bims-senagi Biomed News
on Senescence and aging
Issue of 2022–03–06
forty-two papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. Senescent skeletal cells cross-talk with synovial cells plays a key role in the pathogenesis of osteoarthritis.
  2. The Role of Senescence-Associated Secretory Phenotype in Bone Loss.
  3. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells.
  4. Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.
  5. Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway.
  6. Sphingomyelin nanosystems decorated with TSP-1 derived peptide targeting senescent cells.
  7. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
  8. miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD+/SIRT inactivation.
  9. Exploiting senescence for the treatment of cancer.
  10. Pin1-mediated regulation of articular cartilage stem/progenitor cell aging.
  11. The role of nutrition in inflammaging.
  12. Epigenetic modifications in spinal ligament aging.
  13. Senescent macrophages in the human adipose tissue as a source of inflammaging.
  14. Intermittent time-restricted feeding promotes longevity through circadian autophagy.
  15. Different responses to DNA damage determine ageing differences between organs.
  16. NLRP3 inflammasome links vascular senescence to diabetic vascular lesions.
  17. Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes.
  18. Cellular senescence, rejuvenation and potential immortality.
  19. Geroprotectors and Skeletal Health: Beyond the Headlines.
  20. Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging.
  21. Aβ promotes CD38 expression in senescent microglia in Alzheimer's disease.
  22. Age-dependent effects of Igf2bp2 on gene regulation, function, and aging of hematopoietic stem cells in mice.
  23. Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling.
  24. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.
  25. In vivo transcriptomic profiling using cell encapsulation identifieseffector pathways of systemic aging.
  26. NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss.
  27. Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
  28. Improving the repopulation capacity of elderly human hepatocytes by decoding aging-associated hepatocyte plasticity.
  29. Angiotensin-(1-7), a protective peptide against vascular aging.
  30. Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation.
  31. SIRT6 Protects Against Myocardial Ischemia-Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation.
  32. mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1.
  33. NAD+ in COVID-19 and viral infections.
  34. Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue.
  35. Nintedanib ameliorates oxidized low-density lipoprotein -induced inflammation and cellular senescence in vascular endothelial cells.
  36. Telomere length in leucocytes and solid tissues of young and aged rats.
  37. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.
  38. Modulation of SIRT1 expression improves erectile function in aged rats.
  39. Premature aging in mice with error-prone protein synthesis.
  40. Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions.
  41. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
  42. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.
  1. Arthritis Res Ther. 2022 Feb 28. 24(1): 59
    Senescent skeletal cells cross-talk with synovial cells plays a key role in the pathogenesis of osteoarthritis.
    Chong-Jie Wu, Ri-Xu Liu, Song-Wei Huan, Wang Tang, Yu-Kai Zeng, Jun-Cheng Zhang, Jie Yang, Zhen-Yan Li, Ying Zhou, Zhen-Gang Zha, Huan-Tian Zhang, Ning Liu.
      Osteoarthritis (OA) has been recognized as an age-related degenerative disease commonly seen in the elderly that affects the whole "organ" including cartilage, subchondral bone, synovium, and muscles. An increasing number of studies have suggested that the accumulation of senescent cells triggering by various stresses in the local joint contributes to the pathogenesis of age-related diseases including OA. In this review, we mainly focus on the role of the senescent skeletal cells (chondrocytes, osteoblasts, osteoclasts, osteocyte, and muscle cells) in initiating the development and progression of OA alone or through cross-talk with the macrophages/synovial cells. Accordingly, we summarize the current OA-targeted therapies based on the abovementioned theory, e.g., by eliminating senescent skeletal cells and/or inhibiting the senescence-associated secretory phenotype (SASP) that drives senescence. Furthermore, the existing animal models for the study of OA from the perspective of senescence are highlighted to fill the gap between basic research and clinical applications. Overall, in this review, we systematically assess the current understanding of cellular senescence in OA, which in turn might shed light on the stratified OA treatments.
