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Furrer R, Handschin C. Biomarkers of aging: from molecules and surrogates to physiology and function. Physiol Rev 2025; 105:1609-1694. [PMID: 40111763 DOI: 10.1152/physrev.00045.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/10/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025] Open
Abstract
Many countries face an unprecedented challenge in aging demographics. This has led to an exponential growth in research on aging, which, coupled to a massive financial influx of funding in the private and public sectors, has resulted in seminal insights into the underpinnings of this biological process. However, critical validation in humans has been hampered by the limited translatability of results obtained in model organisms, additionally confined by the need for extremely time-consuming clinical studies in the ostensible absence of robust biomarkers that would allow monitoring in shorter time frames. In the future, molecular parameters might hold great promise in this regard. In contrast, biomarkers centered on function, resilience, and frailty are available at the present time, with proven predictive value for morbidity and mortality. In this review, the current knowledge of molecular and physiological aspects of human aging, potential antiaging strategies, and the basis, evidence, and potential application of physiological biomarkers in human aging are discussed.
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Mizunoe Y, Kumagai M, Fukai H, Hachiya K, Otani Y, Nozaki Y, Tezuka K, Kobayashi M, Haeno H, Saeki K, Murayama Y, Shimano H, Higami Y. Caloric restriction alters NCOA2 splicing to regulate lipid metabolism in subcutaneous white adipose tissue. Biochem Biophys Res Commun 2025; 765:151871. [PMID: 40267838 DOI: 10.1016/j.bbrc.2025.151871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 04/25/2025]
Abstract
Caloric restriction (CR) promotes longevity and metabolic health by modulating gene expression and cellular processes. However, the role of alternative mRNA splicing in CR-induced metabolic adaptation remains underexplored. In this study, we analyzed RNA sequencing data from the subcutaneous white adipose tissue of CR mice. We identified 6058 differentially expressed genes, with significant upregulation of lipid metabolism pathway genes, such as Elovl6, Fasn, and Srebp1c. We also detected 400 CR-associated alternative splicing events, with the skipped exon and retained intron events predominantly affecting lipid biosynthesis and energy metabolism. Among these events, Ncoa2, a nuclear receptor coactivator involved in lipid metabolism, exhibited increased exon 13 inclusion under CR, favoring the expression of the full-length isoform. Functional assays revealed that full-length NCOA2 enhanced PPARγ-mediated transcriptional activation, while the truncated Δ-NCOA2 isoform exhibited altered coactivator activity. Δ-NCOA2 was found to lack an LXXL motif critical for nuclear receptor interactions, potentially modifying its function. Taken together, these findings indicate that CR-induced alternative splicing fine-tunes metabolic and transcriptional networks, thereby contributing to lipid homeostasis and energy adaptation. Our study highlights a novel regulatory layer by which CR modulates metabolism through coordinated transcriptional and splicing alterations, offering new insights into the molecular mechanisms underlying the beneficial effects of CR on aging and metabolic health. Further investigations are warranted to determine the tissue-specificity of the CR-induced splicing changes and their potential implications for metabolic disorders and lifespan extension.
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Affiliation(s)
- Yuhei Mizunoe
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Mitsuki Kumagai
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Hiroto Fukai
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Kazuki Hachiya
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Yuina Otani
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Yuka Nozaki
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Kyo Tezuka
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
| | - Masaki Kobayashi
- Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, 112-8610, Japan; Institute for Human Life Science, Ochanomizu University, Bunkyo-ku, Tokyo, 112-8610, Japan.
| | - Hiroshi Haeno
- Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba, 278-0022, Japan.
| | - Koichi Saeki
- Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba, 278-0022, Japan.
| | - Yuki Murayama
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Yoshikazu Higami
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan; Division of Cell Fate Regulation, Research Institute for Biomedical Science (RIBS), Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
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Gaesser GA, Hall SE, Angadi SS, Poole DC, Racette SB. Increasing the health span: unique role for exercise. J Appl Physiol (1985) 2025; 138:1285-1308. [PMID: 40244910 DOI: 10.1152/japplphysiol.00049.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/21/2025] [Accepted: 04/02/2025] [Indexed: 04/19/2025] Open
Abstract
Health span, that period between birth and onset of major disease(s), when adequate physical and cognitive function permit those daily living activities essential to life quality, is lower in the United States than other developed countries. Physical inactivity and excessive calorie intake occupy dominant roles both in the problem, and by redressing them, in the solution. Consequently, this review focuses on evidence that appropriate exercise engagement and calorie restriction (CR) can improve physical and mental health with a view to extending the health span. Humanity, writ large, has grasped these underlying concepts for Millennia but has been largely intransigent to them. Thus, the final section proposes a novel Monty Python-esque approach that encompasses humanity's inimical sense of humor to increase physical fitness and mental health, restore energy balance, sustain better cognitive function, and extend the health span.
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Affiliation(s)
- Glenn A Gaesser
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States
| | - Stephanie E Hall
- Colleges of Veterinary Medicine and Health and Human Sciences, Kansas State University, Manhattan, Kansas, United States
| | - Siddhartha S Angadi
- School of Health Education and Human Development, University of Virginia, Charlottesville, Virginia, United States
| | - David C Poole
- Colleges of Veterinary Medicine and Health and Human Sciences, Kansas State University, Manhattan, Kansas, United States
| | - Susan B Racette
- College of Health Solutions, Arizona State University, Phoenix, Arizona, United States
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Zhang Y, Naaz A, Cheng TYN, Lin JJ, Gao M, Dorajoo R, Alfatah M. Systematic transcriptomics analysis of calorie restriction and rapamycin unveils their synergistic interaction in prolonging cellular lifespan. Commun Biol 2025; 8:753. [PMID: 40369174 PMCID: PMC12078523 DOI: 10.1038/s42003-025-08178-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/06/2025] [Indexed: 05/16/2025] Open
Abstract
Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to the development of age-related diseases. In the pursuit of slowing or even reversing the aging process, a prominent strategy of significant interest is calorie restriction (CR), also known as dietary restriction, and the potential influence of a drug called rapamycin (RM). Both CR and RM have demonstrated the capacity to extend healthspan and lifespan across a diverse array of species, including yeast, worms, flies, and mice. Nevertheless, their individual and combined effects on mitotic and postmitotic cells, as well as their comparative analysis, remain areas that demand a thorough investigation. In this study, we employ RNA-sequencing methodologies to comprehensively analyze the impact of CR, RM, and their combination (CR + RM) on gene expression in yeast cells. Our analysis uncovers distinctive, overlapping, and even contrasting patterns of gene regulation, illuminating the unique and shared effects of CR and RM. Furthermore, the transcriptional synergistic interaction of CR + RM is validated in extending the lifespan of both yeast and human cells.
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Affiliation(s)
- Yizhong Zhang
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Arshia Naaz
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Trishia Yi Ning Cheng
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jovian Jing Lin
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Mingtong Gao
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mohammad Alfatah
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore.
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Cagigas ML, De Ciutiis I, Masedunskas A, Fontana L. Dietary and pharmacological energy restriction and exercise for healthspan extension. Trends Endocrinol Metab 2025:S1043-2760(25)00076-1. [PMID: 40318928 DOI: 10.1016/j.tem.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 05/07/2025]
Abstract
Extending healthspan - the years lived in optimal health - holds transformative potential to reduce chronic diseases and healthcare costs. Dietary restriction (DR), particularly when combined with nutrient-rich diets and exercise, is among the most effective, evidence-based strategies for enhancing metabolic health and longevity. By targeting fundamental pathways, it mitigates the onset and progression of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), neurodegeneration, and cancer. This review synthesizes human data on the impact of DR and exercise on metabolic and age-related diseases, while emphasizing key biological mechanisms such as nutrient sensing, insulin sensitivity, inflammation, mitochondrial function, and gut microbiota. We also examine the emerging role of pharmacologically induced DR, focusing on glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) that partially mimic DR and present opportunities for chronic disease prevention.
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Affiliation(s)
- Maria Lastra Cagigas
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Isabella De Ciutiis
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Andrius Masedunskas
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Luigi Fontana
- Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
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Machado IF, Palmeira CM, Rolo AP. Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging. Ageing Res Rev 2025; 109:102762. [PMID: 40320152 DOI: 10.1016/j.arr.2025.102762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/09/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025]
Abstract
Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.
