bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒11‒08
eighteen papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.
  2. Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations.
  3. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.
  4. Advancements in therapeutic drugs targeting of senescence.
  5. A Blueprint for Characterizing Senescence.
  6. Warfarin Accelerates Aortic Calcification by Upregulating Senescence-Associated Secretory Phenotype Maker Expression.
  7. SIRT1 Activation Using CRISPR/dCas9 Promotes Regeneration of Human Corneal Endothelial Cells through Inhibiting Senescence.
  8. Nucleolar stress induces a senescence-like phenotype in smooth muscle cells and promotes development of vascular degeneration.
  9. Hair graying with aging in mice carrying oncogenic RET.
  10. DNA Damage and Mitochondria in Cancer and Aging.
  11. Analysis of transcriptional modules during human fibroblast ageing.
  12. New Insights into the Role of Histone Changes in Aging.
  13. FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.
  14. Aging in COVID-19: Vulnerability, immunity and intervention.
  15. Age-related loss of gene-to-gene transcriptional coordination among single cells.
  16. [How Does Aging Contribute to Cancer?]
  17. Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3.
  18. The use of geroprotectors to prevent multimorbidity: opportunities and challenges.
  1. J Clin Endocrinol Metab. 2020 Nov 06. pii: dgaa728. [Epub ahead of print]
    New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms.
    Tamar Tchkonia, Allyson K Palmer, James L Kirkland.
      The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.
    Keywords:   senolytics; SASP (senescence-associated secretory phenotype); geroscience hypothesis; healthspan; multimorbidity; unitary theory of fundamental aging mechanisms
    DOI:  https://doi.org/10.1210/clinem/dgaa728
  2. Nat Commun. 2020 11 05. 11(1): 5596
    Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations.
    Yuan Wang, Peng Deng, Yuting Liu, Yunshu Wu, Yaqian Chen, Yuchen Guo, Shiwen Zhang, Xiaofei Zheng, Liyan Zhou, Weiqing Liu, Qiwen Li, Weimin Lin, Xingying Qi, Guomin Ou, Cunyu Wang, Quan Yuan.
      Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-020-19360-1
  3. Aging Cell. 2020 Nov 04. e13269
    Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.
    Randy Strong, Richard A Miller, Molly Bogue, Elizabeth Fernandez, Martin A Javors, Sergiy Libert, Paul Anthony Marinez, Michael P Murphy, Nicolas Musi, James F Nelson, Michael Petrascheck, Peter Reifsnyder, Arlan Richardson, Adam B Salmon, Francesca Macchiarini, David E Harrison.
      To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.
    Keywords:  17-DMAG; MitoQ; minocycline; rapamycin; survival; β-GPA
    DOI:  https://doi.org/10.1111/acel.13269
  4. Ther Adv Chronic Dis. 2020 ;11 2040622320964125
    Advancements in therapeutic drugs targeting of senescence.
    Mingsheng Zhu, Ping Meng, Xian Ling, Lili Zhou.
      Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects. In this review, we summarize different types of drugs promoting healthy aging - such as senolytics, senescence-associated secretory phenotype (SASP) inhibitors, and nutrient signaling regulators - and provide an update on their potential therapeutic merits. Taken together, our review synthesizes recent advancements in the therapeutic potentialities of drugs promoting healthy aging with regard to their clinical implications.
    Keywords:  advancement; drug; healthy aging; senescence; senolytics
    DOI:  https://doi.org/10.1177/2040622320964125
  5. Cell. 2020 Oct 29. pii: S0092-8674(20)31396-9. [Epub ahead of print]
    A Blueprint for Characterizing Senescence.
    Ananda L Roy, Felipe Sierra, Kevin Howcroft, Dinah S Singer, Norman Sharpless, Richard J Hodes, Elizabeth L Wilder, James M Anderson.
      Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.
    DOI:  https://doi.org/10.1016/j.cell.2020.10.032
  6. Oxid Med Cell Longev. 2020 ;2020 2043762
    Warfarin Accelerates Aortic Calcification by Upregulating Senescence-Associated Secretory Phenotype Maker Expression.
    Ningle Wei, Liuyi Lu, Huanji Zhang, Ming Gao, Sounak Ghosh, Zhaoyu Liu, Junhua Qi, Jingfeng Wang, Jie Chen, Hui Huang.