    Keywords:  Animal models; Cellular senescence; Osteoarthritis; SASP; Skeletal cells; Targeted therapies
    DOI:  https://doi.org/10.1186/s13075-022-02747-4
  2. Front Cell Dev Biol. 2022 ;10 841612
    The Role of Senescence-Associated Secretory Phenotype in Bone Loss.
    Runjiu Zhu, Haoyang Wan, Hong Yang, Mingrui Song, Yu Chai, Bin Yu.
      As the population of most nations have a large proportion of older individuals, there is an increase in the prevalence of osteoporosis. Consequently, scientists have focused their attention on the pathogenic mechanisms of osteoporosis. Owing to an increase in studies on cellular senescence in recent years, research has begun to focus on the function of the senescent microenvironment in osteoporosis. With chronic inflammation, senescent cells in the bone marrow secrete a series of factors known as senescence-associated secretory phenotype (SASP) factors, acting on their own or surrounding healthy cells and consequently exacerbating ageing.The components of the SASP may differ depending on the cause of osteoporosis. This review aimed to summarize the relationship between SASP factors and osteoporosis and suggest new insights into the mechanistic investigation of osteoporosis.
    Keywords:  bone loss; osteoporosis; senescence; senescence-associated secretory phenotype (SASP); stem cell
    DOI:  https://doi.org/10.3389/fcell.2022.841612
  3. Aging (Albany NY). 2022 Mar 04. 14(undefined):
    Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells.
    Kristie Kim, Tesfahun Dessale Admasu, Alexandra Stolzing, Amit Sharma.
      In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and debility. Given the promise of NK cell-mediated immunotherapies as a safe and effective treatment strategy, we outline an improved method by which primary NK cells can be efficiently enriched from human peripheral blood across multiple donors (ages 20-42 years old), with a practical protocol that reliably enhances both CD56dim and CD56bright NK cells by 15-fold and 3-fold, respectively. Importantly, we show that our co-culture protocol can be used as an easily adaptable tool to assess highly efficient and selective killing of senescent cells by primary NK cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature.
    Keywords:  NKCC; aging; immune surveillance; natural killer cells; senescence
    DOI:  https://doi.org/10.18632/aging.203931
  4. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00171-1. [Epub ahead of print]38(9): 110444
    Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.
    Hitomi Yamamoto-Imoto, Satoshi Minami, Tatsuya Shioda, Yurina Yamashita, Shinsuke Sakai, Shihomi Maeda, Takeshi Yamamoto, Shinya Oki, Mizuki Takashima, Tadashi Yamamuro, Kyosuke Yanagawa, Ryuya Edahiro, Miki Iwatani, Mizue So, Ayaka Tokumura, Toyofumi Abe, Ryoichi Imamura, Norio Nonomura, Yukinori Okada, Donald E Ayer, Hidesato Ogawa, Eiji Hara, Yoshitsugu Takabatake, Yoshitaka Isaka, Shuhei Nakamura, Tamotsu Yoshimori.
      Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.
    Keywords:  C. elegans; MondoA; Rubicon; aging; autophagy; cellular senescence; kidney; mitochondrial homeostasis; mml-1; peroxiredoxin 3
    DOI:  https://doi.org/10.1016/j.celrep.2022.110444
  5. Genes Dis. 2022 Mar;9(2): 494-509
    Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-κB pathway.
    Ruigong Zhu, Xian Ji, Xuan Wu, Jiajing Chen, Xuesong Li, Hong Jiang, Haiping Fu, Hui Wang, Zhe Lin, Xin Tang, Shixiu Sun, Qingguo Li, Bingjian Wang, Hongshan Chen.