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Affiliation(s)
- Ivo F Machado
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute of Interdisciplinary Research, Doctoral Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal
| | - Carlos M Palmeira
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Anabela P Rolo
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
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7
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Gano A, Vore AS, Geraci D, Varlinskaya EI, Deak T. Operant effort-based decision-making task reveals sex differences in motivational behavior but no long-term effects of adolescent intermittent ethanol in Sprague Dawley rats. Pharmacol Biochem Behav 2025; 250:173998. [PMID: 40107424 DOI: 10.1016/j.pbb.2025.173998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/12/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
Loss of motivated behavior, or apathy, is a key feature across multiple affective disorders, and is assessed via operant effort-based decision-making (EBDM). The mechanisms of amotivation have been connected to pro-inflammatory signaling which can directly impact dopamine signaling. Chronic alcohol exposure is associated with altered immune signaling and impaired goal-directed behavior, so the present studies assessed the impact of adolescent intermittent ethanol (AIE) on EBDM in adulthood across sex. Adolescent male and female (N = 32/n = 8 per group) Sprague-Dawley rats were exposed to ethanol (4 g/kg) intragastrically on a 3 days on/2 days off schedule during postnatal days ~30-50 or given vehicle, and allowed to age into adulthood (P80+). All rats were then trained on the operant EBDM concurrent FR5/chow task, after which we tested the impact of sex and AIE history on responding 1) during breakpoint challenge raising the FR requirement in a log2 pattern, 2) 90 min after immune challenge (2 μg/kg IL-1β), 3) 18 h after 3.5 g/kg intraperitoneal ethanol challenge (hangover), and 4) immediately after a 30-min restraint stress challenge. Immune challenge disrupted motivated behavior without affecting appetite. No effects of AIE emerged and sex differences were evident throughout all challenges. Females responded less for pellets yet persisted responding until a higher breakpoint. This work indicates that AIE does not alter baseline or evoked EBDM as can be measured with this approach. Testing across aging and using other modalities should be performed to continue examining the effects of chronic alcohol on apathy.
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Affiliation(s)
- Anny Gano
- Developmental Exposure Alcohol Research Center (DEARC), Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States of America.
| | - Andrew S Vore
- Developmental Exposure Alcohol Research Center (DEARC), Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States of America.
| | - Daniella Geraci
- Developmental Exposure Alcohol Research Center (DEARC), Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States of America.
| | - Elena I Varlinskaya
- Developmental Exposure Alcohol Research Center (DEARC), Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States of America.
| | - Terrence Deak
- Developmental Exposure Alcohol Research Center (DEARC), Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States of America.
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8
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Khurana V, Radu R, Feinstein MJ, Apetrei C, Pandrea I. The heart of the matter: modeling HIV-associated cardiovascular comorbidities in nonhuman primate models. Front Cell Infect Microbiol 2025; 15:1556315. [PMID: 40330026 PMCID: PMC12052898 DOI: 10.3389/fcimb.2025.1556315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 05/08/2025] Open
Abstract
With the advent of antiretroviral therapy (ART) that effectively suppresses HIV replication, and reduced AIDS progression, the clinical spectrum of HIV infection has dramatically changed. Currently, the people living with HIV (PLWH) who receive ART have a nearly normal prognostic of survival, yet they still experience higher morbidity and mortality than age-matched uninfected subjects. The higher risk of death in PLWH is linked to persistence of residual systemic inflammation and T-cell activation. These factors contribute to accelerated aging and higher incidence of HIV-associated non-AIDS conditions, thereby presenting new diagnostic and therapeutic challenges. This new shifting paradigm of HIV infection associates a higher incidence of cardiovascular disease (CVD), such as stroke, acute myocardial infarction and sudden cardiac death, in stark contrast to the reduced incidence of opportunistic infections. The incidence of acute myocardial infarction and coronary disease is several folds higher in PLWH than in the general population. Study of United States (US) death certificates listing HIV infection shows that the deaths from CVD doubled between 1996 and 2006. CVD will become an even more prominent comorbidity considering that more than 50% of PLWH in the US are over 50 years old, an age that more frequently associates CVD, and cardiovascular complications are more frequent in urban African-Americans and Hispanics, which are disproportionately affected by HIV. Therefore, reducing the overall risk of these complications will become the primary challenge in the management of chronic HIV infection. Not surprisingly, the REPRIEVE trial showed a substantial benefit of statins to PLWH, and the current guidelines include statin administration to PLWH. Nonhuman primate (NHP) models for the cardiovascular comorbidities associated with HIV are currently available and their use for testing new therapeutic approaches aimed at countering the effects of hypercoagulability and CVD is discussed. Their use can be of tremendous help to understand the etiology, pathophysiology, and the determinants of CVD in PLWH, which are currently poorly understood. Use of the NHP models could help in dissecting the relative contribution of the virus, behavioral factors, and ART to cardiovascular risk, having the potential to help us establish new strategic approaches aimed at controlling HIV-related CVD.
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Affiliation(s)
- Vansh Khurana
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Rodica Radu
- Internal Medicine Department, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Cardiology Department, Cardiovascular Diseases Institute “Prof. Dr. George I. M. Georgescu”, Iasi, Romania
| | - Matthew J. Feinstein
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Cristian Apetrei
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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Wang A, Speakman JR. Potential downsides of calorie restriction. Nat Rev Endocrinol 2025:10.1038/s41574-025-01111-1. [PMID: 40247012 DOI: 10.1038/s41574-025-01111-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/26/2025] [Indexed: 04/19/2025]
Abstract
Although the potential benefits of calorie restriction on human lifespan remain uncertain, it is currently one of the most extensively researched non-genetic approaches to extending both lifespan and healthspan in animals. Calorie restriction offers numerous health benefits, including a reduced incidence of age-related diseases. However, calorie restriction also produces a range of negative effects, which are not fully documented and require further investigation, particularly in humans. As the viability of calorie restriction in humans will depend on the balance of benefits and detrimental effects, it is crucial to understand the nature of these negative effects and what drives them. In this Review, we summarize the effects of calorie restriction on wound healing, hunger, cold sensitivity, bone health, brain size, cognition, reproductive performance and infection, primarily based on studies of rodents with some data from other species and from humans. Overall, the detrimental effects of calorie restriction seem to stem directly from prioritization of vital functions and downregulation or suppression of energy-demanding processes, which helps preserve survival but can also lead to impaired physiological performance and increased vulnerability to stressors. The exact mechanisms underlying these effects remain unclear. Whether it might be possible to engage in calorie restriction but avoid these negative effects remains uncertain.
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Affiliation(s)
- Anyongqi Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- Beijing Life Science Academy, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - John Roger Speakman
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
- Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
- Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, China.
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
- Institute of Health Sciences, China Medical University, Shenyang, China.
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Moel M, Harinath G, Lee V, Nyquist A, Morgan SL, Isman A, Zalzala S. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging (Albany NY) 2025; 17:908-936. [PMID: 40188830 PMCID: PMC12074816 DOI: 10.18632/aging.206235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/25/2025] [Indexed: 05/08/2025]
Abstract
DESIGN This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring. RESULTS Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (ηp2 = 0.001, p = 0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ηp2 = 0.202, p = 0.013) and self-reported pain (ηp2 = 0.168, p = 0.015) improved significantly for women using 10 mg rapamycin. Self-reported emotional well-being (ηp2 = 0.108, p = 0.023) and general health (ηp2 = 0.166, p = 0.004) also improved for those using 5 mg rapamycin. No other significant effects were observed. CONCLUSIONS Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.
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Affiliation(s)
- Mauricio Moel
- AgelessRx, Ann Arbor, MI 48104, USA
- Division of Research and Applied Sciences, AgelessRx, Ann Arbor, MI 48104, USA
| | - Girish Harinath
- AgelessRx, Ann Arbor, MI 48104, USA
- Division of Research and Applied Sciences, AgelessRx, Ann Arbor, MI 48104, USA
| | - Virginia Lee
- AgelessRx, Ann Arbor, MI 48104, USA
- Division of Research and Applied Sciences, AgelessRx, Ann Arbor, MI 48104, USA
| | | | - Stefanie L. Morgan
- AgelessRx, Ann Arbor, MI 48104, USA
- Division of Research and Applied Sciences, AgelessRx, Ann Arbor, MI 48104, USA
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Ben Kridis W, Hadj Taieb E, Ben Lassoued R, Khanfir A. Fasting during cancer chemotherapy: single centre study. BMJ Support Palliat Care 2025:spcare-2025-005369. [PMID: 40175058 DOI: 10.1136/spcare-2025-005369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/24/2025] [Indexed: 04/04/2025]
Affiliation(s)
| | | | | | - Afef Khanfir
- Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
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12
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Liu Z, Zhang J, Jiang F, Liu C, Shao Y, Le W. Biological Effects of Dietary Restriction on Alzheimer's Disease: Experimental and Clinical Investigations. CNS Neurosci Ther 2025; 31:e70392. [PMID: 40245176 PMCID: PMC12005399 DOI: 10.1111/cns.70392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/24/2025] [Accepted: 04/02/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUNDS Dementia can impose a heavy economic burden on both society and families. Alzheimer's disease (AD), the most prevalent form of dementia, is a complex neurodegenerative disease characterized by the abnormal deposition of extracellular amyloid β-protein (Aβ) and the aggregation of intracellular Tau protein to form neurofibrillary tangles (NFTs). Given the limited efficacy of pharmacological treatment, scientists have already paid more attention to non-pharmacological strategies, including dietary restriction (DR). DR refers to a nutritional paradigm aimed at promoting overall health by modifying the balance between energy consumption and expenditure. Studies have demonstrated that DR effectively extends the healthy lifespan, delays the aging process, and achieves promising results in the prevention and treatment of AD in preclinical studies. METHODS In this review we collected related studies and viewpoints by searching on PubMed database using the keywords. Most of the citations were published between 2015 and 2025. A few older literatures were also included due to their relevance and significance in this field. RESULTS We first provide a concise overview of the current therapeutic and preventive strategies for AD. Then, we introduce several specific DR protocols and their favorable effects on AD. Furthermore, the potential mechanisms underlying the benefits of DR on AD are discussed. Finally, we briefly highlight the role of DR in maintaining brain health. CONCLUSION This review may offer valuable insights into the development of innovative non-pharmacological strategies for AD treatment.
