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Karmakar A, Augustine ABHR, Thummer RP. Genes as Genome Stabilizers in Pluripotent Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40095244 DOI: 10.1007/5584_2025_853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Pluripotent stem cells, comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are characterized by their self-renewal capacity and the ability to differentiate into cells of all three germ layers of an adult animal. Out of the two, iPSCs are generated through the reprogramming of somatic cells by inducing a pluripotency-specific transcriptional program. This process requires a resetting of the somatic cell genome to a pluripotent cell-specific genome, resulting in cellular stress at genomic, epigenetic, and transcriptional levels. Notably, in contrast to the predominant compact and inactive organization of chromatin in somatic cells, the chromatin in ESCs and iPSCs is open. Furthermore, maintaining a pluripotent state needs a plethora of changes in the genetic landscape of the cells. Here, we attempt to elucidate how certain genes safeguard genomic stability in ESCs and iPSCs, aiding in the complex cellular mechanisms that regulate self-renewal, pluripotency, and somatic reprogramming.
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Affiliation(s)
- Asmita Karmakar
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Allan Blessing Harison Raj Augustine
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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2
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Otgaar TC, Bernert M, Morris G, Baichan P, Bignoux MJ, Letsolo B, Weiss SFT, Ferreira E. 37 kDa LRP::FLAG enhances telomerase activity and reduces ageing markers in vivo. Cell Mol Life Sci 2025; 82:83. [PMID: 39985566 PMCID: PMC11846807 DOI: 10.1007/s00018-025-05593-0] [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: 07/16/2024] [Revised: 12/30/2024] [Accepted: 01/13/2025] [Indexed: 02/24/2025]
Abstract
Ageing is a degenerative process characterised by a decline in physiological functioning of the organism. One of the core regulators of cellular ageing are telomeres, repetitive DNA sequences of TTAGGG that cap the ends of chromosomes and are maintained by the ribonucleoprotein complex, telomerase. Age-dependent progressive loss of the telomere ends eventually induces cell cycle arrest for the induction of either replicative senescence or apoptosis. It was previously established that overexpression of the 37 kDa/ 67 kDa laminin receptor (LRP/LR) increased telomerase activity and telomere length while concomitantly reducing senescence markers in aged normal cells in vitro. Therefore, it was hypothesized that elevating LRP/LR in vivo may increase telomerase activity and hinder the ageing process on an organism scale. To this end, aged C57BL/6J mice were treated/transfected to induce an overexpression of LRP::FLAG. Various physiological tests and histological analyses were performed to assess overall organism fitness as well as to discern the treatments' ability at reducing tissue degeneration and atrophy. It was found that mice overexpressing LRP::FLAG displayed improved physiological characteristics and markedly less tissue degeneration and atrophy when compared to control and non-treated mice. Alongside these improvements, certain organs displayed increased telomerase activity with a corresponding elongation in average telomere length. In addition the overexpression of LRP::FLAG significantly improved various proliferative and anti-ageing associated proteins while causing a concomitant decrease in senescence associated proteins. These findings are therefore indicative of a novel function of LRP/LR delaying the onset of senescence, while also promoting healthier ageing through elevating TERT and telomerase activity.
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Affiliation(s)
- Tyrone C Otgaar
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Martin Bernert
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Gavin Morris
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Pavan Baichan
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Monique J Bignoux
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Boitelo Letsolo
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Stefan F T Weiss
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa
| | - Eloise Ferreira
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, Republic of South Africa.
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Fan Z, Wei X, Zhu X, Du Y. Sirtuins in kidney homeostasis and disease: where are we now? Front Endocrinol (Lausanne) 2025; 15:1524674. [PMID: 39911234 PMCID: PMC11794115 DOI: 10.3389/fendo.2024.1524674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
Sirtuins, identified as (NAD+)- dependent class III histone deacetylases, engage in a spectrum of biological functions, encompassing DNA damage repair, oxidative stress, immune modulation, mitochondrial homeostasis, apoptosis and autophagy. Sirtuins play an apoptosis role in regulating cellular operations and overall organism health. Mounting data indicate that dysregulated sirtuin expression is linked to the onset of renal diseases. Effective modulation of sirtuins expression and activity has been shown to improve renal function and attenuate the advancement of kidney diseases. In this review, we present a comprehensive overview of the biological impacts of sirtuins and their molecular targets in regulating renal diseases. Additionally, we detail advancements in elucidating sirtuin roles in the pathophysiology of both chronic and acute renal disorders. We review compounds that modulate sirtuin activity through activation or inhibition, potentially improving outcomes in renal disease. In summary, strategic manipulation of sirtuin activity represents a prospective therapeutic approach for renal diseases.
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Affiliation(s)
| | | | | | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
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Mani AK, Parvathi VD, Ravindran S. The Anti-Elixir Triad: Non-Synced Circadian Rhythm, Gut Dysbiosis, and Telomeric Damage. Med Princ Pract 2024:1-14. [PMID: 39536739 DOI: 10.1159/000542557] [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: 06/08/2024] [Accepted: 11/11/2024] [Indexed: 11/16/2024] Open
Abstract
Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells) reaches the limit of its ability to replicate, known as cellular or replicative senescence, and consequently, the organs lose their physiological functions, resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary lifestyle, and genetic abnormalities. These stress factors can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of the effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and the gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome, and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.
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Affiliation(s)
- Anup Kumar Mani
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Venkatachalam Deepa Parvathi
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Sumitha Ravindran
- Department of Biomedical Sciences, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
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Cheng CK, Ye L, Zuo Y, Wang Y, Wang L, Li F, Chen S, Huang Y. Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice. Antioxidants (Basel) 2024; 13:1250. [PMID: 39456503 PMCID: PMC11505429 DOI: 10.3390/antiox13101250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/12/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Aging, an independent risk factor for cardiometabolic diseases, refers to a progressive deterioration in physiological function, characterized by 12 established hallmarks. Vascular aging is driven by endothelial dysfunction, telomere dysfunction, oxidative stress, and vascular inflammation. This study investigated whether aged gut microbiome promotes vascular aging and metabolic impairment. Fecal microbiome transfer (FMT) was conducted from aged (>75 weeks old) to young C57BL/6 mice (8 weeks old) for 6 weeks. Wire myography was used to evaluate endothelial function in aortas and mesenteric arteries. ROS levels were measured by dihydroethidium (DHE) staining and lucigenin-enhanced chemiluminescence. Vascular and intestinal telomere function, in terms of relative telomere length, telomerase reverse transcriptase expression and telomerase activity, were measured. Systemic inflammation, endotoxemia and intestinal integrity of mice were assessed. Gut microbiome profiles were studied by 16S rRNA sequencing. Some middle-aged mice (40-42 weeks old) were subjected to chronic metformin treatment and exercise training for 4 weeks to evaluate their anti-aging benefits. Six-week FMT impaired glucose homeostasis and caused vascular dysfunction in aortas and mesenteric arteries in young mice. FMT triggered vascular inflammation and oxidative stress, along with declined telomerase activity and shorter telomere length in aortas. Additionally, FMT impaired intestinal integrity, and triggered AMPK inactivation and telomere dysfunction in intestines, potentially attributed to the altered gut microbial profiles. Metformin treatment and moderate exercise improved integrity, AMPK activation and telomere function in mouse intestines. Our data highlight aged microbiome as a mechanism that accelerates intestinal and vascular aging, suggesting the gut-vascular connection as a potential intervention target against cardiovascular aging and complications.
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Affiliation(s)
- Chak-Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
| | - Lianwei Ye
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong SAR, China; (L.Y.); (F.L.)
| | - Yuanyuan Zuo
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China;
| | - Yaling Wang
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR, China; (Y.W.); (S.C.)
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
| | - Fuyong Li
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong SAR, China; (L.Y.); (F.L.)
| | - Sheng Chen
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR, China; (Y.W.); (S.C.)
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
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Teramoto N, Okada Y, Aburada N, Hayashi M, Ito J, Shirasuna K, Iwata H. Resveratrol intake by males increased the mitochondrial DNA copy number and telomere length of blastocysts derived from aged mice. J Reprod Dev 2024; 70:247-253. [PMID: 38945863 PMCID: PMC11310382 DOI: 10.1262/jrd.2024-043] [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: 04/26/2024] [Accepted: 06/03/2024] [Indexed: 07/02/2024] Open
Abstract
The present study examined whether male resveratrol intake affected mitochondrial DNA copy number (mt-cn) and telomere length (TL) in blastocysts fathered by young and aged male mice. C57BL/6N male mice supplied with water or water containing 0.1 mM resveratrol were used for embryo production at 14-23 and 48-58 weeks of age. Two-cell-stage embryos were collected from the oviducts of superovulated female mice (8-15 weeks old) and cultured for 3 days until the blastocyst stage. Mt-cn and TL levels were measured by real-time polymerase chain reaction. Resveratrol intake did not affect body weight or water consumption. Resveratrol intake increased the expression levels of SIRT1 in the liver, the antioxidative ability of serum, and extended TL in the heart, whereas there was no significant difference in mt-cn in the heart or TL in sperm. The rate of blastocyst development was significantly lower in aged male mice than in younger mice, and resveratrol intake increased the total number of blastocysts derived from both young and aged males. Resveratrol intake did not affect mt-cn or TL in blastomeres of blastocyst-stage embryos derived from young mice, but significantly increased both mt-cn and TL in blastomeres of blastocysts derived from aged fathers. In conclusion, resveratrol intake increased mt-cn and TL levels in blastocysts derived from aged male mice.