      Warfarin, a vitamin K antagonist (VKA), is known to promote arterial calcification (AC). In the present study, we conducted a case-cohort study within the Multi-Ethnic Study of Atherosclerosis (MESA); 6655 participants were included. From MESA data, we found that AC was related to both age and vitamin K; furthermore, the score of AC increased with SASP marker including interlukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) rising. Next, a total of 79 warfarin users in our center developed significantly more calcified coronary plaques as compared to non-VKA users. We investigated the role of warfarin in phosphate-induced AC in different ages by in vitro experimental study. Furthermore, dose-time-response of warfarin was positively correlated with AC score distribution and plasma levels of the SASP maker IL-6 among patients < 65 years, but not among patients ≥ 65 years. In addition, in vitro research suggested that warfarin treatment tended to deteriorate calcification in young VSMC at the early stage of calcification. Our results suggested that aging and warfarin-treatment were independently related to increased AC. Younger patients were more sensitive to warfarin-related AC than older patients, which was possibly due to accumulated warfarin-induced cellular senescence.
    DOI:  https://doi.org/10.1155/2020/2043762
  7. Antioxidants (Basel). 2020 Nov 04. pii: E1085. [Epub ahead of print]9(11):
    SIRT1 Activation Using CRISPR/dCas9 Promotes Regeneration of Human Corneal Endothelial Cells through Inhibiting Senescence.
    Hye Jun Joo, Dae Joong Ma, Jin Sun Hwang, Young Joo Shin.
      Human corneal endothelial cells (hCECs) are restricted in proliferative capacity in vivo. Reduction in the number of hCEC leads to persistent corneal edema requiring corneal transplantation. This study demonstrates the functions of SIRT1 in hCECs and its potential for corneal endothelial regeneration. Cell morphology, cell growth rates and proliferation-associated proteins were compared in normal and senescent hCECs. SIRT1 was activated using the CRISPR/dCas9 activation system (SIRT1a). The plasmids were transfected into CECs of six-week-old Sprague-Dawley rats using electroporation and cryoinjury was performed. Senescent cells were larger, elongated and showed lower proliferation rates and lower SIRT1 levels. SIRT1 activation promoted the wound healing of CECs. In vivo transfection of SIRT1a promoted the regeneration of CECs. The proportion of the S-phase cells was lower in senescent cells and elevated upon SIRT1a activation. SIRT1 regulated cell proliferation, proliferation-associated proteins, mitochondrial membrane potential, and oxidative stress levels. In conclusion, corneal endothelial senescence is related with a decreased SIRT1 level. SIRT1a promotes the regeneration of CECs by inhibiting cytokine-induced cell death and senescence. Gene function activation therapy using SIRT1a may serve as a novel treatment strategy for hCEC diseases.
    Keywords:  CRISPR/dCas9; SIRT1; corneal endothelial cells; senescence
    DOI:  https://doi.org/10.3390/antiox9111085
  8. Aging (Albany NY). 2020 Nov 04. 12
    Nucleolar stress induces a senescence-like phenotype in smooth muscle cells and promotes development of vascular degeneration.
    Wenjing Zhang, Wen Cheng, Rosanna Parlato, Xiaosun Guo, Xiaopei Cui, Chaochao Dai, Lei Xu, Jiankang Zhu, Min Zhu, Kun Luo, Wencheng Zhang, Bo Dong, Jianli Wang, Fan Jiang.
      Senescence of smooth muscle cells (SMCs) has a crucial role in the pathogenesis of abdominal aortic aneurysm (AAA), a disease of vascular degeneration. Perturbation of cellular ribosomal DNA (rDNA) transcription triggers nucleolar stress response. Previously we demonstrated that induction of nucleolar stress in SMCs elicited cell cycle arrest via the ataxia-telangiectasia mutated (ATM)/ATM- and Rad3-related (ATR)-p53 axis. However, the specific roles of nucleolar stress in vascular degeneration remain unexplored. In the present study, we demonstrated for the first time that in both human and animal AAA tissues, there were non-coordinated changes in the expression of RNA polymerase I machinery components, including a downregulation of transcription initiation factor-IA (TIF-IA). Genetic deletion of TIF-IA in SMCs in mice (smTIF-IA-/-) caused spontaneous aneurysm-like lesions in the aorta. In vitro, induction of nucleolar stress triggered a non-canonical DNA damage response, leading to p53 phosphorylation and a senescence-like phenotype in SMCs. In human AAA tissues, there was increased nucleolar stress in medial cells, accompanied by localized DNA damage response within the nucleolar compartment. Our data suggest that perturbed rDNA transcription and induction of nucleolar stress contribute to the pathogenesis of AAA. Moreover, smTIF-IA-/- mice may be a novel animal model for studying spontaneous AAA-like vascular degenerations.