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Affiliation(s)
- Zijiao Liu
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological DiseasesThe First Affiliated Hospital, Dalian Medical UniversityDalianChina
| | - Jun Zhang
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological DiseasesThe First Affiliated Hospital, Dalian Medical UniversityDalianChina
| | - Fei Jiang
- Clinical Research Center for PsychiatryDalian Seventh People's HospitalDalianChina
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesShanghaiChina
| | - Yaping Shao
- Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological DiseasesThe First Affiliated Hospital, Dalian Medical UniversityDalianChina
| | - Weidong Le
- Center for Clinical and Translational ResearchShanghai University of Medicine and Health SciencesShanghaiChina
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13
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Stephens EB, Senadheera C, Roa-Diaz S, Peralta S, Alexander L, Silverman-Martin W, Yukawa M, Morris J, Johnson JB, Newman JC, Stubbs BJ. A Randomized Open-Label, Observational Study of the Novel Ketone Ester, Bis Octanoyl (R)-1,3-Butanediol, and Its Acute Effect on ß-Hydroxybutyrate and Glucose Concentrations in Healthy Older Adults. J Nutr Gerontol Geriatr 2025; 44:103-122. [PMID: 39985761 DOI: 10.1080/21551197.2025.2466163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2025]
Abstract
Bis-octanoyl-(R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentration rapidly after ingestion. KE is hypothesized to improve function in older adults. Whilst many studies have investigated KE in young adults, they have not been studied in healthy older adults (HOA), for whom age-related differences in metabolism may alter the effects. This randomized, observational, open-label study in HOA (n = 30, 50% male, age = 76.5y) aimed to elucidate tolerance, blood BHB and glucose concentrations for 4h following consumption of either 12.5 or 25 g of BO-BD formulated in ready-to-drink beverage (n = 30), and re-constituted powder (n = 21) with a meal. All study interventions were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥0.5 mM) until the end of the study. Peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 vs 12.5 g of BO-BD in both formulations. There were no significant differences in Cmax or iAUC between formulations. Blood glucose increased in all conditions following the meal, with no consistent significant differences between conditions. These results demonstrate that both powder and beverage formulations of the KE, BO-BD, induce ketosis in HOA adults, facilitating future research on functional effects of KE in aging.
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Affiliation(s)
| | | | | | - Sawyer Peralta
- Buck Institute for Research on Aging, Novato, California, USA
| | - Laura Alexander
- Buck Institute for Research on Aging, Novato, California, USA
| | | | - Michi Yukawa
- Veteran's Affairs Medical Center, San Francisco, California, USA
| | - Jennifer Morris
- Veteran's Affairs Medical Center, San Francisco, California, USA
| | | | - John C Newman
- Buck Institute for Research on Aging, Novato, California, USA
- Division of Geriatrics, University of California, San Francisco, California, USA
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14
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Liu Y, Dong Y, Jiang Y, Han S, Liu X, Xu X, Zhu A, Zhao Z, Gao Y, Zou Y, Zhang C, Bian Y, Zhang Y, Liu J, Zhao S, Zhao H, Chen ZJ. Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming. Cell Metab 2025; 37:920-935.e6. [PMID: 39986273 DOI: 10.1016/j.cmet.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 10/17/2024] [Accepted: 01/15/2025] [Indexed: 02/24/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS.
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Affiliation(s)
- Yue Liu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Center for Reproductive Medicine, Gusu School, The First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, Nanjing 212028, Jiangsu, China
| | - Yi Dong
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Yonghui Jiang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Shan Han
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Xin Liu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Xin Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Aiqing Zhu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Zihe Zhao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Yuan Gao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Yang Zou
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Chuanxin Zhang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Yuehong Bian
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Yuqing Zhang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China
| | - Jiang Liu
- Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China
| | - Shigang Zhao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China.
| | - Han Zhao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Center for Reproductive Medicine, Gusu School, The First Affiliated Hospital of Nanjing Medical University/Jiangsu Province Hospital, Nanjing 212028, Jiangsu, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China.
| | - Zi-Jiang Chen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, The Second Hospital, Institute of Women, Children and Reproductive Health, Shandong University, Jinan 250012, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250012, Shandong, China; Shandong Technology Innovation Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan 250012, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan 250012, Shandong, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan 250012, Shandong, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200025, China; Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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15
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Jiang Q, Liu J, Huang S, Wang XY, Chen X, Liu GH, Ye K, Song W, Masters CL, Wang J, Wang YJ. Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances. Signal Transduct Target Ther 2025; 10:76. [PMID: 40059211 PMCID: PMC11891338 DOI: 10.1038/s41392-025-02145-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/29/2024] [Accepted: 01/15/2025] [Indexed: 05/13/2025] Open
Abstract
In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.
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Affiliation(s)
- Qiu Jiang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Jie Liu
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Shan Huang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Xuan-Yue Wang
- Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China
| | - Xiaowei Chen
- Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China
- Brain Research Center, Third Military Medical University, Chongqing, China
| | - Guang-Hui Liu
- University of Chinese Academy of Sciences, Beijing, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Keqiang Ye
- Faculty of Life and Health Sciences, and Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Weihong Song
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province. Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Colin L Masters
- The Florey Institute, The University of Melbourne, Parkville, VIC, Australia.
| | - Jun Wang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China.
| | - Yan-Jiang Wang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China.
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China.
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16
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Clark JP, Rhoads TW, McIlwain SJ, Polewski MA, Pavelec DM, Colman RJ, Anderson RM. Caloric restriction reprograms adipose tissues in rhesus monkeys. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.03.641286. [PMID: 40093109 PMCID: PMC11908232 DOI: 10.1101/2025.03.03.641286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Caloric restriction (CR) is a dietary intervention that delays the onset of age-related diseases and enhances survival in diverse organisms, and although changes in adipose tissues have been implicated in the beneficial effects of CR the molecular details are unknown. Here we show shared and depot-specific adaptations to life-long CR in subcutaneous and visceral adipose depots taken from advanced age male rhesus monkeys. Differential gene expression and pathway analysis identified key differences between the depots in metabolic, immune, and inflammatory pathways. In response to CR, RNA processing and proteostasis-related pathways were enriched in both depots but changes in metabolic, growth, and inflammatory pathways were depot-specific. Commonalities and differences that distinguish adipose depots are shared among monkeys and humans and the response to CR is highly conserved. These data reveal depot-specificity in adipose tissue adaptation that likely reflects differences in function and contribution to age-related disease vulnerability.
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Affiliation(s)
- Josef P Clark
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53705
| | - Timothy W Rhoads
- Department of Nutritional Sciences, University of Wisconsin-Madison, United States, 53706
| | - Sean J McIlwain
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53792
- Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53792
| | - Michael A Polewski
- Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI, USA, 53706
| | - Derek M Pavelec
- Biotechnology Center, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53706
| | - Ricki J Colman
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53715
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53705
| | - Rozalyn M Anderson
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States, 53705
- William S. Middleton Memorial Veterans Hospital, Geriatric Research, Education, and Clinical Center, Madison, Wisconsin, United States, 53705
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17
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Oudmaijer CAJ, Komninos DSJ, Ozinga RA, Smit K, Rozendaal NEM, Hoeijmakers JHJ, Vermeij WP, Aerts JGJV, IJzermans JNM, Willemsen M. Short-term fasting before living kidney donation has an immune-modulatory effect. Front Immunol 2025; 16:1488324. [PMID: 40051619 PMCID: PMC11882433 DOI: 10.3389/fimmu.2025.1488324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/13/2025] [Indexed: 03/09/2025] Open
Abstract
Background Short-Term Fasting (STF) is an intervention reducing the intake of calories, without causing undernutrition or micronutrient-related malnutrition. It aims to systemically improve resilience against acute stress. Several (pre-)clinical studies have suggested protective effects of STF, marking the systemic effects STF can induce in respect to surgery and ischemia-reperfusion injury. In addition, STF also affects the number of circulating immune cells. We aim to determine the effect of STF on the abundance and phenotype of different immune cell populations. Methods Thirty participants were randomly selected from the FAST clinical trial, including living kidney donors, randomized to an STF-diet or control arm. In an observational cohort sub-study we prospectively included 30 patients who donated blood samples repeatedly during study runtime. Using flow cytometry analyses, immune cell phenotyping was performed on peripheral blood mononuclear cells. Three panels were designed to investigate the presence and activation status of peripheral T cells, B cells, dendritic cells (DCs) and myeloid cells. Results Eight participants were excluded due to sample constraints. Baseline characteristics showed no significant differences, except for fasting duration. Weight changes were minimal and non-significant across different time intervals, with slight trends toward long-term weight loss pre-surgery. Glucose, insulin, and β-hydroxybutyrate levels differed significantly between groups, reflecting adherence to the fasting diet. Flow cytometry and RNA sequencing analysis revealed no baseline differences between groups, with high variability within each group. STF changes the levels and phenotype of immune cells, reducing the abundance and activation of T cells, including regulatory T cells, increased presence of (naïve) B cells, and elevation of type 1 conventional DCs (cDC1s). In addition, a decrease in central memory T cells was observed. Discussion In this study, we observed significant changes due to fasting in B cells, T cells, and DCs, specifically toward less specialized lymphocytes, suggesting an arrest in B and T cell development. Further research should focus on the clinical implications of changes in immune cells and significance of these observed immunological changes. Conclusion STF results in reduced numbers and activation status of T cells and Tregs, increased presence of (naïve) B cells, and elevation of cDC1s.