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Affiliation(s)
- Noko Teramoto
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Yuri Okada
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Nao Aburada
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Masamune Hayashi
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Jun Ito
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Komei Shirasuna
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Hisataka Iwata
- Department of Animal Science, Tokyo University of Agriculture, Tokyo 156-8502, Japan
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Lee SE, Lee SB, Roh JI, Kim KP, Lee JH, Lee HW. SIRT1 regulates the localization and stability of telomerase protein by direct interaction. Biochem Biophys Res Commun 2024; 720:150098. [PMID: 38749190 DOI: 10.1016/j.bbrc.2024.150098] [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: 03/31/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 06/05/2024]
Abstract
Telomerase reverse transcriptase (TERT) not only upholds telomeric equilibrium but also plays a pivotal role in multiple non-canonical cellular mechanisms, particularly in the context of aging, cancer, and genomic stability. Though depletion of SIRT1 in mouse embryonic fibroblasts has demonstrated telomere shortening, the impact of SIRT1 on enabling TERT to regulate telomeric homeostasis remains enigmatic. Here, we reveal that SIRT1 directly interacts with TERT, and promotes the nuclear localization and stability of TERT. Reverse transcriptase (RT) domain of TERT and N-terminus of SIRT1 mainly participated in their direct interaction. TERT, concomitantly expressed with intact SIRT1, exhibits nuclear localization, whereas TERT co-expressed with N-terminal-deleted SIRT1 remains in the cytosol. Furthermore, overexpression of SIRT1 enhances the nuclear localization and protein stability of TERT, akin to overexpression of deacetylase-inactive SIRT1, whereas N-terminal-deleted SIRT1 has no effect on TERT. These findings suggest a novel regulatory role of SIRT1 for TERT through direct interaction. This interaction provides new insights into the fields of aging, cancer, and genome stability governed by TERT and SIRT1.
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Affiliation(s)
- Seung Eon Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
| | - Su Bin Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
| | - Jae-Il Roh
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea; ReCerise Therapeutics Inc., 400-12, Yangcheon-ro, Gangseo-gu, Seoul, 07573, Republic of Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin-si, 17104, Gyeonggi-do, Republic of Korea
| | - Jae Hoon Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea; GEMCRO, Inc., Seoul, 03722, Republic of Korea.
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea; GEMCRO, Inc., Seoul, 03722, Republic of Korea.
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Zhang L, Pang B, Wang R, Yang B, Jia X. Nesfatin-1 attenuated lipopolysaccharide-induced inflammatory response and senescence in human dental pulp cells. Heliyon 2024; 10:e32108. [PMID: 38975143 PMCID: PMC11226773 DOI: 10.1016/j.heliyon.2024.e32108] [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: 02/10/2023] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 07/09/2024] Open
Abstract
Lipopolysaccharide (LPS)-triggered damage in human dental pulp cells (hDPCs) is associated with the progression of gingivitis, which is inflammation of the gingival tissue. Nesfatin-1 is a peptide secreted by neurons and peripheral tissues. Here, we report a novel property of Nesfatin-1 in ameliorating LPS-induced inflammatory response and senescence in hDPCs. First, we demonstrate that Nesfatin-1 repressed LPS-triggered expression of inflammatory factors. Secondly, Nesfatin-1 restored telomerase activity and the expression of human telomerase reverse transcriptase (hTERT) and telomeric repeat binding factor 2 (TERF2) against LPS. Senescence-associated β-galactosidase (SA-β-gal) staining assay revealed that Nesfatin-1 attenuated LPS-induced cellular senescence in hDPCs. We also found that Nesfatin-1 increased telomerase activity in LPS-challenged hDPCs. It is also shown that Nesfatin-1 reduced the expression of plasminogen activator inhibitor-1 (PAI-1) and p16. Additionally, LPS stimulation reduced the expression of SIRT1, which was rescued by Nesfatin-1. However, the silencing of sirtuin1 (SIRT1) abrogated the protective property of Nesfatin-1 in preventing cellular senescence, implying that the function of Nesfatin-1 is regulated by SIRT1. Taken together, our findings suggest that Nesfatin-1 might possess a protective effect against gingivitis.
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Affiliation(s)
- Lili Zhang
- Department of Stomatology, Shijingshan Teaching Hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing, 100043, China
| | - Bo Pang
- Department of Big Data, Computer Network Information Center, Chinese Academy of Sciences, Beijing, 100190, China
| | - Rong Wang
- Department of Stomatology, Shijingshan Teaching Hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing, 100043, China
| | - Bin Yang
- Department of Stomatology, Shijingshan Teaching Hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing, 100043, China
| | - Xubei Jia
- Department of Stomatology, Shijingshan Teaching Hospital of Capital Medical University, Beijing Shijingshan Hospital, Beijing, 100043, China
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Bonet ML, Ribot J, Sánchez J, Palou A, Picó C. Early Life Programming of Adipose Tissue Remodeling and Browning Capacity by Micronutrients and Bioactive Compounds as a Potential Anti-Obesity Strategy. Cells 2024; 13:870. [PMID: 38786092 PMCID: PMC11120104 DOI: 10.3390/cells13100870] [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: 04/09/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024] Open
Abstract
The early stages of life, especially the period from conception to two years, are crucial for shaping metabolic health and the risk of obesity in adulthood. Adipose tissue (AT) plays a crucial role in regulating energy homeostasis and metabolism, and brown AT (BAT) and the browning of white AT (WAT) are promising targets for combating weight gain. Nutritional factors during prenatal and early postnatal stages can influence the development of AT, affecting the likelihood of obesity later on. This narrative review focuses on the nutritional programming of AT features. Research conducted across various animal models with diverse interventions has provided insights into the effects of specific compounds on AT development and function, influencing the development of crucial structures and neuroendocrine circuits responsible for energy balance. The hormone leptin has been identified as an essential nutrient during lactation for healthy metabolic programming against obesity development in adults. Studies have also highlighted that maternal supplementation with polyunsaturated fatty acids (PUFAs), vitamin A, nicotinamide riboside, and polyphenols during pregnancy and lactation, as well as offspring supplementation with myo-inositol, vitamin A, nicotinamide riboside, and resveratrol during the suckling period, can impact AT features and long-term health outcomes and help understand predisposition to obesity later in life.
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Affiliation(s)
- M. Luisa Bonet
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
| | - Joan Ribot
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Juana Sánchez
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
| | - Andreu Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
| | - Catalina Picó
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Group of Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands, 07122 Palma, Spain; (M.L.B.); (J.S.); (A.P.); (C.P.)
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 28029 Madrid, Spain
- Artificial Intelligence Research Institute of the Balearic Islands (IAIB), University of the Balearic Islands, 07122 Palma, Spain
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10
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Ozturk S. The close relationship between oocyte aging and telomere shortening, and possible interventions for telomere protection. Mech Ageing Dev 2024; 218:111913. [PMID: 38307343 DOI: 10.1016/j.mad.2024.111913] [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: 10/16/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 02/04/2024]
Abstract
As women delay childbearing due to socioeconomic reasons, understanding molecular mechanisms decreasing oocyte quantity and quality during ovarian aging becomes increasingly important. The ovary undergoes biological aging at a higher pace when compared to other organs. As is known, telomeres play crucial roles in maintaining genomic integrity, and their shortening owing to increased reactive oxygen species, consecutive cellular divisions, genetic and epigenetic alterations is associated with loss of developmental competence of oocytes. Novel interventions such as antioxidant treatments and regulation of gene expression are being investigated to prevent or rescue telomere attrition and thereby oocyte aging. Herein, potential factors and molecular mechanisms causing telomere shortening in aging oocytes were comprehensively reviewed. For the purpose of extending reproductive lifespan, possible therapeutic interventions to protect telomere length were also discussed.
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Affiliation(s)
- Saffet Ozturk
- Department of Histology and Embryology, Akdeniz University School of Medicine, Antalya, Turkey.
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11
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Podgrajsek R, Ban Frangez H, Stimpfel M. Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility. Int J Mol Sci 2024; 25:3613. [PMID: 38612425 PMCID: PMC11011890 DOI: 10.3390/ijms25073613] [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: 02/27/2024] [Revised: 03/19/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.
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Affiliation(s)
- Rebeka Podgrajsek
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
| | - Helena Ban Frangez
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Martin Stimpfel
- Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (R.P.); (H.B.F.)
- Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
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12
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Jin Q, Ma F, Liu T, Yang L, Mao H, Wang Y, Peng L, Li P, Zhan Y. Sirtuins in kidney diseases: potential mechanism and therapeutic targets. Cell Commun Signal 2024; 22:114. [PMID: 38347622 PMCID: PMC10860260 DOI: 10.1186/s12964-023-01442-4] [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: 08/04/2023] [Accepted: 12/12/2023] [Indexed: 02/15/2024] Open
Abstract
Sirtuins, which are NAD+-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins are essential regulators of cellular function and organismal health. Increasing evidence suggests that the development of age-related diseases, including kidney diseases, is associated with aberrant expression of sirtuins, and that regulation of sirtuins expression and activity can effectively improve kidney function and delay the progression of kidney disease. In this review, we summarise current studies highlighting the role of sirtuins in renal diseases. First, we discuss sirtuin family members and their main mechanisms of action. We then outline the possible roles of sirtuins in various cell types in kidney diseases. Finally, we summarise the compounds that activate or inhibit sirtuin activity and that consequently ameliorate renal diseases. In conclusion, targeted modulation of sirtuins is a potential therapeutic strategy for kidney diseases. Video Abstract.