      Cellular senescence is closely associated with age-related diseases. Ovarian aging, a special type of organ senescence, is the pathophysiological foundation of the diseases of the reproductive system. It is characterized by the loss of integrity of the surface epithelium and a gradual decrease in the number of human ovarian surface epithelial cells (HOSEpiCs). To contribute to the research on delaying ovarian aging, we aimed to investigate the novel epigenetic mechanism of melatonin in protecting HOSEpiCs. We discovered that melatonin has antagonistic effects against the oncogene-induced senescence (OIS) of HOSEpiCs. Mechanistically, the oncogene Ras decreased the expression of YTHDF2, which is the reader of RNA-m6A, by stimulating the generation of reactive oxygen species (ROS). Moreover, we found that the suppression of YTHDF2 increased the expression of MAP2K4 and MAP4K4 by enhancing the stability of the transcription of their mRNAs, thereby upregulating the expression of the senescence-associated secretory phenotype (SASP) through the activation of the MAP2K4 and MAP4K4-dependent nuclear factor-κB (NF-κB) signaling pathways. We further determined that melatonin has antagonistic effects against the OIS of HOSEpiCs by inhibiting the ROS-YTHDF2-MAPK-NF-κB pathway. These findings provide key insights into the potential avenues for preventing and treating ovarian aging.
    Keywords:  Gene expression; Inflammation; Melatonin; Senescence; YTHDF2
    DOI:  https://doi.org/10.1016/j.gendis.2020.08.005
  6. Int J Pharm. 2022 Feb 24. pii: S0378-5173(22)00173-9. [Epub ahead of print] 121618
    Sphingomyelin nanosystems decorated with TSP-1 derived peptide targeting senescent cells.
    Raneem Jatal, Sofia Mendes Saraiva, Carlos Vázquez-Vázquez, Eric Lelievre, Olivier Coqueret, Rafael López-López, Maria de la Fuente.
      Senescent cells accumulation can contribute to the development of several age-related diseases, including cancer. Targeting and eliminating senescence cells, would allow the development of new therapeutic approaches for the treatment of different diseases. The 4N1Ks peptide, a 10 amino acid peptide derived from TSP1 protein, combines both features by targeting the CD47 receptor present in the surface of senescent cells and demonstrating senolytic activity, thereby representing a new strategy to take into account. Nonetheless, peptide drugs are known for their biopharmaceutical issues, such as low short half-life and tendency to aggregate, which reduces their bioavailability and limits their therapeutic potential. In order to overcome this problem, herein we propose the use of biodegradable and biocompatible sphingomyelin nanosystems (SNs), decorated with this peptide for the targeting of senescent cells. In order to efficiently associate the 4N1Ks peptide to the nanosystems while exposing it on their surface for an effective targeting of senescent cells, the 4N1Ks peptide was chemically conjugated to a PEGylated hydrophobic chain. The resulting SNs-4N1Ks (SNs-Ks), were extensively characterized for their physicochemical properties, by dynamic light scattering, multiple-angle dynamic light scattering, nanoparticle tracking analysis and atomic force microscopy. The SNs-Ks demonstrated suitable features in terms of size (∼ 100 nm), association efficiency (87.2 ± 6.9%) and stability in different biorelevant media. Cell toxicity experiments in MCF7 cancer cells indicated an improved cytotoxic effect of SNs-Ks, decreasing cancer cells capacity to form colonies, with respect to free peptide, and an improved hemocompatibility. Lastly, senescence escape preliminary experiments demonstrated the improvement of SNs-Ks senolytic activity of in chemotherapy-induced senescence model of breast cancer cells. Therefore, these results demonstrate for the first time the potential of the combination of SNs with 4N1Ks peptide for the development of innovative senolytic therapies to battle cancer.
    Keywords:  Cellular senescence; TSP-1; sphingomyelin nanoemulsions
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121618
  7. Aging Cell. 2022 Mar 02. e13578
    Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
    Dafni Chondronasiou, Diljeet Gill, Lluc Mosteiro, Rocio G Urdinguio, Antonio Berenguer-Llergo, Mònica Aguilera, Sylvere Durand, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Abad, Daniel E Martin-Herranz, Camille Stephan-Otto Attolini, Neus Prats, Guido Kroemer, Mario F Fraga, Wolf Reik, Manuel Serrano.