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Affiliation(s)
- Christiaan A. J. Oudmaijer
- Erasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Daphne S. J. Komninos
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Rutger A. Ozinga
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Kimberly Smit
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Nina E. M. Rozendaal
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jan H. J. Hoeijmakers
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
- Erasmus MC Cancer Institute, Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
- Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Germany, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Wilbert P. Vermeij
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Joachim G. J. V. Aerts
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jan N. M. IJzermans
- Erasmus MC Transplant Institute, Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Marcella Willemsen
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
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18
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Zhou Y, Ahsan FM, Soukas AA. The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.17.638704. [PMID: 40027662 PMCID: PMC11870510 DOI: 10.1101/2025.02.17.638704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
As the only gateway governing nucleocytoplasmic transport, the nuclear pore complex (NPC) maintains fundamental cellular processes and deteriorates with age. However, the study of age-related roles of single NPC components remains challenging owing to the complexity of NPC composition. Here we demonstrate that the master energy sensor, AMPK, post-translationally regulates the abundance of the nucleoporin NPP-16/NUP50 in response to nutrient availability and energetic stress. In turn, NPP-16/NUP50 promotes transcriptomic activation of lipid catabolism to extend the lifespan of Caenorhabditis elegans independently of its role in nuclear transport. Rather, the intrinsically disordered region (IDR) of NPP-16/NUP50, through direct interaction with the transcriptional machinery, transactivates the promoters of catabolic genes. Remarkably, elevated NPP-16/NUP50 levels are sufficient to promote longevity and metabolic stress defenses. AMPK-NUP50 signaling is conserved to human, indicating that bridging energy sensing to metabolic adaptation is an ancient role of this signaling axis.
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Affiliation(s)
- Yifei Zhou
- Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States
- Broad Institute of Harvard and MIT, Cambridge, United States
| | - Fasih M Ahsan
- Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States
- Broad Institute of Harvard and MIT, Cambridge, United States
- Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, United States
| | - Alexander A Soukas
- Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, United States
- Broad Institute of Harvard and MIT, Cambridge, United States
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19
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Caprara G, Pallavi R, Sanyal S, Pelicci PG. Dietary Restrictions and Cancer Prevention: State of the Art. Nutrients 2025; 17:503. [PMID: 39940361 PMCID: PMC11820753 DOI: 10.3390/nu17030503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/22/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise to 16.3 million by 2040. Primary prevention has long been acknowledged as a crucial approach to reducing cancer incidence. In fact, between 30 and 50 percent of all tumors are known to be preventable by eating a healthy diet, staying active, avoiding alcohol, smoking, and being overweight. Accordingly, many international organizations have created tumor prevention guidelines, which underlie the importance of following a diet that emphasizes eating plant-based foods while minimizing the consumption of red/processed meat, sugars, processed foods, and alcohol. However, further research is needed to define the relationship between the effect of specific diets or nutritional components on cancer prevention. Interestingly, reductions in food intake and dietetic restrictions can extend the lifespan of yeast, nematodes, flies, and rodents. Despite controversial results in humans, those approaches have the potential to ameliorate health via direct and indirect effects on specific signaling pathways involved in cancer onset. Here, we describe the latest knowledge on the cancer-preventive potential of dietary restrictions and the biochemical processes involved. Molecular, preclinical, and clinical studies evaluating the effects of different fasting strategies will also be reviewed.
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Affiliation(s)
- Greta Caprara
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
| | - Rani Pallavi
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
- Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad 500034, India
- The Operation Eyesight Universal Institute for Eye Cancer, L. V. Prasad Eye Institute, Hyderabad 500034, India; (R.P.); (S.S.)
| | - Shalini Sanyal
- Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad 500034, India
- The Operation Eyesight Universal Institute for Eye Cancer, L. V. Prasad Eye Institute, Hyderabad 500034, India; (R.P.); (S.S.)
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20139 Milan, Italy
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20
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Altab G, Merry BJ, Beckett CW, Raina P, Lopes I, Goljanek-Whysall K, de Magalhães JP. Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing. BMC Genomics 2025; 26:29. [PMID: 39800693 PMCID: PMC11727704 DOI: 10.1186/s12864-024-11051-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.
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Affiliation(s)
- Gulam Altab
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
| | - Brian J Merry
- Institute of Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK
| | - Charles W Beckett
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
| | - Priyanka Raina
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
| | - Inês Lopes
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
| | - Katarzyna Goljanek-Whysall
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
- College of Medicine, Nursing and Health Sciences, University of Galway, Galway, H91 TK33, Ireland
| | - João Pedro de Magalhães
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK.
- Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital, Mindelsohn Way, Birmingham, B15 2WB, UK.
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21
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Santisteban MM, Iadecola C. The pathobiology of neurovascular aging. Neuron 2025; 113:49-70. [PMID: 39788087 DOI: 10.1016/j.neuron.2024.12.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/12/2025]
Abstract
As global life expectancy increases, age-related brain diseases such as stroke and dementia have become leading causes of death and disability. The aging of the neurovasculature is a critical determinant of brain aging and disease risk. Neurovascular cells are particularly vulnerable to aging, which induces significant structural and functional changes in arterial, venous, and lymphatic vessels. Consequently, neurovascular aging impairs oxygen and glucose delivery to active brain regions, disrupts endothelial transport mechanisms essential for blood-brain exchange, compromises proteostasis by reducing the clearance of potentially toxic proteins, weakens immune surveillance and privilege, and deprives the brain of key growth factors required for repair and renewal. In this review, we examine the effects of neurovascular aging on brain function and its role in stroke, vascular cognitive impairment, and Alzheimer's disease. Finally, we discuss key unanswered questions that must be addressed to develop neurovascular strategies aimed at promoting healthy brain aging.
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Affiliation(s)
- Monica M Santisteban
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
| | - Costantino Iadecola
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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22
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Sato M, Torigoe D, Kinoshita Y, Cyuman M, Toda C, Sato M, Ikeda K, Kadomatsu T, Horiguchi H, Morinaga J, Fukami H, Sugizaki T, Miyata K, Kusaba R, Okadome Y, Matsunaga E, Node K, Oike Y. Long-term intake of Tamogi-take mushroom (Pleurotus cornucopiae) mitigates age-related cardiovascular dysfunction and extends healthy life expectancy. NPJ AGING 2025; 11:1. [PMID: 39779757 PMCID: PMC11711650 DOI: 10.1038/s41514-024-00191-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025]
Abstract
Age-related declines in cardiac function and exercise tolerance interfere with healthy living and decrease healthy life expectancy in older individuals. Tamogi-take mushrooms (Pleurotus cornucopiae) are known to contain high levels of Ergothioneine (EGT), an antioxidant with potential health benefits. In this study, we assessed the possibility that long-term consumption of Tamogi-take mushrooms might attenuate age-related decline in cardiac and vascular endothelial function in mice. We found that long-term intake of Tamogi-take mushrooms significantly maintained cardiac and vascular endothelial function and improved exercise tolerance in mice. Long-term mushroom consumption also increased levels of Nrf2 (Nuclear factor E2-related factor 2) protein in heart tissues and increased translation of HO-1 (Heme Oxygenase 1) proteins, which have antioxidant effects in heart and aortic tissues. Finally, long-term Tamogi-take mushroom consumption inhibited ROS accumulation with aging and reduced expression of inflammatory biomarkers. We conclude that ingestion of Tamogi-take mushrooms could serve as a dietary intervention to promote cardiovascular health, support healthy aging and slow the progression of age-related diseases.