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Affiliation(s)
- Qi Jin
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fang Ma
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tongtong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Liping Yang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huimin Mao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuyang Wang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Liang Peng
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China.
| | - Ping Li
- China-Japan Friendship Hospital, Institute of Clinical Medical Sciences, Beijing, China.
| | - Yongli Zhan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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13
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Schellnegger M, Hofmann E, Carnieletto M, Kamolz LP. Unlocking longevity: the role of telomeres and its targeting interventions. FRONTIERS IN AGING 2024; 5:1339317. [PMID: 38333665 PMCID: PMC10850353 DOI: 10.3389/fragi.2024.1339317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/11/2024] [Indexed: 02/10/2024]
Abstract
Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.
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Affiliation(s)
- Marlies Schellnegger
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
| | - Elisabeth Hofmann
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
- Research Unit for Tissue Regeneration, Repair and Reconstruction, Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Martina Carnieletto
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
| | - Lars-Peter Kamolz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria
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14
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Dhillon VS, Shahid M, Deo P, Fenech M. Reduced SIRT1 and SIRT3 and Lower Antioxidant Capacity of Seminal Plasma Is Associated with Shorter Sperm Telomere Length in Oligospermic Men. Int J Mol Sci 2024; 25:718. [PMID: 38255792 PMCID: PMC10815409 DOI: 10.3390/ijms25020718] [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: 11/24/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Infertility affects millions of couples worldwide and has a profound impact not only on their families, but also on communities. Telomere attrition has been associated with infertility, DNA damage and fragmentation. Oxidative stress has been shown to affect sperm DNA integrity and telomere length. Sirtuins such as SIRT1 and SIRT3 are involved in aging and oxidative stress response. The aim of the present study is to determine the role of SIRT1 and SIRT3 in regulating oxidative stress, telomere shortening, and their association with oligospermia. Therefore, we assessed the protein levels of SIRT1 and SIRT3, total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase activity (CAT) in the seminal plasma of 272 patients with oligospermia and 251 fertile men. We also measured sperm telomere length (STL) and leukocyte telomere length (LTL) using a standard real-time quantitative PCR assay. Sperm chromatin and protamine deficiency were also measured as per standard methods. Our results for oligospermic patients demonstrate significant reductions in semen parameters, shorter STL and LTL, lower levels of SOD, TAC, CAT, SIRT1 and SIRT3 levels, and also significant protamine deficiency and higher levels of MDA and DNA fragmentation. We conclude that a shorter TL in sperms and leukocytes is associated with increased oxidative stress that also accounts for high levels of DNA fragmentation in sperms. Our results support the hypothesis that various sperm parameters in the state of oligospermia are associated with or caused by reduced levels of SIRT1 and SIRT3 proteins.
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Affiliation(s)
- Varinderpal S. Dhillon
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia; (P.D.); (M.F.)
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Permal Deo
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia; (P.D.); (M.F.)
| | - Michael Fenech
- Health and Biomedical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia; (P.D.); (M.F.)
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15
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Borsky P, Holmannova D, Andrys C, Kremlacek J, Fiala Z, Parova H, Rehacek V, Svadlakova T, Byma S, Kucera O, Borska L. Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho. Biogerontology 2023; 24:937-955. [PMID: 37523061 PMCID: PMC10615959 DOI: 10.1007/s10522-023-10054-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/14/2023] [Indexed: 08/01/2023]
Abstract
Aging is a natural process of gradual decrease in physical and mental capacity. Biological age (accumulation of changes and damage) and chronological age (years lived) may differ. Biological age reflects the risk of various types of disease and death from any cause. We selected potential biomarkers of aging - telomerase, AGEs, GDF11 and 15 (growth differentiation factor 11/15), sirtuin 1, NAD+ (nicotinamide adenine dinucleotide), inflammasome NLRP3, DNA/RNA damage, and klotho to investigate changes in their levels depending on age and sex. We included 169 healthy volunteers and divided them into groups according to age (under 35; 35-50; over 50) and sex (male, female; male and female under 35; 35-50, over 50). Markers were analyzed using commercial ELISA kits. We found differences in values depending on age and gender. GDF15 increased with age (under 30 and 35-50 p < 0.002; 35-50 and over 50; p < 0.001; under 35 and over 50; p < 0.001) as well as GDF11 (35-50 and over 50; p < 0.03; under 35 and over 50; p < 0.02), AGEs (under 30 and 35-50; p < 0.005), NLRP3 (under 35 over 50; p < 0.03), sirtuin 1 (35-50 and over 50; p < 0.0001; under 35 and over 50; p < 0.004). AGEs and GDF11 differed between males and females. Correlations were identified between individual markers, markers and age, and markers and sex. Markers that reflect the progression of biological aging vary with age (GDF15, GDF11, AGEs, NLRP3, sirtuin) and sex (AGEs, GDF11). Their levels could be used in clinical practice, determining biological age, risk of age-related diseases and death of all-causes, and initiating or contraindicating a therapy in the elderly based on the patient's health status.
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Affiliation(s)
- Pavel Borsky
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Drahomira Holmannova
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic.
| | - Ctirad Andrys
- Institute of Clinical Immunology and Allergology, University Hospital and Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Jan Kremlacek
- Institute of Medical Biophysics, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Zdenek Fiala
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Helena Parova
- Institute of Clinical Biochemistry and Diagnostics, University Hospital and Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Vit Rehacek
- Transfusion Center, University Hospital, 50003, Hradec Kralove, Czech Republic
| | - Tereza Svadlakova
- Institute of Clinical Immunology and Allergology, University Hospital and Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Svatopluk Byma
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Otto Kucera
- Institute of Physiology, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
| | - Lenka Borska
- Institute of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, 50003, Hradec Kralove, Czech Republic
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16
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Yang K, Hou R, Zhao J, Wang X, Wei J, Pan X, Zhu X. Lifestyle effects on aging and CVD: A spotlight on the nutrient-sensing network. Ageing Res Rev 2023; 92:102121. [PMID: 37944707 DOI: 10.1016/j.arr.2023.102121] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/12/2023] [Accepted: 11/04/2023] [Indexed: 11/12/2023]
Abstract
Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.
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Affiliation(s)
- Kaiying Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Rongyao Hou
- Department of Neurology, The Affiliated Hiser Hospital of Qingdao University, Qingdao 266000, China
| | - Jie Zhao
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xia Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jin Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
| | - Xiaoyan Zhu
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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17
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Qin B. Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review. Diabetes Metab Syndr Obes 2023; 16:3739-3750. [PMID: 38028989 PMCID: PMC10676684 DOI: 10.2147/dmso.s428560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 10/07/2023] [Indexed: 12/01/2023] Open
Abstract
The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.
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Affiliation(s)
- Baoding Qin
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
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18
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Sun C, Bai S, Liang Y, Liu D, Liao J, Chen Y, Zhao X, Wu B, Huang D, Chen M, Wu D. The role of Sirtuin 1 and its activators in age-related lung disease. Biomed Pharmacother 2023; 162:114573. [PMID: 37018986 DOI: 10.1016/j.biopha.2023.114573] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023] Open
Abstract
Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease.
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19
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Li H, Chen X, Zuo Z, Wang J, Guo Y. Identification and Characterization of Peptides from Bovine Collagen Hydrolysates that Promote Myogenic Cell Proliferation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:4876-4889. [PMID: 36917229 DOI: 10.1021/acs.jafc.2c08929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
In this study, bovine collagen hydrolysate was purified via a series of chromatograms, and the peptides with the highest activity for promoting myoblast proliferation were identified by LC-MS-MS. It was demonstrated that the peptide GDAGPPGPAGPAGPPGPIG (hydroxylation) could promote C2C12 proliferation (+18.5% ± 0.04, P < 0.05). The certain peptide was capable of regulating the myogenic cell cycle and inhibiting myogenic cell apoptosis. By combining molecular docking, quantitative real-time PCR, and metabonomics, we suggested that the peptide GDAGPPGPAGPAGPPGPIG (hydroxylation) might bind to FGFR1 and affect the expression of genes downstream of FGFR1 and influence protein synthesis to promote myoblast proliferation. The above results showed that the peptides isolated in this study have the potential to alleviate sarcopenia in the elderly.