      The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
    Keywords:  OSKM; Yamanaka; aging; epigenetic clocks; pluripotency; reprogramming; transcriptomic clocks
    DOI:  https://doi.org/10.1111/acel.13578
  8. Signal Transduct Target Ther. 2022 Mar 04. 7(1): 66
    miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD+/SIRT inactivation.
    Hui Gong, Honghan Chen, Peng Xiao, Ning Huang, Xiaojuan Han, Jian Zhang, Yu Yang, Tiepeng Li, Tingting Zhao, Haoran Tai, Weitong Xu, Gongchang Zhang, Chuhui Gong, Ming Yang, Xiaoqiang Tang, Hengyi Xiao.
      Nicotinamide adenine dinucleotide (NAD+) is indispensable for the anti-aging activity of the sirtuin (SIRT) family enzymes. AMP-activated protein kinase (AMPK) upregulates NAD+ synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase (NAMPT)-dependent manner. However, the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD+/SIRT activation remain unclear. In this study, we tried to identify senescence-associated microRNAs (miRNAs) that negatively regulate the cascade linking AMPK and NAMPT expression. miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation. Additionally, miR-146a overexpression weakened the metformin-mediated upregulation of NAMPT expression, NAD+ synthesis, SIRT activity, and senescence protection, whereas treatment with the miR-146a inhibitor reversed this effect. Importantly, these findings were observed both in vitro and in vivo. Mechanistically, miR-146a directly targeted the 3'-UTR of Nampt mRNA to reduce the expression of NAMPT. AMPK activators metformin and 5-aminoimidazole-4-carboxamide (AICAR) hindered miR-146a expression at the transcriptional level by promoting IκB kinase (IKK) phosphorylation to attenuate nuclear factor-kappaB (NF-κB) activity. These findings identified a novel cascade that negatively regulates the NAD+/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation. Furthermore, our results showed that miR-146a impedes the anti-aging effect of AMPK. This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD+/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s41392-022-00886-3
  9. Nat Rev Cancer. 2022 Mar 03.
    Exploiting senescence for the treatment of cancer.
    Liqin Wang, Lina Lankhorst, René Bernards.
      Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a 'one-two punch' sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.
    DOI:  https://doi.org/10.1038/s41568-022-00450-9
  10. Tissue Cell. 2022 Feb 22. pii: S0040-8166(22)00037-4. [Epub ahead of print]76 101765
    Pin1-mediated regulation of articular cartilage stem/progenitor cell aging.
    Xiao Zhang, Weiwei Sun, Weijie Wu, Minhao Chen, Tianyi Ji, Hua Xu, Youhua Wang.
      Cartilage stem/progenitor cells (CSPCs) was recently isolated and identified from the cartilage tissue. CSPCs is essential for repair and regeneration of cartilage in osteoarthritis (OA). Aging is a primary risk factor for cartilage damage and joint OA. Although studies have confirmed the link between cell aging and OA, the underlying molecular mechanisms regulating CSPCs aging are not fully understood. In this study, we investigated the role of Pin1 in the aging of rat knee joint CSPCs. We isolated CSPCs from rat knee joints and demonstrated that, in long-term in vitro culture, Pin1 protein levels are significantly reduced. At the same time, expression of the senescence-related β-galactosidase and the senescence marker p16INK4A were markedly elevated. In addition, Pin1 overexpression reversed the progression of cellular senescence, as evidenced by the down-regulation of senescence-related β-galactosidase, increased EdU positive cells and diminished levels of p16INK4A. In contrast, Pin1 siRNA incorporation promoted CSPCs senescence. In addition, we also observed the distribution of cell cycles through flow cytometry and revealed that Pin1 deficiency results in cell cycle arrest in the G1 phase, suggesting severe lack of proliferation ability, a sign of cellular senescence. Collectively, these results validated that Pin1 is an essential regulator of CSPCs aging.