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Affiliation(s)
- Michio Sato
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, Japan
- Division of Kumamoto Mouse Clinic (KMC), Kumamoto University, Kumamoto, Japan
| | - Daisuke Torigoe
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan
| | - Yuya Kinoshita
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Momoka Cyuman
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan
| | - Chitoku Toda
- Department of Neuroscience for Metabolic Control, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaru Sato
- Laboratory of Biomolecule Analysis, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
| | - Kazutaka Ikeda
- Laboratory of Biomolecule Analysis, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
- Laboratory of Omics and Informatics, Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | | | - Haruki Horiguchi
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Jun Morinaga
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
- Department of Disease Genome Epidemiology, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kumamoto, Japan
| | - Hirotaka Fukami
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Taichi Sugizaki
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Keishi Miyata
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Ryoko Kusaba
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Yusuke Okadome
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Eiji Matsunaga
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.
- Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
- Division of Laboratory Animal Science, Institute of Resource Development and Analysis (IRDA), Kumamoto University, Kumamoto, Japan.
- Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
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23
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Atalay B, Dogan S, Gudu BO, Yilmaz E, Ayden A, Ozorhan U, Cicekdal MB, Yaltirik K, Ekici ID, Tuna BG. Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels. Behav Brain Res 2025; 476:115258. [PMID: 39332639 DOI: 10.1016/j.bbr.2024.115258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Calorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR. METHODS Mice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications. RESULTS In the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number. CONCLUSION This study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.
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Affiliation(s)
- Basar Atalay
- University of Yeditepe, School of Medicine, Department of Neurosurgery, Istanbul, Turkiye; University of Miami Miller School of Medicine, Department of Neurology, Neurocriticalcare, Miami, USA; Jackson Memorial Hospital, Department of Neurology, Neurocritical Care, Miami, USA
| | - Soner Dogan
- Yeditepe University, School of Medicine, Department of Medical Biology, Istanbul, Turkiye
| | - Burhan Oral Gudu
- University of Yeditepe, School of Medicine, Department of Neurosurgery, Istanbul, Turkiye
| | - Elif Yilmaz
- Yeditepe University, School of Medicine, Department of Medical Biology, Istanbul, Turkiye
| | - Atakan Ayden
- Yeditepe University, School of Medicine, Department of Medical Biology, Istanbul, Turkiye
| | - Umit Ozorhan
- University of Lübeck, Institude of Experimental ans Clinical Pharmacology and Toxicology, Lübeck, Germany
| | - Munevver Burcu Cicekdal
- University of Ghent, Medical Biology, School of Medicine and Health Sciences, Ghent, Belgium
| | - Kaan Yaltirik
- University of Yeditepe, School of Medicine, Department of Neurosurgery, Istanbul, Turkiye
| | - Isin Dogan Ekici
- Yeditepe University, School of Medicine, Department of Pathology, Istanbul, Turkiye
| | - Bilge Guvenc Tuna
- Yeditepe University, School of Medicine, Department of Biophysics, Istanbul, Turkiye.
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24
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Shay JES, Yilmaz ÖH. Dietary and metabolic effects on intestinal stem cells in health and disease. Nat Rev Gastroenterol Hepatol 2025; 22:23-38. [PMID: 39358589 PMCID: PMC12105169 DOI: 10.1038/s41575-024-00980-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 10/04/2024]
Abstract
Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment.
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Affiliation(s)
- Jessica E S Shay
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
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25
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Castro JP. Metformin and monkeys: what can we learn about delaying aging? Lab Anim (NY) 2025; 54:7-8. [PMID: 39609627 DOI: 10.1038/s41684-024-01492-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Affiliation(s)
- José Pedro Castro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
- Aging and Aneuploidy Laboratory, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
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26
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Wang Z, Yang B. Pro-Aging Metabolic Reprogramming: A Unified Theory of Aging. ENGINEERING 2025; 44:37-43. [DOI: 10.1016/j.eng.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
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27
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Locasale JW, Goncalves MD, Di Tano M, Burgos-Barragan G. Diet and Cancer Metabolism. Cold Spring Harb Perspect Med 2024; 14:a041549. [PMID: 38621831 PMCID: PMC11610756 DOI: 10.1101/cshperspect.a041549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for cancer patients. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this work, we propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, we also discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.
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Affiliation(s)
- Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, Durham, Norh Carolina 27710, USA
| | - Marcus D Goncalves
- Division of Endocrinology, Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA
| | - Maira Di Tano
- Division of Endocrinology, Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA
| | - Guillermo Burgos-Barragan
- Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10056, USA
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28
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Mishra A, Sobha D, Patel D, Suresh PS. Intermittent fasting in health and disease. Arch Physiol Biochem 2024; 130:755-767. [PMID: 37828854 DOI: 10.1080/13813455.2023.2268301] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/29/2023] [Indexed: 10/14/2023]
Abstract
CONTEXT Intermittent fasting, a new-age dietary concept derived from an age-old tradition, involves repetitive cycles of fasting/calorie restriction and eating. OBJECTIVE We aim to take a deep dive into the biological responses to intermittent fasting, delineate the disease-modifying and cognitive effects of intermittent fasting, and also shed light on the possible side effects. METHODS Numerous in vitro and in vivo studies were reviewed, followed by an in-depth analysis, and compilation of their implications in health and disease. RESULTS Intermittent fasting improves the body's stress tolerance, which is further amplified with exercise. It impacts various pathological conditions like cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases. CONCLUSION During dietary restriction, the human body experiences a metabolic switch due to the depletion of liver glycogen, which promotes a shift towards utilising fatty acids and ketones in the system, thereby significantly impacting adiposity, ageing and the immune response to various diseases.
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Affiliation(s)
- Anubhav Mishra
- School of Biotechnology, National Institute of Technology, Calicut, Calicut, India
| | - Devika Sobha
- School of Biotechnology, National Institute of Technology, Calicut, Calicut, India
| | - Dimple Patel
- School of Biotechnology, National Institute of Technology, Calicut, Calicut, India
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut, Calicut, India
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29
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Quaytman JA, David NL, Venugopal S, Amorim T, Beatrice B, Toledo FGS, Miller RG, Steinhauser ML, Fazeli PK. Intermittent fasting for systemic triglyceride metabolic reprogramming (IFAST): Design and methods of a prospective, randomized, controlled trial. Contemp Clin Trials 2024; 146:107698. [PMID: 39299543 PMCID: PMC11625453 DOI: 10.1016/j.cct.2024.107698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/27/2024] [Accepted: 09/14/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Caloric restriction prolongs lifespan in model organisms and improves metrics of aging-related diseases in humans, but daily compliance is challenging. Intermittent fasting improves metrics of lipid and glucose metabolism in the setting of weight loss but whether these metrics are improved independent of weight loss is not known. METHODS We seek to address this gap with IFAST, a single-center, three-arm, prospective, randomized, controlled clinical trial. Eligible study participants are adults with no chronic medical conditions beyond prediabetes or overweight but who are at high risk for type 2 diabetes mellitus (T2D), defined as having a history of gestational diabetes or a first-degree relative with T2D. Participants will be randomized in a 1:2:2 schema to either a control group, a fasting group, or a fasting/weight maintenance group. The fasting groups will complete a 24-h fast one day per week for 12 weeks. The key mechanistic endpoint is change in triglyceride composition (defined by carbon content and degree of saturation) as measured by longitudinal metabolomics. The key safety endpoint is percent change from baseline in bone volume fraction (BV/TV; high-resolution peripheral quantitative CT) at the radius in the fasting group. Secondary endpoints include measures of insulin sensitivity (hyperinsulinemic-euglycemic clamp), clinical lipid profiling, systemic inflammation markers, hunger assessment, bone density, and bone microarchitecture with high-resolution peripheral quantitative CT. CONCLUSION IFAST will investigate intrinsic metabolic benefits of intermittent fasting beyond weight loss. TRIAL REGISTRATION ClinicalTrials.gov ID NCT05722873.
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Affiliation(s)
- Jacob A Quaytman
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Natalie L David
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Human Integrative Physiology, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Sharini Venugopal
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Tânia Amorim
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Human Integrative Physiology, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Britney Beatrice
- Department of Sports Medicine and Nutrition, University of Pittsburgh School of Health and Rehabilitation Sciences, Pittsburgh, PA 15260, USA
| | - Frederico G S Toledo
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Rachel G Miller
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Matthew L Steinhauser
- Center for Human Integrative Physiology, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Division of Cardiovascular Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
| | - Pouneh K Fazeli
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Human Integrative Physiology, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Neuroendocrinology Unit, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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30
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McKimpson WM, Spiegel S, Mukhanova M, Kraakman M, Du W, Kitamoto T, Yu J, Deng Z, Pajvani U, Accili D. Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells. J Cell Biol 2024; 223:e202305093. [PMID: 38958606 PMCID: PMC11222742 DOI: 10.1083/jcb.202305093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 05/02/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024] Open
Abstract
Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.