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Affiliation(s)
- Hanfeng Li
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Yuquan Road 19A, Beijing 100049, China
| | - Xin Chen
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Yuquan Road 19A, Beijing 100049, China
| | - Zhijie Zuo
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Yuquan Road 19A, Beijing 100049, China
| | - Jianing Wang
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Yanchuan Guo
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Yuquan Road 19A, Beijing 100049, China
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20
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Opstad TB, Alexander J, Aaseth J, Larsson A, Seljeflot I, Alehagen U. Increased SIRT1 Concentration Following Four Years of Selenium and Q 10 Intervention Associated with Reduced Cardiovascular Mortality at 10-Year Follow-Up-Sub-Study of a Previous Prospective Double-Blind Placebo-Controlled Randomized Clinical Trial. Antioxidants (Basel) 2023; 12:antiox12030759. [PMID: 36979007 PMCID: PMC10045001 DOI: 10.3390/antiox12030759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/02/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Background: Selenium and coenzyme Q10 (SeQ10) possess antioxidant and anti-inflammatory properties, potentially mediated via Sirtuin1 (SIRT1). We aimed to investigate the influence of a SeQ10 intervention on SIRT1 concentration, with potential interactions with microRNAs. Methods: In this sub-study of a prospective double-blind placebo-controlled clinical trial, healthy subjects (mean age 76 years) were randomized to receive an active treatment (n = 165, combined 200 µg/day of Se and 200 mg/day of Q10) or a placebo (n = 161). SIRT1 concentration and microRNAs were measured with ELISA and PCR, respectively. Results: After four years, SIRT1 concentration was increased in the active treatment group, with mean (SD) ng/mL of 469 (436) vs. 252 (162), p < 0.001, and decreased in the placebo group, 190 (186) vs. 269 (172), p = 0.002, and the differences between the groups were significant (p = 0.006, adjusted). Those who suffered CV death during a 10-year follow-up (n = 25 and n = 52 in the active treatment and placebo groups, respectively) had significantly lower baseline SIRT1 concentrations compared to the survivors (p < 0.001). MiR-130a-3p was significantly downregulated during the intervention and correlated inversely with SIRT1 at baseline (r = -0.466, p = 0.007). Conclusion: The increased SIRT1 concentration after the SeQ10 intervention associated with reduced CV mortality, partly mediated via miR-1303a-3p, suggests that SIRT1 is an additional mediator of the intervention, preventing vascular ageing.
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Affiliation(s)
- Trine Baur Opstad
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, P.O. Box 4950, Nydalen, N-0424 Oslo, Norway
- Faculty of Medicine, University of Oslo, N-0370 Oslo, Norway
| | - Jan Alexander
- Norwegian Institute of Public Health, P.O. Box 222, Skøyen, N-0213 Oslo, Norway
| | - Jan Aaseth
- Department of Research, Innlandet Hospital Trust, P.O. Box 104, N-2381 Brumunddal, Norway
- Faculty of Health and Social Sciences, Inland Norway University of Applied Sciences, N-2624 Lillehammer, Norway
| | - Anders Larsson
- Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Ingebjørg Seljeflot
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, P.O. Box 4950, Nydalen, N-0424 Oslo, Norway
- Faculty of Medicine, University of Oslo, N-0370 Oslo, Norway
| | - Urban Alehagen
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
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21
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Mormone E, Iorio EL, Abate L, Rodolfo C. Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming. Front Neurosci 2023; 17:1073689. [PMID: 36816109 PMCID: PMC9929468 DOI: 10.3389/fnins.2023.1073689] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/13/2023] [Indexed: 02/04/2023] Open
Abstract
Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation's steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency's reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD+-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere's chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.
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Affiliation(s)
- Elisabetta Mormone
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy,*Correspondence: Elisabetta Mormone, ;
| | | | - Lucrezia Abate
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carlo Rodolfo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy,Department of Paediatric Onco-Haematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy,Carlo Rodolfo,
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22
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Erenpreisa J, Giuliani A, Yoshikawa K, Falk M, Hildenbrand G, Salmina K, Freivalds T, Vainshelbaum N, Weidner J, Sievers A, Pilarczyk G, Hausmann M. Spatial-Temporal Genome Regulation in Stress-Response and Cell-Fate Change. Int J Mol Sci 2023; 24:2658. [PMID: 36769000 PMCID: PMC9917235 DOI: 10.3390/ijms24032658] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/17/2023] [Accepted: 01/22/2023] [Indexed: 02/04/2023] Open
Abstract
Complex functioning of the genome in the cell nucleus is controlled at different levels: (a) the DNA base sequence containing all relevant inherited information; (b) epigenetic pathways consisting of protein interactions and feedback loops; (c) the genome architecture and organization activating or suppressing genetic interactions between different parts of the genome. Most research so far has shed light on the puzzle pieces at these levels. This article, however, attempts an integrative approach to genome expression regulation incorporating these different layers. Under environmental stress or during cell development, differentiation towards specialized cell types, or to dysfunctional tumor, the cell nucleus seems to react as a whole through coordinated changes at all levels of control. This implies the need for a framework in which biological, chemical, and physical manifestations can serve as a basis for a coherent theory of gene self-organization. An international symposium held at the Biomedical Research and Study Center in Riga, Latvia, on 25 July 2022 addressed novel aspects of the abovementioned topic. The present article reviews the most recent results and conclusions of the state-of-the-art research in this multidisciplinary field of science, which were delivered and discussed by scholars at the Riga symposium.
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Affiliation(s)
| | - Alessandro Giuliani
- Istituto Superiore di Sanita Environment and Health Department, 00161 Roma, Italy
| | - Kenichi Yoshikawa
- Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0394, Japan
| | - Martin Falk
- Institute of Biophysics, The Czech Academy of Sciences, 612 65 Brno, Czech Republic
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
| | - Georg Hildenbrand
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
- Faculty of Engineering, University of Applied Science Aschaffenburg, 63743 Aschaffenburg, Germany
| | - Kristine Salmina
- Latvian Biomedicine Research and Study Centre, LV1067 Riga, Latvia
| | - Talivaldis Freivalds
- Institute of Cardiology and Regenerative Medicine, University of Latvia, LV1004 Riga, Latvia
| | - Ninel Vainshelbaum
- Latvian Biomedicine Research and Study Centre, LV1067 Riga, Latvia
- Doctoral Study Program, University of Latvia, LV1004 Riga, Latvia
| | - Jonas Weidner
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
| | - Aaron Sievers
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
- Institute for Human Genetics, University Hospital Heidelberg, 69117 Heidelberg, Germany
| | - Götz Pilarczyk
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
| | - Michael Hausmann
- Kirchhoff Institute for Physics, Heidelberg University, 69120 Heidelberg, Germany
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Sharma A, Mahur P, Muthukumaran J, Singh AK, Jain M. Shedding light on structure, function and regulation of human sirtuins: a comprehensive review. 3 Biotech 2023; 13:29. [PMID: 36597461 PMCID: PMC9805487 DOI: 10.1007/s13205-022-03455-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 12/25/2022] [Indexed: 01/01/2023] Open
Abstract
Sirtuins play an important role in signalling pathways associated with various metabolic regulations. They possess mono-ADP-ribosyltransferase or deacylase activity like demalonylase, deacetylase, depalmitoylase, demyristoylase and desuccinylase activity. Sirtuins are histone deacetylases which depends upon nicotinamide adenine dinucleotide (NAD) that deacetylate lysine residues. There are a total of seven human sirtuins that have been identified namely, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7. The subcellular location of mammalian sirtuins, SIRT1, SIRT6, and SIRT7 are in the nucleus; SIRT3, SIRT4, and SIRT5 are in mitochondria, and SIRT2 is in cytoplasm. Structurally sirtuins contains a N-terminal, a C-terminal and a Zn+ binding domain. The sirtuin family has been found to be crucial for maintaining lipid and glucose homeostasis, and also for regulating insulin secretion and sensitivity, DNA repair pathways, neurogenesis, inflammation, and ageing. Based on the literature, sirtuins are overexpressed and play an important role in tumorigenicity in various types of cancer such as non-small cell lung cancer, colorectal cancer, etc. In this review, we have discussed about the different types of human sirtuins along with their structural and functional features. We have also discussed about the various natural and synthetic regulators of sirtuin activities like resveratrol. Our overall study shows that the correct regulation of sirtuins can be a good target for preventing and treating various diseases for improving the human lifespan. To investigate the true therapeutic potential of sirtuin proteins and their efficacy in a variety of pathological diseases, a better knowledge of the link between the structure and function of sirtuin proteins would be necessary.
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Affiliation(s)
- Abhishek Sharma
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Pragati Mahur
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Jayaraman Muthukumaran
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Amit Kumar Singh
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
| | - Monika Jain
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
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24
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Grzeczka A, Kordowitzki P. Resveratrol and SIRT1: Antiaging Cornerstones for Oocytes? Nutrients 2022; 14:5101. [PMID: 36501130 PMCID: PMC9736670 DOI: 10.3390/nu14235101] [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: 10/12/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
It is well-known that there is an enormous variability in the aging-related decline of oocytes' quantity and their developmental competence among mammalian species. The implication of female germline aging is profound from the perspective of evolutionary conservation of the aging mechanism, a topic of continuous and widespread interest that has yet to be fully addressed for the mammalian oocyte. There is a certain need to develop novel antiaging strategies to delay or slow down aging, or even to reverse the aging phenotype in the oocyte. In the past two decades, several antioxidants have been tested for this purpose. Resveratrol is one of these latter-mentioned compounds, which has shown anti-inflammatory and antiaging properties in a dose-dependent manner. Interestingly, resveratrol appears to enhance the activity of so-called Sirtuin 1, too. Therefore, the aim of this review is to summarize and discuss the latest findings related to resveratrol, Sirtuin 1, and their crosstalk and influence on the mammalian oocyte to elucidate the question of whether these factors can delay or slow down reproductive aging.