    Keywords:  Aging; Cartilage-derived stem/progenitor cells; OA; P16(INK4A); Pin1
    DOI:  https://doi.org/10.1016/j.tice.2022.101765
  11. Ageing Res Rev. 2022 Feb 24. pii: S1568-1637(22)00038-1. [Epub ahead of print]77 101596
    The role of nutrition in inflammaging.
    Paolo Di Giosia, Cosimo Andrea Stamerra, Paolo Giorgini, Tannaz Jamialahamdi, Alexandra E Butler, Amirhossein Sahebkar.
       BACKGROUND: Old age is characterized by a peculiar low-grade, chronic, and "sterile" inflammatory state, which has been termed "inflammaging." This is believed to substantially contribute to the pathogenesis of many age-related diseases and to the progression of the ageing process. An adequate nutritional status is of great importance for maintaining proper immune system functionality and preventing frailty in the elderly.
    METHODS: The purpose of this narrative review is to synthesize what is known about the interaction between inflammaging and nutrition, focusing on the role of the Mediterranean diet, gut microbiota and calorie restriction (CR) in reducing systemic inflammation and improving clinical outcomes.
    CONCLUSIONS: Dietary components may affect inflammation directly, counteracting the low grade age-related inflammation. In this regard, healthy diets, including the Mediterranean diet, are associated with lower concentrations of inflammatory mediators, like C-reactive protein (CRP) and Tumor Necrosis Factor-α (TNF-α), that are hallmarks of inflammaging. Among the components of a healthy diet, a higher intake of whole grains, vegetables and fruits, nuts and fish are all associated with lower inflammation. One area of promising research is the microbiome-ageing interaction. Indeed, dysbiosis plays a role in sub-optimal metabolism, immune function and brain function and contributes to the poor health and impaired well-being associated with ageing. Modulation of the gut microbiota has shown promising results in some disorders. Additionally, the discovery of several molecular pathways associated with ageing, and the characterization of the beneficial effects of calorie restriction (CR) in modulating metabolic pathways and preventing inflammation, should encourage research on CR mimetics, drugs able to promote lifespan and extend healthspan.
    Keywords:  Caloric restriction; Immunosenescence; Inflammaging; Intermitting fasting; Mediterranean diet; Microbioma; Nutrition
    DOI:  https://doi.org/10.1016/j.arr.2022.101596
  12. Ageing Res Rev. 2022 Feb 24. pii: S1568-1637(22)00040-X. [Epub ahead of print]77 101598
    Epigenetic modifications in spinal ligament aging.
    Qian Xiang, Yongzhao Zhao, Jialiang Lin, Shuai Jiang, Weishi Li.
      Spinal stenosis is a common degenerative spine disorder in the aged population and the spinal ligament aging is a main contributor to this chronic disease. However, the underlying mechanisms of spinal ligament aging remain unclear. Epigenetics is the study of heritable and reversible changes in the function of a gene or genome that occur without any alteration in the primary DNA sequence. Epigenetic alterations have been demonstrated to play crucial roles in age-related diseases and conditions, and they are recently studied as biomarkers and therapeutic targets in the field of cancer research. The main epigenetic modifications, including DNA methylation alteration, histone modifications as well as dysregulated noncoding RNA modulation, have all been implicated in spinal ligament aging diseases. DNA methylation modulates the expression of critical genes including WNT5A, GDNF, ACSM5, miR-497 and miR-195 during spinal ligament degeneration. Histone modifications widely affect gene expression and obvious histone modification abnormalities have been found in spinal ligament aging. MicroRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) exert crucial regulating effects on spinal ligament aging conditions via targeting various osteogenic or fibrogenic differentiation related genes. To our knowledge, there is no systematic review yet to summarize the involvement of epigenetic mechanisms of spinal ligament aging in degenerative spinal diseases. In this study, we systematically discussed the different epigenetic modifications and their potential functions in spinal ligament aging process.