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Affiliation(s)
- Wendy M. McKimpson
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Sophia Spiegel
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Maria Mukhanova
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Michael Kraakman
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Wen Du
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Takumi Kitamoto
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Junjie Yu
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Zhaobin Deng
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Utpal Pajvani
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Domenico Accili
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
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31
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Oudmaijer CAJ, Komninos DSJ, Hoeijmakers JHJ, IJzermans JNM, Vermeij WP. Clinical implications of nutritional interventions reducing calories, a systematic scoping review. Clin Nutr ESPEN 2024; 63:427-439. [PMID: 38986906 DOI: 10.1016/j.clnesp.2024.06.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND & AIMS Caloric restriction (CR) constitutes a dietary approach of (temporarily) reducing calorie intake thereby inducing resilience and resistance mechanisms and promoting health. While CR's feasibility and safety have been proven in human trials, its full benefits and translation to different study populations warrants further exploration. METHODS We here conducted a systematic scoping review adhering to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS Our search resulted in 3745 individual records, of which 40 were included. We showed that all studies consistently demonstrated the feasibility and safety of CR-like interventions. The specific effects of nutritional preconditioning vary, further underscoring the need for carefully crafted strategies, according to the intended effect, patient population, and logistical limitations. CONCLUSIONS CR-like interventions (long-term CR or short-term fasting) are feasible in a broad range of patient populations. Whether it has clinical benefit, f.i. reducing treatment-induced side effects and enhancing therapy efficacy, has to be investigated further.
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Affiliation(s)
- C A J Oudmaijer
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Erasmus MC Transplant Institute, Division of Hepatobiliary and Transplantation Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
| | - D S J Komninos
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
| | - J H J Hoeijmakers
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Oncode Institute, Utrecht, The Netherlands; Erasmus MC Cancer Institute, Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, The Netherlands; Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
| | - J N M IJzermans
- Erasmus MC Transplant Institute, Division of Hepatobiliary and Transplantation Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - W P Vermeij
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
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32
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Suda M, Paul KH, Tripathi U, Minamino T, Tchkonia T, Kirkland JL. Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction. Endocr Rev 2024; 45:655-675. [PMID: 38500373 PMCID: PMC11405506 DOI: 10.1210/endrev/bnae010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 01/11/2024] [Accepted: 03/12/2024] [Indexed: 03/20/2024]
Abstract
Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type 2 diabetes mellitus. Drugs that selectively induce senescent cell removal, "senolytics,", and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, "senomorphics," appear to delay the onset of or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. More than 30 clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.
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Affiliation(s)
- Masayoshi Suda
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Karl H Paul
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Pharmacology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
| | - Utkarsh Tripathi
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
- Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan
| | - Tamara Tchkonia
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - James L Kirkland
- Departments of Medicine and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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33
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Ege T, Tao L, North BJ. The Role of Molecular and Cellular Aging Pathways on Age-Related Hearing Loss. Int J Mol Sci 2024; 25:9705. [PMID: 39273652 PMCID: PMC11396656 DOI: 10.3390/ijms25179705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 08/27/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Aging, a complex process marked by molecular and cellular changes, inevitably influences tissue and organ homeostasis and leads to an increased onset or progression of many chronic diseases and conditions, one of which is age-related hearing loss (ARHL). ARHL, known as presbycusis, is characterized by the gradual and irreversible decline in auditory sensitivity, accompanied by the loss of auditory sensory cells and neurons, and the decline in auditory processing abilities associated with aging. The extended human lifespan achieved by modern medicine simultaneously exposes a rising prevalence of age-related conditions, with ARHL being one of the most significant. While our understanding of the molecular basis for aging has increased over the past three decades, a further understanding of the interrelationship between the key pathways controlling the aging process and the development of ARHL is needed to identify novel targets for the treatment of AHRL. The dysregulation of molecular pathways (AMPK, mTOR, insulin/IGF-1, and sirtuins) and cellular pathways (senescence, autophagy, and oxidative stress) have been shown to contribute to ARHL. However, the mechanistic basis for these pathways in the initiation and progression of ARHL needs to be clarified. Therefore, understanding how longevity pathways are associated with ARHL will directly influence the development of therapeutic strategies to treat or prevent ARHL. This review explores our current understanding of the molecular and cellular mechanisms of aging and hearing loss and their potential to provide new approaches for early diagnosis, prevention, and treatment of ARHL.
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Affiliation(s)
| | - Litao Tao
- Biomedical Sciences Department, School of Medicine, Creighton University, Omaha, NE 68178, USA;
| | - Brian J. North
- Biomedical Sciences Department, School of Medicine, Creighton University, Omaha, NE 68178, USA;
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Fontana A, Kyriazis M. How evolution makes us age: Introducing the evolvable soma theory of ageing. Biosystems 2024; 243:105271. [PMID: 39038529 DOI: 10.1016/j.biosystems.2024.105271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 06/17/2024] [Accepted: 07/11/2024] [Indexed: 07/24/2024]
Abstract
At any moment in time, evolution is faced with a formidable challenge: refining the already highly optimised design of biological species, a feat accomplished through all preceding generations. In such a scenario, the impact of random changes (the method employed by evolution) is much more likely to be harmful than advantageous, potentially lowering the reproductive fitness of the affected individuals. Our hypothesis is that ageing is, at least in part, caused by the cumulative effect of all the experiments carried out by evolution to improve a species' design. These experiments are almost always unsuccessful, as expected given their pseudorandom nature, cause harm to the body and ultimately lead to death. This hypothesis is consistent with the concept of "terminal addition", by which nature is biased towards adding innovations at the end of development. From the perspective of evolution as an optimisation algorithm, ageing is advantageous as it allows to test innovations during a phase when their impact on fitness is present but less pronounced. Our inference suggests that ageing has a key biological role, as it contributes to the system's evolvability by exerting a regularisation effect on the fitness landscape of evolution.
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Viña J, Borrás C. Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan. FEBS Lett 2024; 598:2135-2144. [PMID: 38956807 DOI: 10.1002/1873-3468.14963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/04/2024]
Abstract
In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well-being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.
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Affiliation(s)
- Jose Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), Institute of Health Research-INCLIVA, University of Valencia, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), Institute of Health Research-INCLIVA, University of Valencia, Spain
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36
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Vitantonio AT, Dimovasili C, Mortazavi F, Vaughan KL, Mattison JA, Rosene DL. Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain. Neurobiol Aging 2024; 141:1-13. [PMID: 38788462 DOI: 10.1016/j.neurobiolaging.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 04/29/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024]
Abstract
Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain.
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Affiliation(s)
- Ana T Vitantonio
- Boston University Chobanian and Avedisian School of Medicine, Department of Pharmacology, Physiology, and Biophysics, 700 Albany St., Room 308, Boston, MA 02118, USA; Boston University Chobanian and Avedisian School of Medicine, Department of Anatomy & Neurobiology, 72 East Concord St, Room L1004, Boston, MA 02118, USA.
| | - Christina Dimovasili
- Boston University Chobanian and Avedisian School of Medicine, Department of Anatomy & Neurobiology, 72 East Concord St, Room L1004, Boston, MA 02118, USA
| | - Farzad Mortazavi
- Boston University Chobanian and Avedisian School of Medicine, Department of Anatomy & Neurobiology, 72 East Concord St, Room L1004, Boston, MA 02118, USA
| | - Kelli L Vaughan
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
| | - Julie A Mattison
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
| | - Douglas L Rosene
- Boston University Chobanian and Avedisian School of Medicine, Department of Anatomy & Neurobiology, 72 East Concord St, Room L1004, Boston, MA 02118, USA; Boston University, Center for Systems Neuroscience, 610 Commonwealth Ave., 7th Floor, Boston, MA 02215, USA
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Navakkode S, Kennedy BK. Neural ageing and synaptic plasticity: prioritizing brain health in healthy longevity. Front Aging Neurosci 2024; 16:1428244. [PMID: 39161341 PMCID: PMC11330810 DOI: 10.3389/fnagi.2024.1428244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 07/24/2024] [Indexed: 08/21/2024] Open
Abstract
Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve. Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activity-dependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important. In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity.
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Affiliation(s)
- Sheeja Navakkode
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, Centre for Healthy Longevity, National University Health System, National University of Singapore, Singapore, Singapore
- Life Sciences Institute Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - Brian K. Kennedy
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, Centre for Healthy Longevity, National University Health System, National University of Singapore, Singapore, Singapore
- Life Sciences Institute Neurobiology Programme, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Departments of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Buck Institute for Research on Ageing, Novato, CA, United States
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38
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Pergande MR, Osterbauer KJ, Buck KM, Roberts DS, Wood NN, Balasubramanian P, Mann MW, Rossler KJ, Diffee GM, Colman RJ, Anderson RM, Ge Y. Mass Spectrometry-Based Multiomics Identifies Metabolic Signatures of Sarcopenia in Rhesus Monkey Skeletal Muscle. J Proteome Res 2024; 23:2845-2856. [PMID: 37991985 PMCID: PMC11109024 DOI: 10.1021/acs.jproteome.3c00474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Sarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in "omics" technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offers new insights into the molecular mechanisms underlying sarcopenia for the evaluation and monitoring of a therapeutic treatment of sarcopenia.
