucci, Luigi, Liu, Yie, de Cabo, Rafael, Lakatta, Edward G., and Gorospe, Myriam

Subjects
Protease inhibitors -- Testing, Hemostasis -- Health aspects, Cell cycle -- Health aspects, Vascular smooth muscle -- Health aspects, Muscle cells -- Health aspects, Atherosclerosis -- Development and progression -- Care and treatment, Health care industry
Abstract

Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease., Introduction Atherosclerosis, the buildup of plaque and hardening of the arteries over time, is a widespread and debilitating disease in older populations. Many risk factors contribute to the development of [...]

Published
2023
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27. microRNA-33 controls hunger signaling in hypothalamic AgRP neurons

Author

Price, Nathan L., primary, Fernández-Tussy, Pablo, additional, Varela, Luis, additional, Cardelo, Magdalena P., additional, Shanabrough, Marya, additional, Aryal, Binod, additional, de Cabo, Rafael, additional, Suárez, Yajaira, additional, Horvath, Tamas L., additional, and Fernández-Hernando, Carlos, additional

Published
2024
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31. Kaempferol increases levels of coenzyme Q in kidney cells and serves as a biosynthetic ring precursor.

Author

Fernández-Del-Río, Lucía, Nag, Anish, Gutiérrez Casado, Elena, Ariza, Julia, Awad, Agape M, Joseph, Akil I, Kwon, Ohyun, Verdin, Eric, de Cabo, Rafael, Schneider, Claus, Torres, Jorge Z, Burón, María I, Clarke, Catherine F, and Villalba, José M

Subjects
Kidney Tubules, Proximal, Cell Line, HL-60 Cells, Mitochondria, Fibroblasts, Epithelial Cells, Animals, Humans, Mice, Saccharomyces cerevisiae, Carbon Isotopes, Ubiquinone, Kaempferols, Antioxidants, Isotope Labeling, Sirtuin 3, Hep G2 Cells, HEK293 Cells, Polyphenols, 4-hydroxybenzoic acid, Coenzyme Q, Flavonols, Kaempferol, Kidney cells, Plant polyphenols, Sirt3, Nutrition, Kidney Disease, Complementary and Integrative Health, Underpinning research, 1.1 Normal biological development and functioning, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

Coenzyme Q (Q) is a lipid-soluble antioxidant essential in cellular physiology. Patients with Q deficiencies, with few exceptions, seldom respond to treatment. Current therapies rely on dietary supplementation with Q10, but due to its highly lipophilic nature, Q10 is difficult to absorb by tissues and cells. Plant polyphenols, present in the human diet, are redox active and modulate numerous cellular pathways. In the present study, we tested whether treatment with polyphenols affected the content or biosynthesis of Q. Mouse kidney proximal tubule epithelial (Tkpts) cells and human embryonic kidney cells 293 (HEK 293) were treated with several types of polyphenols, and kaempferol produced the largest increase in Q levels. Experiments with stable isotope 13C-labeled kaempferol demonstrated a previously unrecognized role of kaempferol as an aromatic ring precursor in Q biosynthesis. Investigations of the structure-function relationship of related flavonols showed the importance of two hydroxyl groups, located at C3 of the C ring and C4' of the B ring, both present in kaempferol, as important determinants of kaempferol as a Q biosynthetic precursor. Concurrently, through a mechanism not related to the enhancement of Q biosynthesis, kaempferol also augmented mitochondrial localization of Sirt3. The role of kaempferol as a precursor that increases Q levels, combined with its ability to upregulate Sirt3, identify kaempferol as a potential candidate in the design of interventions aimed on increasing endogenous Q biosynthesis, particularly in kidney.

Published
2017

33. Metformin: A hopeful promise in aging research

Author

Garrido Novelle, Marta, Ali, Ahmed, Diéguez, Carlos, Bernier, Michel, De Cabo, Rafael, Garrido Novelle, Marta, Ali, Ahmed, Diéguez, Carlos, Bernier, Michel, and De Cabo, Rafael

Abstract

This work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector., Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Published
2024

34. Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.

Author

Jafari, Maryam, Macho-González, Adrián, Diaz, Antonio, Lindenau, Kristen, Santiago-Fernández, Olaya, Mei Zeng, Massey, Ashish C., de Cabo, Rafael, Kaushik, Susmita, and Cuervo, Ana Maria

Subjects
LOW-calorie diet, AUTOPHAGY, MEMBRANE proteins, HOMEOSTASIS, FIBROBLASTS
Abstract

Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Disulfiram Treatment Normalizes Body Weight in Obese Mice

Author

Bernier, Michel, Mitchell, Sarah J., Wahl, Devin, Diaz, Antonio, Singh, Abhishek, Seo, Wonhyo, Wang, Mingy, Ali, Ahmed, Kaiser, Tamzin, Price, Nathan L., Aon, Miguel A., Kim, Eun-Young, Petr, Michael A., Cai, Huan, Warren, Alessa, Di Germanio, Clara, Di Francesco, Andrea, Fishbein, Ken, Guiterrez, Vince, Harney, Dylan, Koay, Yen Chin, Mach, John, Enamorado, Ignacio Navas, Pulpitel, Tamara, Wang, Yushi, Zhang, Jing, Zhang, Li, Spencer, Richard G., Becker, Kevin G., Egan, Josephine M., Lakatta, Edward G., O’Sullivan, John, Larance, Mark, LeCouteur, David G., Cogger, Victoria C., Gao, Bin, Fernandez-Hernando, Carlos, Cuervo, Ana Maria, and de Cabo, Rafael