    Keywords:  DNA methylation; Degenerative spinal stenosis; Epigenetics; Histone acetylation; Non-coding RNAs; Spinal ligament aging
    DOI:  https://doi.org/10.1016/j.arr.2022.101598
  13. Geroscience. 2022 Mar 05.
    Senescent macrophages in the human adipose tissue as a source of inflammaging.
    Giulia Matacchione, Jessica Perugini, Eleonora Di Mercurio, Jacopo Sabbatinelli, Francesco Prattichizzo, Martina Senzacqua, Gianluca Storci, Christian Dani, Giovanni Lezoche, Mario Guerrieri, Antonio Giordano, Massimiliano Bonafè, Fabiola Olivieri.
      Obesity is a major risk factor for type 2 diabetes and a trigger of chronic and systemic inflammation. Recent evidence suggests that an increased burden of senescent cells (SCs) in the adipose tissue of obese/diabetic animal models might underlie such pro-inflammatory phenotype. However, the role of macrophages as candidate SCs, their phenotype, the distribution of SCs among fat depots, and clinical relevance are debated. The senescence marker β-galactosidase and the macrophage marker CD68 were scored in visceral (vWAT) and subcutaneous (scWAT) adipose tissue from obese patients (n=17) undergoing bariatric surgery and control patients (n=4) subjected to cholecystectomy. A correlation was made between the number of SCs and BMI, serum insulin, and the insulin resistance (IR) index HOMA. The monocyte cell line (THP-1) was cultured in vitro in high glucose milieu (60 mM D-glucose) and subsequently co-cultured with human adipocytes (hMADS) to investigate the reciprocal inflammatory activation. In obese patients, a significantly higher number of SCs was observed in vWAT compared to scWAT; about 70% of these cells expressed the macrophage marker CD68; and the number of SCs in vWAT, but not in scWAT, positively correlated with BMI, HOMA-IR, and insulin. THP-1 cultured in vitro in high glucose milieu acquired a senescent-like phenotype (HgSMs), characterized by a polarization toward a mixed M1/M2-like secretory phenotype. Co-culturing HgSMs with hMADS elicited pro-inflammatory cytokine expression in both cell types, and defective insulin signaling in hMADS. In morbid obesity, expansion of visceral adipose depots involves an increased burden of macrophages with senescent-like phenotype that may promote a pro-inflammatory profile and impair insulin signaling in adipocytes, supporting a framework where senescent macrophages fuel obesity-induced systemic inflammation and possibly contribute to the development of IR.
    Keywords:  Adipose tissue; Inflammaging; Insulin resistance; Macrophage; Obesity; Senescent cell
    DOI:  https://doi.org/10.1007/s11357-022-00536-0
  14. Autophagy. 2022 Feb 27. 1-2
    Intermittent time-restricted feeding promotes longevity through circadian autophagy.
    Zhangyuan Yin, Daniel J Klionsky.
      Macroautophagy/autophagy plays crucial roles in aging and the pathogenesis of age-related diseases. Studies in various animal models demonstrate the conserved requirement for autophagy-related genes in multiple anti-aging interventions. A recent study from the Shirasu-Hiza lab showed that a newly designed intermittent time-restricted feeding (iTRF) dietary regimen can robustly extend fly healthspan and lifespan through circadian rhythm-dependent activation of autophagy. The night-specific induction of autophagy is both necessary and sufficient for iTRF-mediated health benefits. The study provides the intriguing possibility that novel behavioral or pharmaceutical interventions that promote night-specific autophagy can be used to promote healthy aging.
    Keywords:  Aging; autophagy; circadian rhythm; lifespan; time-restricted feeding
    DOI:  https://doi.org/10.1080/15548627.2022.2039524
  15. Aging Cell. 2022 Mar 04. e13562
    Different responses to DNA damage determine ageing differences between organs.