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Affiliation(s)
- Melissa R. Pergande
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Katie J. Osterbauer
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kevin M. Buck
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - David S. Roberts
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Nina N. Wood
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | | | - Morgan W. Mann
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kalina J. Rossler
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Gary M. Diffee
- Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Ricki J. Colman
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Rozalyn M. Anderson
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
| | - Ying Ge
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
- Human Proteomics Program, University of Wisconsin-Madison, Madison, WI 53705, USA
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Tizazu AM. Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging. Aging Med (Milton) 2024; 7:499-509. [PMID: 39234195 PMCID: PMC11369340 DOI: 10.1002/agm2.12342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/31/2024] [Indexed: 09/06/2024] Open
Abstract
Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored. Identifying the effect of fasting and CR on the immune system and how it modulates different parameters of immunosenescence could be important in designing pharmacological or nutritional interventions that slow or revert immunosenescence and strengthen the immune system of elderly individuals. Furthermore, clinical intervention can also be planned, by incorporating fasting or CR with medication, chemotherapy, and vaccination regimes. This review discusses age-associated changes in the immune system and how these changes are modified by fasting and CR which add information on interventions that promote healthy aging and longevity in the growing aging population.
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Affiliation(s)
- Anteneh Mehari Tizazu
- Department of Microbiology, Immunology, and Parasitology, School of MedicineSt. Paul's Hospital Millennium Medical CollegeAddis AbabaEthiopia
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40
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Zocher S. Targeting neuronal epigenomes for brain rejuvenation. EMBO J 2024; 43:3312-3326. [PMID: 39009672 PMCID: PMC11329789 DOI: 10.1038/s44318-024-00148-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/21/2024] [Accepted: 05/28/2024] [Indexed: 07/17/2024] Open
Abstract
Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain.
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Affiliation(s)
- Sara Zocher
- German Center for Neurodegenerative Diseases, Tatzberg 41, 01307, Dresden, Germany.
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41
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Yu Z, Zhou Y, Mao K, Pang B, Wang K, Jin T, Zheng H, Zhai H, Wang Y, Xu X, Liu H, Wang Y, Han JDJ. Thermal facial image analyses reveal quantitative hallmarks of aging and metabolic diseases. Cell Metab 2024; 36:1482-1493.e7. [PMID: 38959862 DOI: 10.1016/j.cmet.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 03/19/2024] [Accepted: 05/22/2024] [Indexed: 07/05/2024]
Abstract
Although human core body temperature is known to decrease with age, the age dependency of facial temperature and its potential to indicate aging rate or aging-related diseases remains uncertain. Here, we collected thermal facial images of 2,811 Han Chinese individuals 20-90 years old, developed the ThermoFace method to automatically process and analyze images, and then generated thermal age and disease prediction models. The ThermoFace deep learning model for thermal facial age has a mean absolute deviation of about 5 years in cross-validation and 5.18 years in an independent cohort. The difference between predicted and chronological age is highly associated with metabolic parameters, sleep time, and gene expression pathways like DNA repair, lipolysis, and ATPase in the blood transcriptome, and it is modifiable by exercise. Consistently, ThermoFace disease predictors forecast metabolic diseases like fatty liver with high accuracy (AUC > 0.80), with predicted disease probability correlated with metabolic parameters.
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Affiliation(s)
- Zhengqing Yu
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Yong Zhou
- Clinical Research Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kehang Mao
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Bo Pang
- Clinical Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kai Wang
- International Center for Aging and Cancer (ICAC), Hainan Medical University, Haikou, China
| | - Tang Jin
- International Center for Aging and Cancer (ICAC), Hainan Medical University, Haikou, China
| | - Haonan Zheng
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Haotian Zhai
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Yiyang Wang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China
| | - Xiaohan Xu
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongxiao Liu
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Wang
- Kailuan Majiagou Hospital, Tangshan, Hebei Province, China
| | - Jing-Dong J Han
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing, China; International Center for Aging and Cancer (ICAC), Hainan Medical University, Haikou, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, China.
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42
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Reddy BL, Reddy VS, Saier MH. Health Benefits of Intermittent Fasting. Microb Physiol 2024; 34:142-152. [PMID: 38955141 PMCID: PMC11262566 DOI: 10.1159/000540068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/27/2024] [Indexed: 07/04/2024]
Abstract
We propose that intermittent fasting (time-restricted eating), in agreement with the conclusions of other biologists, as revealed in recent publications, promotes the achievement of numerous health benefits including the extension of human and animal lifespans. Background: There is evidence, obtained both with animal model systems and with humans, that intermittent fasting has health benefits. These benefits include extended longevity, weight loss, and counteracting various disease conditions. Such procedures positively influence the benefits of human tissue-specific microbiomes and minimize the consequences of organellar apoptosis. Key Messages: In this review, we attempt to summarize the predominant evidence, published in the scientific literature, relevant to the conclusions that in general, and in many specific instances, intermittent fasting has long-term benefits to animals, including humans, with respect to overall and specific organismal health and longevity.
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Affiliation(s)
- B. Lakshmi Reddy
- Department of Molecular Biology, University of California at San Diego 9500 Gilman Dr. La Jolla, CA 92093-0116 USA
| | | | - Milton H. Saier
- Department of Molecular Biology, University of California at San Diego 9500 Gilman Dr. La Jolla, CA 92093-0116 USA
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43
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Kidd RL, Agyemang-Prempeh A, Sanderson A, Stuart C, Mahajan S, Verschuur CA, Newman TA. Longitudinal urinary neopterin is associated with hearing threshold change over time in independent older adults. Sci Rep 2024; 14:13685. [PMID: 38871776 DOI: 10.1038/s41598-024-64648-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 06/11/2024] [Indexed: 06/15/2024] Open
Abstract
Low-grade chronic inflammation is associated with many age-related conditions. Non-invasive methods to monitor low-grade chronic inflammation may improve the management of older people at risk of poorer outcomes. This longitudinal cohort study has determined baseline inflammation using neopterin volatility in monthly urine samples of 45 independent older adults (aged 65-75 years). Measurement of neopterin, an inflammatory metabolite, enabled stratification of individuals into risk categories based on how often in a 12-month period their neopterin level was raised. Hearing was measured (pure-tone audiometry) at baseline, 1 year and 3 years of the study. Results show that those in the highest risk category (neopterin raised greater than 50% of the time) saw greater deterioration, particularly in high-frequency, hearing. A one-way Welch's ANOVA showed a significant difference between the risk categories for change in high-frequency hearing (W (3, 19.6) = 9.164, p = 0.0005). Despite the study size and duration individuals in the highest risk category were more than twice as likely to have an additional age-related morbidity than those in the lowest risk category. We conclude that volatility of neopterin in urine may enable stratification of those at greatest risk of progression of hearing loss.
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Affiliation(s)
- Rachel L Kidd
- CES, Medicine, B85, University of Southampton, Southampton, SO17 1BJ, UK
| | - Akosua Agyemang-Prempeh
- ISVR, USAIS, FEPs, B19, University of Southampton, Southampton, SO17 1BJ, UK
- ENT Unit, Komfo Anokye Teaching Hospital, PO Box 1934, Kumasi, Ghana
| | - Alan Sanderson
- ISVR, USAIS, FEPs, B19, University of Southampton, Southampton, SO17 1BJ, UK
| | - Charlotte Stuart
- CES, Medicine, B85, University of Southampton, Southampton, SO17 1BJ, UK
| | - Sumeet Mahajan
- Institute of Life Sciences, B85, University of Southampton Highfield, Southampton, SO17 1BJ, UK
| | - Carl A Verschuur
- ISVR, USAIS, FEPs, B19, University of Southampton, Southampton, SO17 1BJ, UK
| | - Tracey A Newman
- CES, Medicine, B85, University of Southampton, Southampton, SO17 1BJ, UK.
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44
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Chmilar SL, Luzardo AC, Dutt P, Pawluk A, Thwaites VC, Laird RA. Caloric restriction extends lifespan in a clonal plant. Ecol Lett 2024; 27:e14444. [PMID: 38814322 DOI: 10.1111/ele.14444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/25/2024] [Accepted: 05/02/2024] [Indexed: 05/31/2024]
Abstract
When subjected to dietary caloric restriction (CR), individual animals often outlive well-fed conspecifics. Here, we address whether CR also extends lifespan in plants. Whereas caloric intake in animals comes from ingestion, in plants it derives from photosynthesis. Thus, factors that reduce photosynthesis, such as reduced light intensity, can induce CR. In two lab experiments investigating the aquatic macrophyte Lemna minor, we tracked hundreds of individuals longitudinally, with light intensity-and hence, CR-manipulated using neutral-density filters. In both experiments, CR dramatically increased lifespan through a process of temporal scaling. Moreover, the magnitude of lifespan extension accorded with the assumptions that (a) light intensity positively relates to photosynthesis following Michaelis-Menten kinetics, and (b) photosynthesis negatively relates to lifespan via a power law. Our results emphasize that CR-mediated lifespan extension applies to autotrophs as well as heterotrophs, and suggest that variation in light intensity has quantitatively predictable effects on plant aging trajectories.