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Affiliation(s)
| | - Paweł Kordowitzki
- Department of Preclinical and Basic Sciences, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Gagarina Street 1, 87-100 Torun, Poland
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25
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Meshchaninov VN, Tsyvian PB, Myakotnykh VS, Kovtun OP, Shcherbakov DL, Blagodareva MS. Ontogenetic Principles of Accelerated Aging and the Prospects for Its Prevention and Treatment. ADVANCES IN GERONTOLOGY 2022. [DOI: 10.1134/s2079057022030080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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26
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Karnewar S, Pulipaka S, Katta S, Panuganti D, Neeli PK, Thennati R, Jerald MK, Kotamraju S. Mitochondria-targeted esculetin mitigates atherosclerosis in the setting of aging via the modulation of SIRT1-mediated vascular cell senescence and mitochondrial function in Apoe mice. Atherosclerosis 2022; 356:28-40. [DOI: 10.1016/j.atherosclerosis.2022.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022]
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27
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Ebata H, Loo TM, Takahashi A. Telomere Maintenance and the cGAS-STING Pathway in Cancer. Cells 2022; 11:1958. [PMID: 35741087 PMCID: PMC9221635 DOI: 10.3390/cells11121958] [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: 05/28/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer cells exhibit the unique characteristics of high proliferation and aberrant DNA damage response, which prevents cancer therapy from effectively eliminating them. The machinery required for telomere maintenance, such as telomerase and the alternative lengthening of telomeres (ALT), enables cancer cells to proliferate indefinitely. In addition, the molecules in this system are involved in noncanonical pro-tumorigenic functions. Of these, the function of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contains telomere-related molecules, is a well-known contributor to the tumor microenvironment (TME). This review summarizes the current knowledge of the role of telomerase and ALT in cancer regulation, with emphasis on their noncanonical roles beyond telomere maintenance. The components of the cGAS-STING pathway are summarized with respect to intercell communication in the TME. Elucidating the underlying functional connection between telomere-related molecules and TME regulation is important for the development of cancer therapeutics that target cancer-specific pathways in different contexts. Finally, strategies for designing new cancer therapies that target cancer cells and the TME are discussed.
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Affiliation(s)
- Hiroshi Ebata
- Department of Biological Sciences, Faculty of Science, The University of Tokyo, Tokyo 113-0033, Japan;
- Project for Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan;
| | - Tze Mun Loo
- Project for Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan;
| | - Akiko Takahashi
- Project for Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan;
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28
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Gonçalinho GHF, Nascimento JRDO, Mioto BM, Amato RV, Moretti MA, Strunz CMC, César LAM, Mansur ADP. Effects of Coffee on Sirtuin-1, Homocysteine, and Cholesterol of Healthy Adults: Does the Coffee Powder Matter? J Clin Med 2022; 11:2985. [PMID: 35683374 PMCID: PMC9181040 DOI: 10.3390/jcm11112985] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Coffee is one of the most popular beverages globally and contains several bioactive compounds that are relevant to human health. Many nutritional strategies modulate sirtuin-1, thereby impacting aging and cardiometabolic health. This study investigated the influence of different blended coffees on serum sirtuin-1, blood lipids, and plasma homocysteine. Methods: An eight-week randomized clinical trial that included 53 healthy adults of both sexes analyzed the effects of daily intake of 450 to 600 mL of pure Arabica or blended (Arabica + Robusta) coffee intake of filtered coffee on blood sirtuin-1, lipids, and homocysteine. Results: Both Arabica and blended coffees similarly increased serum sirtuin-1 concentration, from 0.51 to 0.58 ng/mL (p = 0.004) and from 0.40 to 0.49 ng/mL (p = 0.003), respectively, without changing plasma homocysteine, folic acid, glucose, and CRP. However, the blended coffee intake increased total cholesterol from 4.70 to 5.17 mmol/L (p < 0.001) and LDL-cholesterol from 2.98 to 3.32 mmol/L (p < 0.001), as well as HDL-c from 1.26 to 1.36 mmol/L (p < 0.001). Conclusion: Both coffee powders increased sirtuin-1 expression, but our results suggest that blended coffee had hypercholesterolemic effects which could increase cardiovascular risk. Therefore, preference should be given to Arabica coffee for the best cardiometabolic benefits of coffee.
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Affiliation(s)
- Gustavo Henrique Ferreira Gonçalinho
- Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil; (G.H.F.G.); (J.R.d.O.N.); (L.A.M.C.)
- Servico de Prevencao e Reabilitacao Cardiovascular, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil
| | - José Rafael de Oliveira Nascimento
- Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil; (G.H.F.G.); (J.R.d.O.N.); (L.A.M.C.)
- Servico de Prevencao e Reabilitacao Cardiovascular, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil
| | - Bruno Mahler Mioto
- Unidade Clinica de Coronariopatias Cronicas, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil; (B.M.M.); (R.V.A.); (M.A.M.)
| | - Reynaldo Vicente Amato
- Unidade Clinica de Coronariopatias Cronicas, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil; (B.M.M.); (R.V.A.); (M.A.M.)
| | - Miguel Antonio Moretti
- Unidade Clinica de Coronariopatias Cronicas, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil; (B.M.M.); (R.V.A.); (M.A.M.)
| | - Célia Maria Cassaro Strunz
- Laboratorio de Analises Clínicas, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil;
| | - Luiz Antonio Machado César
- Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil; (G.H.F.G.); (J.R.d.O.N.); (L.A.M.C.)
- Unidade Clinica de Coronariopatias Cronicas, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil; (B.M.M.); (R.V.A.); (M.A.M.)
| | - Antonio de Padua Mansur
- Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil; (G.H.F.G.); (J.R.d.O.N.); (L.A.M.C.)
- Servico de Prevencao e Reabilitacao Cardiovascular, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-900, SP, Brazil
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Pun FW, Leung GHD, Leung HW, Liu BHM, Long X, Ozerov IV, Wang J, Ren F, Aliper A, Izumchenko E, Moskalev A, de Magalhães JP, Zhavoronkov A. Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine. Aging (Albany NY) 2022; 14:2475-2506. [PMID: 35347083 PMCID: PMC9004567 DOI: 10.18632/aging.203960] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/06/2022] [Indexed: 11/25/2022]
Abstract
Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.
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Affiliation(s)
- Frank W. Pun
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Geoffrey Ho Duen Leung
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Hoi Wing Leung
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Bonnie Hei Man Liu
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Xi Long
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Ivan V. Ozerov
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Ju Wang
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Feng Ren
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Alexander Aliper
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637, USA
| | - Alexey Moskalev
- School of Systems Biology, George Mason University (GMU), Fairfax, VA 22030, USA
| | - João Pedro de Magalhães
- Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK
| | - Alex Zhavoronkov
- Insilico Medicine Hong Kong Ltd., Hong Kong Science and Technology Park, New Territories, Hong Kong, China
- Buck Institute for Research on Aging, Novato, CA 94945, USA
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30
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Vainshelbaum NM, Salmina K, Gerashchenko BI, Lazovska M, Zayakin P, Cragg MS, Pjanova D, Erenpreisa J. Role of the Circadian Clock "Death-Loop" in the DNA Damage Response Underpinning Cancer Treatment Resistance. Cells 2022; 11:880. [PMID: 35269502 PMCID: PMC8909334 DOI: 10.3390/cells11050880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/14/2022] [Accepted: 03/01/2022] [Indexed: 12/11/2022] Open
Abstract
Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.
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Affiliation(s)
- Ninel Miriam Vainshelbaum
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
- Faculty of Biology, University of Latvia, LV-1050 Riga, Latvia
| | - Kristine Salmina
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
| | - Bogdan I. Gerashchenko
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, 03022 Kyiv, Ukraine;
| | - Marija Lazovska
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
| | - Pawel Zayakin
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
| | - Mark Steven Cragg
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK;
| | - Dace Pjanova
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
| | - Jekaterina Erenpreisa
- Cancer Research Division, Latvian Biomedicine Research and Study Centre, LV-1067 Riga, Latvia; (N.M.V.); Latvia; (K.S.); (M.L.); (P.Z.); (D.P.)
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31
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Athanasopoulou S, Kapetanou M, Magouritsas MG, Mougkolia N, Taouxidou P, Papacharalambous M, Sakellaridis F, Gonos E. Antioxidant and Antiaging Properties of a Novel Synergistic Nutraceutical Complex: Readouts from an In Cellulo Study and an In Vivo Prospective, Randomized Trial. Antioxidants (Basel) 2022; 11:antiox11030468. [PMID: 35326118 PMCID: PMC8944750 DOI: 10.3390/antiox11030468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/04/2023] Open
Abstract
Aging is a dynamic procedure that is developed in multiple layers and characterized by distinct hallmarks. The use of biomarkers that target different hallmarks of aging is substantial in predicting adverse outcomes during the aging process, implementing specifically designed antiaging interventions and monitoring responses to these interventions. The present study aimed to develop a novel composition of plant extracts, comprising identified active ingredients that synergistically target different hallmarks of aging in cellulo and in vivo. The selected single extracts and the developed composition were tested through a powerful set of biomarkers that we have previously identified and studied. The composition of selected extracts simultaneously increased cellular lifespan, reduced the cellular oxidative load and enhanced antioxidant defense mechanisms by increasing proteasome activity and content. In addition, the combination prevented telomere attrition and preserved optimum DNA methylation levels. Remarkably, biomarker profiling of healthy volunteers who received the identified combination in the form of a nutritional supplement within the frame of a prospective, randomized, controlled 3-month trial revealed an unprecedented antioxidant capacity in humans. In conclusion, our results support the notion that interventions with specifically designed combinations of natural compounds targeting multiple hallmarks of aging represent an effective way to improve healthspan and well-being.