    Maria Vougioukalaki, Joris Demmers, Wilbert P Vermeij, Marjolein Baar, Serena Bruens, Aristea Magaraki, Ewart Kuijk, Myrthe Jager, Sarra Merzouk, Renata M C Brandt, Janneke Kouwenberg, Ruben van Boxtel, Edwin Cuppen, Joris Pothof, Jan H J Hoeijmakers.
      Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1Δ /- mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1Δ /- intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over-proliferation. ISCs retain their organoid-forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1-KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1Δ /- liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA-damaging agents, and lower lesion removal. Our findings reveal organ-specific anti-ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self-renewal mainly invokes replication-linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA-repair-deficient progerias.
    Keywords:  DNA damage response; ERCC1; adult stem cells; genome maintenance; liver; nucleotide excision repair; organoids; small intestine
    DOI:  https://doi.org/10.1111/acel.13562
  16. Pharmacol Res. 2022 Feb 24. pii: S1043-6618(22)00088-3. [Epub ahead of print]178 106143
    NLRP3 inflammasome links vascular senescence to diabetic vascular lesions.
    Guang-Jie Tai, Qing-Qing Yu, Jia-Peng Li, Wei Wei, Xiao-Man Ji, Rui-Fang Zheng, Xiao-Xue Li, Li Wei, Ming Xu.
      Vascular senescence is inextricably linked to the onset and progression of cardiovascular diseases (CVDs), which are the main cause of mortality in people with Type 2 diabetes (T2DM). Previous studies have emphasized the importance of chronic aseptic inflammation in diabetic vasculopathy. Here, we found the abnormal activation of NLRP3 inflammasome in the aorta of both old and T2DM mice by immunofluorescence and Western Blot analysis. Histopathological and isometry tension analysis showed that the presence of T2DM triggered or aggravated the increase of vascular aging markers, as well as age-associated vascular impairment and vasomotor dysfunction, which were improved by NLRP3 deletion or inhibition. Differential expression of aortic genes links to senescence activation and vascular remodeling supports the favorable benefits of NLRP3-/- during T2DM. In vitro results based on primary mice aortic endothelial cells (MAECs) and vascular smooth muscle cells (VSMCs) demonstrate that NLRP3 deficiency attenuated premature senescence and restored proliferation and migration capability under-stimulation, and partially ameliorated replicative senescence. These results provide an insight into the critical role of NLRP3 signaling in T2DM-induced vascular aging and loss of vascular homeostasis, and provide the possibility that targeting NLRP3 inflammasome might be a promising strategy to prevent diabetic vascular senescence and associated vascular lesions.
    Keywords:  NLRP3 inflammasome; T2DM; Vascular senescence
    DOI:  https://doi.org/10.1016/j.phrs.2022.106143
  17. Cell Biol Toxicol. 2022 Mar 02.
    Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes.
    Xiu Mei Ma, Kang Geng, Betty Yuen-Kwan Law, Peng Wang, Yue Li Pu, Qing Chen, Hui Wen Xu, Xiao Zhen Tan, Zong Zhe Jiang, Yong Xu.
      Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.
    Keywords:  Diabetic cardiomyopathy; Lipotoxicity; cGAS-STING; mtDNA release
    DOI:  https://doi.org/10.1007/s10565-021-09692-z
  18. Proc Biol Sci. 2022 Mar 09. 289(1970): 20212434
    Cellular senescence, rejuvenation and potential immortality.
    A Rupert Sheldrake.