    Keywords:  RNA polymerase I; TIF-IA; aortic aneurysm; nucleolar stress response; senescence
    DOI:  https://doi.org/10.18632/aging.104094
  9. Aging Cell. 2020 Nov 07. e13273
    Hair graying with aging in mice carrying oncogenic RET.
    Machiko Iida, Akira Tazaki, Ichiro Yajima, Nobutaka Ohgami, Nobuhiko Taguchi, Yuji Goto, Mayuko Y Kumasaka, Armelle Prévost-Blondel, Michihiro Kono, Masashi Akiyama, Masahide Takahashi, Masashi Kato.
      Hair graying is a representative sign of aging in animals and humans. However, the mechanism for hair graying with aging remains largely unknown. In this study, we found that the microscopic appearance of hair follicles without melanocyte stem cells (MSCs) and descendant melanocytes as well as macroscopic appearances of hair graying in RET-transgenic mice carrying RET oncogene (RET-mice) are in accordance with previously reported results for hair graying in humans. Therefore, RET-mice could be a novel model mouse line for age-related hair graying. We further showed hair graying with aging in RET-mice associated with RET-mediated acceleration of hair cycles, increase of senescent follicular keratinocyte stem cells (KSCs), and decreased expression levels of endothelin-1 (ET-1) in bulges, decreased endothelin receptor B (Ednrb) expression in MSCs, resulting in a decreased number of follicular MSCs. We then showed that hair graying in RET-mice was accelerated by congenitally decreased Ednrb expression in MSCs in heterozygously Ednrb-deleted RET-mice [Ednrb(+/-);RET-mice]. We finally partially confirmed common mechanisms of hair graying with aging in mice and humans. Taken together, our results suggest that age-related dysfunction between ET-1 in follicular KSCs and endothelin receptor B (Ednrb) in follicular MSCs via cumulative hair cycles is correlated with hair graying with aging.
    Keywords:  RET; age-related hair graying; endothelin; keratinocyte stem cells; melanocyte stem cells
    DOI:  https://doi.org/10.1111/acel.13273
  10. Carcinogenesis. 2020 Nov 04. pii: bgaa114. [Epub ahead of print]
    DNA Damage and Mitochondria in Cancer and Aging.
    Jaimin Patel, Beverly A Baptiste, Edward Kim, Mansoor Hussain, Deborah L Croteau, Vilhelm A Bohr.
      Age and DNA repair deficiencies are strong risk factors for developing cancer. This is reflected in the comorbidity of cancer with premature aging diseases associated with DNA damage repair deficiencies. Recent research has suggested that DNA damage accumulation, telomere dysfunction, and the accompanying mitochondrial dysfunction exacerbate the aging process and may increase the risk of cancer development. Thus, an area of interest in both cancer and aging research is the elucidation of the dynamic crosstalk between the nucleus and the mitochondria. In this review, we discuss current research on aging and cancer with specific focus on the role of mitochondrial dysfunction in cancer and aging as well as how nuclear to mitochondrial DNA damage signaling may be a driving factor in the increased cancer incidence with aging. We suggest that therapeutic interventions aimed at induction of autophagy and mediation of nuclear to mitochondrial signaling may provide a mechanism for healthier aging and reduced tumorigenesis.
    DOI:  https://doi.org/10.1093/carcin/bgaa114
  11. Sci Rep. 2020 Nov 05. 10(1): 19086
    Analysis of transcriptional modules during human fibroblast ageing.
    Yaelim Lee, G V Shivashankar.
      For systematic identification of transcription signatures of human cell aging, we carried out Weighted Gene Co-expression Network Analysis (WGCNA) with the RNA-sequencing data generated with young to old human dermal fibroblasts. By relating the modules to the donor's traits, we uncovered the natural aging- and premature aging disease-associated modules. The STRING functional association networks built with the core module memberships provided a systematic overview of genome-wide transcriptional changes upon aging. We validated the selected candidates via quantitative reverse transcription PCR (RT-qPCR) assay with young and aged human fibroblasts, and uncovered several genes involved in ECM, cell, and nuclear mechanics as a potential aging biomarker. Collectively, our study not only provides a snapshot of functional changes during human fibroblast aging but also presents potential aging markers that are relevant to cell mechanics.