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Affiliation(s)
- Suzanne L Chmilar
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Amanda C Luzardo
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Priyanka Dutt
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Abbe Pawluk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Victoria C Thwaites
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Robert A Laird
- Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada
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45
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Nguyen NTA, Jiang Y, McQuade JL. Eating away cancer: the potential of diet and the microbiome for shaping immunotherapy outcome. Front Immunol 2024; 15:1409414. [PMID: 38873602 PMCID: PMC11169628 DOI: 10.3389/fimmu.2024.1409414] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/14/2024] [Indexed: 06/15/2024] Open
Abstract
The gut microbiome (GMB) plays a substantial role in human health and disease. From affecting gut barrier integrity to promoting immune cell differentiation, the GMB is capable of shaping host immunity and thus oncogenesis and anti-cancer therapeutic response, particularly with immunotherapy. Dietary patterns and components are key determinants of GMB composition, supporting the investigation of the diet-microbiome-immunity axis as a potential avenue to enhance immunotherapy response in cancer patients. As such, this review will discuss the role of the GMB and diet on anti-cancer immunity. We demonstrate that diet affects anti-cancer immunity through both GMB-independent and GMB-mediated mechanisms, and that different diet patterns mold the GMB's functional and taxonomic composition in distinctive ways. Dietary modulation therefore shows promise as an intervention for improving cancer outcome; however, further and more extensive research in human cancer populations is needed.
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Affiliation(s)
| | | | - Jennifer L. McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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46
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Chen M, Tan J, Jin Z, Jiang T, Wu J, Yu X. Research progress on Sirtuins (SIRTs) family modulators. Biomed Pharmacother 2024; 174:116481. [PMID: 38522239 DOI: 10.1016/j.biopha.2024.116481] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024] Open
Abstract
Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions.
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Affiliation(s)
- Mingkai Chen
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Junfei Tan
- School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zihan Jin
- Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou City, China
| | - Tingting Jiang
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Jiabiao Wu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Xiaolong Yu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China.
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47
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Missong H, Joshi R, Khullar N, Thareja S, Navik U, Bhatti GK, Bhatti JS. Nutrient-epigenome interactions: Implications for personalized nutrition against aging-associated diseases. J Nutr Biochem 2024; 127:109592. [PMID: 38325612 DOI: 10.1016/j.jnutbio.2024.109592] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/09/2024]
Abstract
Aging is a multifaceted process involving genetic and environmental interactions often resulting in epigenetic changes, potentially leading to aging-related diseases. Various strategies, like dietary interventions and calorie restrictions, have been employed to modify these epigenetic landscapes. A burgeoning field of interest focuses on the role of microbiota in human health, emphasizing system biology and computational approaches. These methods help decipher the intricate interplay between diet and gut microbiota, facilitating the creation of personalized nutrition strategies. In this review, we analysed the mechanisms related to nutritional interventions while highlighting the influence of dietary strategies, like calorie restriction and intermittent fasting, on microbial composition and function. We explore how gut microbiota affects the efficacy of interventions using tools like multi-omics data integration, network analysis, and machine learning. These tools enable us to pinpoint critical regulatory elements and generate individualized models for dietary responses. Lastly, we emphasize the need for a deeper comprehension of nutrient-epigenome interactions and the potential of personalized nutrition informed by individual genetic and epigenetic profiles. As knowledge and technology advance, dietary epigenetics stands on the cusp of reshaping our strategy against aging and related diseases.
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Affiliation(s)
- Hemi Missong
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Riya Joshi
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab, India
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India.
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48
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Stephens EB, Senadheera C, Roa-Diaz S, Peralta S, Alexander L, Silverman-Martin W, Yukawa M, Morris J, Johnson JB, Newman JC, Stubbs BJ. A randomized open-label, observational study of the novel ketone ester, bis octanoyl (R)-1,3-butanediol, and its acute effect on ß-hydroxybutyrate and glucose concentrations in healthy older adults. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.04.16.24305925. [PMID: 38699344 PMCID: PMC11065008 DOI: 10.1101/2024.04.16.24305925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentrations rapidly after ingestion. KE is hypothesized to have beneficial metabolic effects on health and performance, especially in older adults. Whilst many studies have investigated the ketogenic effect of KE in young adults, they have not been studied in an exclusively older adult population, for whom age-related differences in body composition and metabolism may alter the effects. This randomized, observational, open-label study in healthy older adults (n = 30, 50% male, age = 76.5 years, BMI = 25.2 kg/m2) aimed to elucidate acute tolerance, blood BHB and blood glucose concentrations for 4 hours following consumption of either 12.5 or 25 g of BO-BD formulated firstly as a ready-to-drink beverage (n = 30), then as a re-constituted powder (n = 21), taken with a standard meal. Both serving sizes and formulations of BO-BD were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥ 0.5mM) that lasted until the end of the study. Ketosis was dose responsive; peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 g compared to 12.5 g of BO-BD in both formulations. There were no significant differences in Cmax or iAUC between formulations. Blood glucose increased in all conditions following the meal; there were no consistent significant differences in glucose response between conditions. These results demonstrate that both powder and beverage formulations of the novel KE, BO-BD, induce ketosis in healthy older adults, facilitating future research on functional effects of this ingredient in aging.
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Affiliation(s)
| | | | | | | | | | | | - Michi Yukawa
- Veteran’s Affairs Medical Center, San Francisco, CA, USA
| | | | | | - John C. Newman
- Buck Institute for Research on Aging, Novato, CA, USA
- Division of Geriatrics, University of California, San Francisco, CA, USA
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49
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Brandhorst S, Longo VD. Exploring juventology: unlocking the secrets of youthspan and longevity programs. FRONTIERS IN AGING 2024; 5:1379289. [PMID: 38638872 PMCID: PMC11024265 DOI: 10.3389/fragi.2024.1379289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 03/20/2024] [Indexed: 04/20/2024]
Abstract
In recent decades, the study of biological aging has evolved from simplistic theories like the free radical theory to more complex and nuanced perspectives. In particular, the identification of evolutionary conserved genes and signaling pathways that can modulate both lifespan but also healthspan has resulted in the expanding understanding of the link between nutrients, signal transduction proteins, and aging along with substantial support for the existence of multiple "longevity programs," which are activated based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a longevity program characterized by cellular protection and optimized function, and the activation of regenerative processes that lead to rejuvenation. This review discusses the idea of juventology, a novel field proposing the existence of longevity programs that can maintain organisms in a highly functional state for extended periods of time. Drawing upon research on Saccharomyces cerevisiae and other model organisms, the review explores the distinctiveness of juventology from traditional aging-centered views. The focus on the "age of youth" challenges conventional thinking and opens new avenues for understanding and extending the period of peak functionality in organisms. Thus, a "juventology"-based strategy can complement the traditional gerontology approach by focusing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully functional.
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Affiliation(s)
- Sebastian Brandhorst
- Leonard Davis School of Gerontology, Longevity Institute, University of Southern California, Los Angeles, CA, United States
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50
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Phua QH, Ng SY, Soh BS. Mitochondria: A Potential Rejuvenation Tool against Aging. Aging Dis 2024; 15:503-516. [PMID: 37815912 PMCID: PMC10917551 DOI: 10.14336/ad.2023.0712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/12/2023] [Indexed: 10/12/2023] Open
Abstract
Aging is a complex physiological process encompassing both physical and cognitive decline over time. This intricate process is governed by a multitude of hallmarks and pathways, which collectively contribute to the emergence of numerous age-related diseases. In response to the remarkable increase in human life expectancy, there has been a substantial rise in research focusing on the development of anti-aging therapies and pharmacological interventions. Mitochondrial dysfunction, a critical factor in the aging process, significantly impacts overall cellular health. In this extensive review, we will explore the contemporary landscape of anti-aging strategies, placing particular emphasis on the promising potential of mitotherapy as a ground-breaking approach to counteract the aging process. Moreover, we will investigate the successful application of mitochondrial transplantation in both animal models and clinical trials, emphasizing its translational potential. Finally, we will discuss the inherent challenges and future possibilities of mitotherapy within the realm of aging research and intervention.
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Affiliation(s)
- Qian Hua Phua
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Proteos, Singapore.
- Department of Biological Sciences, National University of Singapore, Singapore.
| | - Shi Yan Ng
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Proteos, Singapore.
- National University of Singapore, Yong Loo Lin School of Medicine (Department of Physiology), Singapore.
- National Neuroscience Institute, Singapore.
| | - Boon-Seng Soh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Proteos, Singapore.
- Department of Biological Sciences, National University of Singapore, Singapore.
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