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Affiliation(s)
- Sophia Athanasopoulou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (S.A.); (M.K.); (N.M.)
- Faculty of Medicine, School of Health Sciences, University of Thessaly, 41334 Larisa, Greece
| | - Marianna Kapetanou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (S.A.); (M.K.); (N.M.)
| | | | - Nikoletta Mougkolia
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (S.A.); (M.K.); (N.M.)
| | - Polykseni Taouxidou
- Department of Physical Education and Sport Science, Aristotle University, 57001 Thessaloniki, Greece;
| | | | | | - Efstathios Gonos
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece; (S.A.); (M.K.); (N.M.)
- Hellenic Pasteur Institute, 11521 Athens, Greece
- Correspondence: ; Tel.: +30-210-6478860
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32
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Kim S, Hwang S. G-Quadruplex Matters in Tissue-Specific Tumorigenesis by BRCA1 Deficiency. Genes (Basel) 2022; 13:genes13030391. [PMID: 35327946 PMCID: PMC8948836 DOI: 10.3390/genes13030391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/14/2022] Open
Abstract
How and why distinct genetic alterations, such as BRCA1 mutation, promote tumorigenesis in certain tissues, but not others, remain an important issue in cancer research. The underlying mechanisms may reveal tissue-specific therapeutic vulnerabilities. Although the roles of BRCA1, such as DNA damage repair and stalled fork stabilization, obviously contribute to tumor suppression, these ubiquitously important functions cannot explain tissue-specific tumorigenesis by BRCA1 mutations. Recent advances in our understanding of the cancer genome and fundamental cellular processes on DNA, such as transcription and DNA replication, have provided new insights regarding BRCA1-associated tumorigenesis, suggesting that G-quadruplex (G4) plays a critical role. In this review, we summarize the importance of G4 structures in mutagenesis of the cancer genome and cell type-specific gene regulation, and discuss a recently revealed molecular mechanism of G4/base excision repair (BER)-mediated transcriptional activation. The latter adequately explains the correlation between the accumulation of unresolved transcriptional regulatory G4s and multi-level genomic alterations observed in BRCA1-associated tumors. In summary, tissue-specific tumorigenesis by BRCA1 deficiency can be explained by cell type-specific levels of transcriptional regulatory G4s and the role of BRCA1 in resolving it. This mechanism would provide an integrated understanding of the initiation and development of BRCA1-associated tumors.
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Affiliation(s)
- Sanghyun Kim
- Department of Biomedical Science, College of Life Science, CHA University, Sungnam 13488, Korea;
| | - Sohyun Hwang
- Department of Biomedical Science, College of Life Science, CHA University, Sungnam 13488, Korea;
- Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Sungnam 13496, Korea
- Correspondence:
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Palmer RD, Vaccarezza M. Nicotinamide adenine dinucleotide and the sirtuins caution: Pro-cancer functions. Aging Med (Milton) 2021; 4:337-344. [PMID: 34964015 PMCID: PMC8711221 DOI: 10.1002/agm2.12184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/10/2022] Open
Abstract
This scoping review aims to perform a brief but comprehensive assessment of existing peer-reviewed literature and determine whether raising nicotinamide adenine dinucleotide can prevent or promote tumorigenesis. The examination of extensive peer-reviewed data regarding the synthesis of nicotinamide adenine dinucleotide has been performed with a focus on nuclear dynamics and the deoxyribose nucleic acid repair pathway. Various enzymatic protective functions have been identified from nicotinamide adenine dinucleotide levels, as well as the threat role that is also explored. Nicotinamide adenine dinucleotide precursors and sirtuin-activating compounds are becoming ubiquitous in the commercial market. Further research into whether elevating levels of nicotinamide adenine dinucleotide or overexpression of sirtuins can increase the potential for neoplasm or other age-related pathophysiology is warranted due to the high energy requirements of certain diseases such as cancer.
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Affiliation(s)
| | - Mauro Vaccarezza
- School of MedicineFaculty of Health SciencesCurtin UniversityBentley, PerthWestern AustraliaAustralia
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34
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Morales-Tarré O, Alonso-Bastida R, Arcos-Encarnación B, Pérez-Martínez L, Encarnación-Guevara S. Protein lysine acetylation and its role in different human pathologies: a proteomic approach. Expert Rev Proteomics 2021; 18:949-975. [PMID: 34791964 DOI: 10.1080/14789450.2021.2007766] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Lysine acetylation is a reversible post-translational modification (PTM) regulated through the action of specific types of enzymes: lysine acetyltransferases (KATs) and lysine deacetylases (HDACs), in addition to bromodomains, which are a group of conserved domains which identify acetylated lysine residues, several of the players in the process of protein acetylation, including enzymes and bromodomain-containing proteins, have been related to the progression of several diseases. The combination of high-resolution mass spectrometry-based proteomics, and immunoprecipitation to enrich acetylated peptides has contributed in recent years to expand the knowledge about this PTM described initially in histones and nuclear proteins, and is currently reported in more than 5000 human proteins, that are regulated by this PTM. AREAS COVERED This review presents an overview of the main participant elements, the scenario in the development of protein lysine acetylation, and its role in different human pathologies. EXPERT OPINION Acetylation targets are practically all cellular processes in eukaryotes and prokaryotes organisms. Consequently, this modification has been linked to many pathologies like cancer, viral infection, obesity, diabetes, cardiovascular, and nervous system-associated diseases, to mention a few relevant examples. Accordingly, some intermediate mediators in the acetylation process have been projected as therapeutic targets.
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Affiliation(s)
- Orlando Morales-Tarré
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Ramiro Alonso-Bastida
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Bolivar Arcos-Encarnación
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular Y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Leonor Pérez-Martínez
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular Y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
| | - Sergio Encarnación-Guevara
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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Mojiri A, Walther BK, Jiang C, Matrone G, Holgate R, Xu Q, Morales E, Wang G, Gu J, Wang R, Cooke JP. Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice. Eur Heart J 2021; 42:4352-4369. [PMID: 34389865 PMCID: PMC8603239 DOI: 10.1093/eurheartj/ehab547] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/29/2021] [Accepted: 08/12/2021] [Indexed: 12/28/2022] Open
Abstract
AIMS Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing. METHODS AND RESULTS We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice. CONCLUSION Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.
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Affiliation(s)
- Anahita Mojiri
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Brandon K Walther
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St., College Station, TX 77840, USA
| | - Chongming Jiang
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Gianfranco Matrone
- British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Rhonda Holgate
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Qiu Xu
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Elisa Morales
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Jianhua Gu
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
| | - Rongfu Wang
- Department of Medicine, and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - John P Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6670 Bertner Ave., R10-South, Houston, TX 77030, USA
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Ministrini S, Puspitasari YM, Beer G, Liberale L, Montecucco F, Camici GG. Sirtuin 1 in Endothelial Dysfunction and Cardiovascular Aging. Front Physiol 2021; 12:733696. [PMID: 34690807 PMCID: PMC8527036 DOI: 10.3389/fphys.2021.733696] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/30/2021] [Indexed: 01/10/2023] Open
Abstract
Sirtuin 1 (SIRT1) is a histone deacetylase belonging to the family of Sirtuins, a class of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes with multiple metabolic functions. SIRT1 localizes in the nucleus and cytoplasm, and is implicated in the regulation of cell survival in response to several stimuli, including metabolic ones. The expression of SIRT1 is associated with lifespan and is reduced with aging both in animal models and in humans, where the lack of SIRT1 is regarded as a potential mediator of age-related cardiovascular diseases. In this review, we will summarize the extensive evidence linking SIRT1 functional and quantitative defects to cellular senescence and aging, with particular regard to their role in determining endothelial dysfunction and consequent cardiovascular diseases. Ultimately, we outline the translational perspectives for this topic, in order to highlight the missing evidence and the future research steps.
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Affiliation(s)
- Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
- Internal Medicine, Angiology and Atherosclerosis, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Georgia Beer
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Luca Liberale
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- Istituto di Ricerca e Cura a Carattere Scientifico Ospedale Policlinico San Martino Genoa–Italian Cardiovascular Network, Genoa, Italy
| | - Giovanni G. Camici
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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Qiu P, Hou W, Wang H, Lei KKW, Wang S, Chen W, Pardeshi LA, Prothro K, Shukla Y, Su SSM, Schrump DS, Chen Q, Deng CX, Xu X, Wang R. Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice. Oncogene 2021; 40:6023-6033. [PMID: 34433910 PMCID: PMC10184507 DOI: 10.1038/s41388-021-01993-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/27/2021] [Accepted: 08/10/2021] [Indexed: 02/07/2023]
Abstract
Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.