    DOI:  https://doi.org/10.1038/s41598-020-76117-y
  12. Int J Mol Sci. 2020 Nov 03. pii: E8241. [Epub ahead of print]21(21):
    New Insights into the Role of Histone Changes in Aging.
    Sun-Ju Yi, Kyunghwan Kim.
      Aging is the progressive decline or loss of function at the cellular, tissue, and organismal levels that ultimately leads to death. A number of external and internal factors, including diet, exercise, metabolic dysfunction, genome instability, and epigenetic imbalance, affect the lifespan of an organism. These aging factors regulate transcriptome changes related to the aging process through chromatin remodeling. Many epigenetic regulators, such as histone modification, histone variants, and ATP-dependent chromatin remodeling factors, play roles in chromatin reorganization. The key to understanding the role of gene regulatory networks in aging lies in characterizing the epigenetic regulators responsible for reorganizing and potentiating particular chromatin structures. This review covers epigenetic studies on aging, discusses the impact of epigenetic modifications on gene expression, and provides future directions in this area.
    Keywords:  aging; chromatin remodeling; epigenetics; histone level; histone modification; histone variant
    DOI:  https://doi.org/10.3390/ijms21218241
  13. Aging Cell. 2020 Nov 06. e13226
    FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.
    Jessica Voisin, Francesca Farina, Swati Naphade, Morgane Fontaine, Kizito-Tshitoko Tshilenge, Carlos Galicia Aguirre, Alejandro Lopez-Ramirez, Julia Dancourt, Aurélie Ginisty, Satish Sasidharan Nair, Kuruwitage Lakshika Madushani, Ningzhe Zhang, François-Xavier Lejeune, Marc Verny, Judith Campisi, Lisa M Ellerby, Christian Neri.
      Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a , a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3-ETS2-p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.
    Keywords:  neurodegenerative disease; neuronal differentiation; neuronal senescence; response mechanisms; temporal dynamics
    DOI:  https://doi.org/10.1111/acel.13226
  14. Ageing Res Rev. 2020 Oct 30. pii: S1568-1637(20)30340-8. [Epub ahead of print] 101205
    Aging in COVID-19: Vulnerability, immunity and intervention.
    Yiyin Chen, Sabra L Klein, Brian T Garibaldi, Huifen Li, Cunjin Wu, Nicole M Osevala, Taisheng Li, Joseph B Margolick, Graham Pawelec, Sean X Leng.
      The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic was first reported in Wuhan, China in December 2019, moved across the globe at an unprecedented speed, and has caused a profound and yet still unfolding health and socioeconomic impacts. SARS-CoV-2, a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the 2019 coronavirus disease (COVID-19). Clinical experience thus far indicates that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19. We hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults. Much remains to be learned about the immune responses to SARS-CoV-2 infection. We need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. Such knowledge is critical not only for understanding of COVID-19 pathogenesis but also for COVID-19 vaccine development.
    Keywords:  Aging; Anti-IL-6 therapy; COVID-19; Cytokine storm; Immunopathology; Immunosenescence; Inflammaging; SARS-CoV-2; Vaccination
    DOI:  https://doi.org/10.1016/j.arr.2020.101205
  15. Nat Metab. 2020 Nov 02.
    Age-related loss of gene-to-gene transcriptional coordination among single cells.
    Orr Levy, Guy Amit, Dana Vaknin, Tom Snir, Sol Efroni, Peter Castaldi, Yang-Yu Liu, Haim Y Cohen, Amir Bashan.
      A long-standing model holds that stochastic aberrations of transcriptional regulation play a key role in the process of ageing. While transcriptional dysregulation is observed in many cell types in the form of increased cell-to-cell variability, its generality to all cell types remains doubted. Here, we propose a new approach for analysing transcriptional regulation in single-cell RNA sequencing data by focusing on the global coordination between the genes rather than the variability of individual genes or correlations between pairs of genes. Consistently, across very different organisms and cell types, we find a decrease in the gene-to-gene transcriptional coordination in ageing cells. In addition, we find that loss of gene-to-gene transcriptional coordination is associated with high mutational load of a specific, age-related signature and with radiation-induced DNA damage. These observations suggest a general, potentially universal, stochastic attribute of transcriptional dysregulation in ageing.