Published
2020
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37. Long-Term NMN Treatment Increases Lifespan and Healthspan in Mice in a Sex Dependent Manner

Author

Kane, Alice E., primary, Chellappa, Karthikeyani, additional, S, M, additional, Arnold, Matthew, additional, Li, Jien, additional, Amorim, Joao A., additional, Diener, Christian, additional, Zhu, Dantong, additional, Mitchell, Sarah J., additional, Griffin, Patrick, additional, Tian, Xiao, additional, Petty, Christopher, additional, Conway, Ryan J., additional, Walsh, Katie, additional, Shelerud, Lukas, additional, Duesing, Charlotte, additional, Mueller, Amber, additional, Li, Karlin, additional, McNamara, Maeve S., additional, Shima, Rafaella T., additional, Mitchell, James R., additional, Bonkowski, Michael S., additional, De Cabo, Rafael, additional, Gibbons, Sean, additional, Wu, Lindsay, additional, Ikeno, Yuji, additional, Baur, Joseph A., additional, Rajman, Luis A., additional, and Sinclair, David A., additional

Published
2024
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38. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie‐restricted mice

Author

Calvo‐Rubio, Miguel, Burón, Mª Isabel, López‐Lluch, Guillermo, Navas, Plácido, de Cabo, Rafael, Ramsey, Jon J, Villalba, José M, and González‐Reyes, José A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Prevention, Kidney Disease, Aging, Underpinning research, 1.1 Normal biological development and functioning, Cardiovascular, Metabolic and endocrine, Renal and urogenital, Animals, Autophagy, Biomarkers, Blotting, Western, Body Weight, Caloric Restriction, Creatinine, Cyclin-Dependent Kinase Inhibitor p16, Dietary Fats, Epithelial Cells, Glomerular Filtration Rate, Kidney Glomerulus, Kidney Tubules, Proximal, Male, Mice, Inbred C57BL, Mitochondria, Urea, aging, calorie restriction, dietary fat, kidney, mice, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Calorie restriction (CR) has been repeatedly shown to prevent cancer, diabetes, hypertension, and other age-related diseases in a wide range of animals, including non-human primates and humans. In rodents, CR also increases lifespan and is a powerful tool for studying the aging process. Recently, it has been reported in mice that dietary fat plays an important role in determining lifespan extension with 40% CR. In these conditions, animals fed lard as dietary fat showed an increased longevity compared with mice fed soybean or fish oils. In this paper, we study the effect of these dietary fats on structural and physiological parameters of kidney from mice maintained on 40% CR for 6 and 18 months. Analyses were performed using quantitative electron microcopy techniques and protein expression in Western blots. CR mitigated most of the analyzed age-related parameters in kidney, such as glomerular basement membrane thickness, mitochondrial mass in convoluted proximal tubules and autophagic markers in renal homogenates. The lard group showed improved preservation of several renal structures with aging when compared to the other CR diet groups. These results indicate that dietary fat modulates renal structure and function in CR mice and plays an essential role in the determination of health span in rodents.

Published
2016

44. A time to fast

Author

Di Francesco, Andrea, Di Germanio, Clara, Bernier, Michel, and de Cabo, Rafael

Published
2018

45. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition

Author

Pomatto-Watson, Laura C. D., Bodogai, Monica, Bosompra, Oye, Kato, Jonathan, Wong, Sarah, Carpenter, Melissa, Duregon, Eleonora, Chowdhury, Dolly, Krishna, Priya, Ng, Sandy, Ragonnaud, Emeline, Salgado, Roberto, Gonzalez Ericsson, Paula, Diaz-Ruiz, Alberto, Bernier, Michel, Price, Nathan L., Biragyn, Arya, Longo, Valter D., and de Cabo, Rafael

Published
2021
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46. Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance

Author

Schumann, Tina, König, Jörg, von Loeffelholz, Christian, Vatner, Daniel F., Zhang, Dongyan, Perry, Rachel J., Bernier, Michel, Chami, Jason, Henke, Christine, Kurzbach, Anica, El-Agroudy, Nermeen N., Willmes, Diana M., Pesta, Dominik, de Cabo, Rafael, O´Sullivan, John F., Simon, Eric, Shulman, Gerald I., Hamilton, Bradford S., and Birkenfeld, Andreas L.

Published
2021
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48. Publisher Correction: Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance

Author

Schumann, Tina, König, Jörg, von Loeffelholz, Christian, Vatner, Daniel F., Zhang, Dongyan, Perry, Rachel J., Bernier, Michel, Chami, Jason, Henke, Christine, Kurzbach, Anica, El-Agroudy, Nermeen N., Willmes, Diana M., Pesta, Dominik, de Cabo, Rafael, O´Sullivan, John F., Simon, Eric, Shulman, Gerald I., Hamilton, Bradford S., and Birkenfeld, Andreas L.

Published
2021
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50. Age-induced accumulation of methylmalonic acid promotes tumour progression

Author

Gomes, Ana P., Ilter, Didem, Low, Vivien, Endress, Jennifer E., Fernández-García, Juan, Rosenzweig, Adam, Schild, Tanya, Broekaert, Dorien, Ahmed, Adnan, Planque, Melanie, Elia, Ilaria, Han, Julie, Kinzig, Charles, Mullarky, Edouard, Mutvei, Anders P., Asara, John, de Cabo, Rafael, Cantley, Lewis C., Dephoure, Noah, Fendt, Sarah-Maria, and Blenis, John

Published
2020
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