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Affiliation(s)
- Pengxiang Qiu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Weilong Hou
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Haitao Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Kimmy Ka Wing Lei
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Shaowei Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Weiping Chen
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | | | - Katherine Prothro
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yashvita Shukla
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samson Sek Man Su
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - David S Schrump
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Qiang Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Chu-Xia Deng
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China.
| | - Xiaoling Xu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China.
| | - Ruihong Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Kovács Z, Brunner B, Ari C. Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases. Nutrients 2021; 13:nu13072197. [PMID: 34206738 PMCID: PMC8308443 DOI: 10.3390/nu13072197] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022] Open
Abstract
Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.
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Affiliation(s)
- Zsolt Kovács
- Department of Biology, Savaria University Centre, ELTE Eötvös Loránd University, Károlyi Gáspár tér 4., 9700 Szombathely, Hungary; (Z.K.); (B.B.)
| | - Brigitta Brunner
- Department of Biology, Savaria University Centre, ELTE Eötvös Loránd University, Károlyi Gáspár tér 4., 9700 Szombathely, Hungary; (Z.K.); (B.B.)
- Faculty of Sciences, Institute of Biology, University of Pécs, Ifjúság Str. 6, 7624 Pécs, Hungary
| | - Csilla Ari
- Behavioral Neuroscience Research Laboratory, Department of Psychology, University of South Florida, 4202 E. Fowler Ave, PCD 3127, Tampa, FL 33620, USA
- Ketone Technologies LLC, 2780 E. Fowler Ave. #226, Tampa, FL 33612, USA
- Correspondence: ; Tel.: +1-(813)-2409925
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Li YF, Wang YX, Wang H, Ma Y, Wang LS. Posttranslational Modifications: Emerging Prospects for Cardiac Regeneration Therapy. J Cardiovasc Transl Res 2021; 15:49-60. [PMID: 34031843 DOI: 10.1007/s12265-021-10135-7] [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: 03/14/2021] [Accepted: 05/07/2021] [Indexed: 11/30/2022]
Abstract
Heart failure (HF) following ischemic heart disease (IHD) remains a hard nut to crack and a leading cause of death worldwide. Cardiac regeneration aims to promote cardiomyocyte (CM) proliferation by transitioning the cell cycle state of CMs from arrest to re-entry. Protein posttranslational modifications (PTMs) have recently attracted extensive attention in the field of cardiac regeneration due to their reversibility and effects on the stability, activity, and subcellular localization of target proteins. The balance of PTMs is disrupted when neonatal CMs withdraw from the cell cycle, resulting in significant dysfunction of downstream substrate protein localization, expression, and activity, ultimately limiting the maintenance of cardiac regeneration ability. In this review, we summarize recent research concerning the role of PTMs in cardiac regeneration, while focusing on phosphorylation, acetylation, ubiquitination, glycosylation, methylation, and neddylation, and the effects of these modifications on CM proliferation, which may provide potential targets for future treatments for IHD.
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Affiliation(s)
- Ya-Fei Li
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ya-Xin Wang
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hao Wang
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yao Ma
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Lian-Sheng Wang
- Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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40
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Tao L, Zhang W, Zhang Y, Zhang M, Zhang Y, Niu X, Zhao Q, Liu Z, Li Y, Diao A. Caffeine promotes the expression of telomerase reverse transcriptase to regulate cellular senescence and aging. Food Funct 2021; 12:2914-2924. [PMID: 33720241 DOI: 10.1039/d0fo03246h] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Telomere shortening is one of the main causes of cellular senescence. Caffeine is a natural stimulant most commonly found in coffee and tea. In this study, caffeine was found to promote the expression of telomerase reverse transcriptase (TERT) at both mRNA and protein levels, and consequently extended the telomere length and prevented cellular senescence. Knockdown of TERT eliminated the effect of caffeine on telomere elongation. Moreover, animal studies indicated that caffeine promoted the expression of TERT and extended the telomere length in the thymus and spleen of mice treated with caffeine for a long period of eight months. In addition, caffeine restored the decline of organ index and improved the histological structural change of the thymus, spleen and liver of mice due to aging. These results suggest that caffeine promotes the expression of TERT to delay cellular senescence and aging, which help to understand the mechanism for the beneficial effects of caffeine containing foods on health.
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Affiliation(s)
- Li Tao
- School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, State Key Laboratory of Food Nutrition and Safety, Tianjin 300457, China.
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Hu D, Xie F, Xiao Y, Lu C, Zhong J, Huang D, Chen J, Wei J, Jiang Y, Zhong T. Metformin: A Potential Candidate for Targeting Aging Mechanisms. Aging Dis 2021; 12:480-493. [PMID: 33815878 PMCID: PMC7990352 DOI: 10.14336/ad.2020.0702] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/02/2020] [Indexed: 12/13/2022] Open
Abstract
Aging is a universal phenomenon in all biological organisms, defined by the loss of reproductive capacity and a progressive decline in fitness. In humans, aging is further associated with an increased incidence of disease conditions. The current aging population has become a primary public burden of the 21st century. Therefore, to delay the aging process and maintain fitness in the aging population, the discovery of novel anti-aging drugs remains an urgent need. In recent years, metformin, a widely used hypoglycemic drug, has attracted growing attention in the field of anti-aging research. Reportedly, numerous studies have indicated that metformin regulates aging-related pathways, possibly delaying the aging process by modulating these pathways. The elucidation of these anti-aging effects may provide insights into the age-retarding potential of metformin. The present review focuses on the predominant molecular mechanisms associated with aging, as well as the anti-aging effects of metformin.
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Affiliation(s)
- Die Hu
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,2Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Fangfang Xie
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,2Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yongwei Xiao
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,2Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Chen Lu
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
| | - Jianing Zhong
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,3Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
| | - Defa Huang
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,4Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jie Chen
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,2Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jifu Wei
- 4Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yu Jiang
- 5Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Tianyu Zhong
- 1The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China.,2Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.,4Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Fukutomi R, Ohishi T, Koyama Y, Pervin M, Nakamura Y, Isemura M. Beneficial Effects of Epigallocatechin-3- O-Gallate, Chlorogenic Acid, Resveratrol, and Curcumin on Neurodegenerative Diseases. Molecules 2021; 26:E415. [PMID: 33466849 PMCID: PMC7829779 DOI: 10.3390/molecules26020415] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/12/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer's and Parkinson's diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.
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Affiliation(s)
- Ryuuta Fukutomi
- Quality Management Division, Higuchi Inc. Minato-ku, Tokyo 108-0075, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, Numazu, Shizuoka 410-0301, Japan;
| | - Yu Koyama
- Shizuoka Eiwa Gakuin University Junior College, Suruga-ku, Shizuoka 422-8545, Japan;
| | - Monira Pervin
- Tea Science Research Center, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan; (M.P.); (Y.N.)
| | - Yoriyuki Nakamura
- Tea Science Research Center, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan; (M.P.); (Y.N.)
| | - Mamoru Isemura
- Tea Science Research Center, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan; (M.P.); (Y.N.)
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Senescence under appraisal: hopes and challenges revisited. Cell Mol Life Sci 2021; 78:3333-3354. [PMID: 33439271 PMCID: PMC8038995 DOI: 10.1007/s00018-020-03746-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/20/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023]
Abstract
In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.
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Cherfils-Vicini J, Gilson É. [Longevity clocks: The promoting role of telomeres?]. Med Sci (Paris) 2020; 36:1113-1117. [PMID: 33296627 DOI: 10.1051/medsci/2020242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aging is an alteration of our physiological capacities that is accompanied by an increased susceptibility to develop a wide range of diseases and which determines in large part our longevity. Despite intensive research on the origin of aging, its etiology is still poorly understood. We discuss here the hypothesis that the telomere shortening, programmed to start at the end of embryogenesis in numerous tissues, couples development with aging by a time-dependent regulation of a set of interconnected processes essential for the somatic maintenance of genome, epigenome, metabolism, circadian clock and immunity.
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Affiliation(s)
- Julien Cherfils-Vicini
- Université Côte-d'Azur, Inserm, CNRS, Institut de recherche sur le cancer et le vieillissement (Institute for Research on Cancer and Aging, Nice IRCAN), FHU OncoAge, 28 avenue Valombrose, Nice, France
| | - Éric Gilson
- Université Côte-d'Azur, Inserm, CNRS, Institut de recherche sur le cancer et le vieillissement (Institute for Research on Cancer and Aging, Nice IRCAN), FHU OncoAge, 28 avenue Valombrose, Nice, France - Département de génétique, CHU, Nice, France
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45
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Vazquez BN, Vaquero A, Schindler K. Sirtuins in female meiosis and in reproductive longevity. Mol Reprod Dev 2020; 87:1175-1187. [PMID: 33184962 PMCID: PMC7775317 DOI: 10.1002/mrd.23437] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/01/2020] [Indexed: 01/03/2023]
Abstract
Transmission of genetic material through high-quality gametes to progeny requires accurate homologous chromosome recombination and segregation during meiosis. A failure to accomplish these processes can have major consequences in reproductive health, including infertility, and development disorders in offspring. Sirtuins, a family of NAD+ -dependent protein deacetylases and ADP-ribosyltransferases, play key roles in genome maintenance, metabolism, and aging. In recent years, Sirtuins have emerged as regulators of several reproductive processes and interventions aiming to target Sirtuin activity are of great interest in the reproductive biology field. Sirtuins are pivotal to protect germ cells against oxidative stress, a major determinant influencing ovarian aging and the quality of gametes. Sirtuins also safeguard the integrity of the genome through epigenetic programs required for regulating gene repression, DNA repair, and chromosome segregation, among others. Although these functions are relatively well characterized in many somatic tissues, how they contribute to reproductive functions is not well understood. This review summarizes our current knowledge on the role of Sirtuins in female reproductive systems and discusses the underlying molecular pathways. In addition, we highlight the importance of Sirtuins as antiaging factors in the ovary and summarize current preclinical efforts to identify treatments to extend female reproductive longevity.