    DOI:  https://doi.org/10.1038/s42255-020-00304-4
  16. Gan To Kagaku Ryoho. 2020 Sep;47(9): 1281-1286
    [How Does Aging Contribute to Cancer?]
    Akira Yokoyama, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Manabu Muto, Seishi Ogawa.
      Advances in sequencing technology have been reported to show cancer driver mutations with aging in a variety of normal tissues at very small clone sizes. In the normal esophagus, prior to carcinogenesis, clones that had acquired driver mutations in esophageal cancer, mainly NOTCH1 mutations, during early life appeared multi-centrically. With aging, the number of driver mutations increased and the clones expanded. In the elderly, most of the normal esophagus was replaced by clones with driver mutations. In contrast, in normal colorectal epithelium, about 1% of crypts contain driver mutations even in the 50s. In normal hepatocytes, age-related mutations are rarely detected. These results suggest that the frequency of detection of driver mutations in normal tissues varies greatly among tissues. The panorama of aging and cancer remains veiled.
  17. Autophagy. 2020 Nov 04. 1-17
    Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3.
    Zheng-Zhao Liu, Chun-Gu Hong, Wen-Bao Hu, Meng-Lu Chen, Ran Duan, Hong-Ming Li, Tao Yue, Jia Cao, Zhen-Xing Wang, Chun-Yuan Chen, Xiong-Ke Hu, Ben Wu, Hao-Ming Liu, Yi-Juan Tan, Jiang-Hua Liu, Zhong-Wei Luo, Yan Zhang, Shan-Shan Rao, Ming-Jie Luo, Hao Yin, Yi-Yi Wang, Kun Xia, Lang Xu, Si-Yuan Tang, Rong-Gui Hu, Hui Xie.
      Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as optn- / - mice. Importantly, restoring Optn by transplanting wild-type MSCs to optn- / - mice or infecting optn- / - mice with Optn-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of OptnK193R failed to reestablish a bone-fat balance. We further identified FABP3 (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. FABP3 promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of FABP3 alleviated bone loss in optn- / - mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of FABP3 degradation via selective autophagy. FABP3 accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting FABP3 would open a new avenue to treat senile OP. Abbreviations: ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; NBR1: NBR1, autophagy cargo receptor; OP: osteoporosis; OPTN: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-GLB1: senescence-associated (SA)-GLB1 (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; μCT: micro computed tomography.
    Keywords:  Adipogenesis; autophagy; bone metabolism; fabp3; mesenchymal stem cell; optineurin; osteogenesis; osteoporosis; senescence
    DOI:  https://doi.org/10.1080/15548627.2020.1839286
  18. Mech Ageing Dev. 2020 Oct 31. pii: S0047-6374(20)30187-1. [Epub ahead of print] 111391
    The use of geroprotectors to prevent multimorbidity: opportunities and challenges.
    Samir Morsli, Ilaria Bellantuono.
      Over 60% of people over the age of 65 will suffer from multiple diseases concomitantly but the common approach is to treat each disease separately. As age-associated diseases have common underlying mechanisms there is potential to tackle many diseases with the same pharmacological intervention. These are known as geroprotectors and could overcome the problems related to polypharmacy seen with the use of the single disease model. With some geroprotectors now reaching the end stage of preclinical studies and early clinical trials, there is a need to review the evidence and assess how they can be translated practically and effectively into routine practice. Despite promising evidence, there are many gaps and challenges in our understanding that must be addressed to make geroprotective medicine effective in the treatment of age-associated multimorbidity. Here we highlight the key barriers to clinical translation and discuss whether geroprotectors such as metformin, rapamycin and senolytics can tackle all age-associated diseases at the same dose, or whether a more nuanced approach is required. The evidence suggests that geroprotectors' mode of action may differ in different tissues or in response to different inducers of accelerating ageing, suggesting that a blunt 'one drug for many diseases' approach may not work. We make the case for the use of artificial intelligence to better understand multimorbidity, allowing identification of clusters and networks of diseases that are significantly associated beyond chance and the underpinning molecular pathway of ageing causal to each cluster. This will allow us to better understand the development of multimorbidity, select a more homogenous group of patients for intervention, match them with the appropriate geroprotector and identify biomarkers specific to the cluster.
    Keywords:  Aging; Geroprotectors; Geroscience; Multimorbidity; Translation
    DOI:  https://doi.org/10.1016/j.mad.2020.111391
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