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Affiliation(s)
- Berta N. Vazquez
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Barcelona, Catalonia, Spain
- Department de Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Alejandro Vaquero
- Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Barcelona, Catalonia, Spain
| | - Karen Schindler
- Human Genetics Institute of New Jersey (HGINJ), Department of Genetics, Rutgers University, 145 Bevier Rd., Piscataway, NJ, 08854, USA
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Impact of circadian disruption on health; SIRT1 and Telomeres. DNA Repair (Amst) 2020; 96:102993. [PMID: 33038659 DOI: 10.1016/j.dnarep.2020.102993] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 12/16/2022]
Abstract
Circadian clock is a biochemical oscillator in organisms that regulates the circadian rhythm of numerous genes over 24 h. The circadian clock is involved in telomere homeostasis by regulating the diurnal rhythms of telomerase activity, TERT mRNA level, TERRA expression, and telomeric heterochromatin formation. Particularly, CLOCK and BMAL1 deficiency contribute to telomere shortening by preventing rhythmic telomerase activity and TERRA expression, respectively. Telomere shortening increases the number of senescent cells with impaired circadian rhythms. In return, telomerase reconstitution improves impaired circadian rhythms of senescent cells. SIRT1 that is an NAD+-dependent deacetylase positively regulates circadian clock and telomere homeostasis. SIRT1 contributes to the circadian clock by mediating CLOCK/BMAL1 complex formation, BMAL1 transcription and PER2 disruption. On the other hand, SIRT1 ensures telomere homeostasis by inducing telomerase and shelterin protein expression and regulating telomere heterochromatin formation. SIRT1 inhibition leads to both circadian clock and telomeres dysfunction that inhibit its activity. In light of this current evidence, we could suggest that the BMAL1/CLOCK complex regulates the telomere homeostasis in SIRT1 dependent manner, and also telomere dysfunction inhibits circadian clock function by suppressing SIRT1 activity to induce age-related diseases. We consider that increasing SIRT1 activity can prevent age-related diseases and help healthy aging by protecting telomere integrity and circadian clock function for individuals subjected to circadian rhythm disruption such as shift works, individuals with sleep disorders, and in the elderly population.
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Duan S, Han X, Akbari M, Croteau DL, Rasmussen LJ, Bohr VA. Interaction between RECQL4 and OGG1 promotes repair of oxidative base lesion 8-oxoG and is regulated by SIRT1 deacetylase. Nucleic Acids Res 2020; 48:6530-6546. [PMID: 32432680 PMCID: PMC7337523 DOI: 10.1093/nar/gkaa392] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/14/2020] [Accepted: 05/04/2020] [Indexed: 12/17/2022] Open
Abstract
OGG1 initiated base excision repair (BER) is the major pathway for repair of oxidative DNA base damage 8-oxoguanine (8-oxoG). Here, we report that RECQL4 DNA helicase, deficient in the cancer-prone and premature aging Rothmund-Thomson syndrome, physically and functionally interacts with OGG1. RECQL4 promotes catalytic activity of OGG1 and RECQL4 deficiency results in defective 8-oxoG repair and increased genomic 8-oxoG. Furthermore, we show that acute oxidative stress leads to increased RECQL4 acetylation and its interaction with OGG1. The NAD+-dependent protein SIRT1 deacetylates RECQL4 in vitro and in cells thereby controlling the interaction between OGG1 and RECQL4 after DNA repair and maintaining RECQL4 in a low acetylated state. Collectively, we find that RECQL4 is involved in 8-oxoG repair through interaction with OGG1, and that SIRT1 indirectly modulates BER of 8-oxoG by controlling RECQL4–OGG1 interaction.
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Affiliation(s)
- Shunlei Duan
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Xuerui Han
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Mansour Akbari
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Deborah L Croteau
- Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Baltimore, MD, 21224, USA
| | - Lene Juel Rasmussen
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Vilhelm A Bohr
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark.,Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Baltimore, MD, 21224, USA
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48
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Proshkina E, Shaposhnikov M, Moskalev A. Genome-Protecting Compounds as Potential Geroprotectors. Int J Mol Sci 2020; 21:E4484. [PMID: 32599754 PMCID: PMC7350017 DOI: 10.3390/ijms21124484] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Throughout life, organisms are exposed to various exogenous and endogenous factors that cause DNA damages and somatic mutations provoking genomic instability. At a young age, compensatory mechanisms of genome protection are activated to prevent phenotypic and functional changes. However, the increasing stress and age-related deterioration in the functioning of these mechanisms result in damage accumulation, overcoming the functional threshold. This leads to aging and the development of age-related diseases. There are several ways to counteract these changes: 1) prevention of DNA damage through stimulation of antioxidant and detoxification systems, as well as transition metal chelation; 2) regulation of DNA methylation, chromatin structure, non-coding RNA activity and prevention of nuclear architecture alterations; 3) improving DNA damage response and repair; 4) selective removal of damaged non-functional and senescent cells. In the article, we have reviewed data about the effects of various trace elements, vitamins, polyphenols, terpenes, and other phytochemicals, as well as a number of synthetic pharmacological substances in these ways. Most of the compounds demonstrate the geroprotective potential and increase the lifespan in model organisms. However, their genome-protecting effects are non-selective and often are conditioned by hormesis. Consequently, the development of selective drugs targeting genome protection is an advanced direction.
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Affiliation(s)
- Ekaterina Proshkina
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
| | - Mikhail Shaposhnikov
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
| | - Alexey Moskalev
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st., 167982 Syktyvkar, Russia; (E.P.); (M.S.)
- Pitirim Sorokin Syktyvkar State University, 55 Oktyabrsky prosp., 167001 Syktyvkar, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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Hepatocellular Expression of SIRT1 and Its Effect on Hepatocellular Carcinoma Progression: A Future Therapeutic Perspective. Int J Hepatol 2020; 2020:2374615. [PMID: 32607257 PMCID: PMC7315277 DOI: 10.1155/2020/2374615] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/11/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary hepatic malignancy with a significant morbidity and mortality rate. Although chemotherapy along with surgical incision is believed to be an effective therapeutic approach, to date recurrence is being lifted a major concern. Thus, identifying another best therapeutic approach is becoming the main aim of physicians and scholars. In support of this, recently, several studies reported a significant observation of Sirtuin1 (SIRT1) overexpression in the malignant tumor cells, including HCC. As a result, they believed that overexpression of SIRT1 may have an effect on the progression of HCC by targeting growth and/or apoptotic controlling transcriptional factors/signaling pathways. Similarly, other reports confirmed that SIRT1 inhibition had a direct or indirect role in the control of tumor cell growth and metastasis. Therefore, inhibiting the expression and activity of SIRT1 might have a therapeutic effect to handle HCC. However, there are a limited number of reviews regarding the issue, and here, we summarized hepatocellular expression of SIRT1 and its role on HCC progression.
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Sung JY, Kim SG, Cho DH, Kim JR, Choi HC. SRT1720-induced activation of SIRT1 alleviates vascular smooth muscle cell senescence through PKA-dependent phosphorylation of AMPKα at Ser485. FEBS Open Bio 2020; 10:1316-1325. [PMID: 32421926 PMCID: PMC7327920 DOI: 10.1002/2211-5463.12895] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/23/2020] [Accepted: 05/14/2020] [Indexed: 01/31/2023] Open
Abstract
Aging is a major risk factor for hypertension and atherosclerosis, and vascular smooth muscle cell (VSMC) senescence can promote aging‐related vascular diseases. Sirtuin‐1 (SIRT1) and AMP‐activated protein kinase (AMPK) were previously reported to modulate vascular senescence; however, its effects have not been well characterized. To determine the nature of the interaction between SIRT1 and AMPK in VSMC senescence, we investigated the effects of SRT1720 on its downstream targets of SIRT1 and the phosphorylation of AMPKα at Ser485. During Adriamycin‐induced VSMC senescence, SRT1720 increased the activity of SIRT1 and AMPKα phosphorylation at Ser485 via the cAMP–protein kinase A (PKA) pathway. Telomere length and telomerase reverse transcriptase expression were increased by SIRT1 activation with SRT1720. Taken together, these data show that activation of the SIRT1/cAMP–PKA/p‐AMPKα (Ser485) pathway may be an effective antisenescence mechanism for VSMCs.
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Affiliation(s)
- Jin Young Sung
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.,Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Korea
| | - Seul Gi Kim
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.,Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Korea
| | - Du Hyong Cho
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.,Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Korea
| | - Jae-Ryong Kim
- Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Korea.,Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, Korea
| | - Hyoung Chul Choi
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Korea.,Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Korea
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