      Ageing, death, and potential immortality lie at the heart of biology, but two seemingly incompatible paradigms coexist in different research communities and have done since the nineteenth century. The universal senescence paradigm sees senescence as inevitable in all cells. Damage accumulates. The potential immortality paradigm sees some cells as potentially immortal, especially unicellular organisms, germ cells and cancerous cells. Recent research with animal cells, yeasts and bacteria show that damaged cell constituents do in fact build up, but can be diluted by growth and cell division, especially by asymmetric cell division. By contrast, mammalian embryonic stem cells and many cancerous and 'immortalized' cell lines divide symmetrically, and yet replicate indefinitely. How do they acquire their potential immortality? I suggest they are rejuvenated by excreting damaged cell constituents in extracellular vesicles. If so, our understanding of cellular senescence, rejuvenation and potential immortality could be brought together in a new synthesis, which I call the cellular rejuvenation hypothesis: damaged cell constituents build up in all cells, but cells can be rejuvenated either by growth and cell division or, in 'immortal' cell lines, by excreting damaged cell constituents. In electronic supplementary material, appendix, I outline nine ways in which this hypothesis could be tested.
    Keywords:  asymmetric cell division; cancer cells; cellular rejuvenation; cellular senescence; damaged cell constituents; stem cells
    DOI:  https://doi.org/10.1098/rspb.2021.2434
  19. Front Cell Dev Biol. 2022 ;10 682045
    Geroprotectors and Skeletal Health: Beyond the Headlines.
    Alexandra Rayson, Maya Boudiffa, Maneeha Naveed, Jon Griffin, Enrico Dall'Ara, Ilaria Bellantuono.
      Osteoporosis and osteoarthritis are the most common age-related diseases of the musculoskeletal system. They are responsible for high level of healthcare use and are often associated with comorbidities. Mechanisms of ageing such as senescence, inflammation and autophagy are common drivers for both diseases and molecules targeting those mechanisms (geroprotectors) have potential to prevent both diseases and their co-morbidities. However, studies to test the efficacy of geroprotectors on bone and joints are scant. The limited studies available show promising results to prevent and reverse Osteoporosis-like disease. In contrast, the effects on the development of Osteoarthritis-like disease in ageing mice has been disappointing thus far. Here we review the literature and report novel data on the effect of geroprotectors for Osteoporosis and Osteoarthritis, we challenge the notion that extension of lifespan correlates with extension of healthspan in all tissues and we highlight the need for more thorough studies to test the effects of geroprotectors on skeletal health in ageing organisms.
    Keywords:  aging; geroprotectors; mouse models; osteoarthritis; osteoporosis; senescence
    DOI:  https://doi.org/10.3389/fcell.2022.682045
  20. Aging Cell. 2022 Mar 02. e13564
    Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging.
    Diana Bou-Teen, Celia Fernandez-Sanz, Elisabet Miro-Casas, Zuzana Nichtova, Elena Bonzon-Kulichenko, Kelly Casós, Javier Inserte, Antonio Rodriguez-Sinovas, Begoña Benito, Shey-Shing Sheu, Jesús Vázquez, Ignacio Ferreira-González, Marisol Ruiz-Meana.
      Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1-ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1-ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes' susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1-ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1-ATP synthase glycation in H9c2 myoblasts recapitulated the age-related defective FoF1-ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1-ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging.
    Keywords:  ATP; ROS; aging; dicarbonyl stress; mitochondria
    DOI:  https://doi.org/10.1111/acel.13564
  21. Biol Res. 2022 Mar 03. 55(1): 10
    Aβ promotes CD38 expression in senescent microglia in Alzheimer's disease.
    Yiran Hu, Yan Huang, Sanli Xing, Chuan Chen, Dingzhu Shen, Jiulin Chen.
       BACKGROUND: In Alzheimer's disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear.
    METHODS: We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aβ1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD + /NADH), and neuroinflammatory factors (IL-1β, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice.
    RESULTS: Following Aβ1-40 injury, SA-β-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD + /NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aβ1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1β, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 + BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved.
    CONCLUSIONS: Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aβ1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.
    Keywords:  CD38; Energy dysmetabolism; Microglia; NAD + ; Neuroinflammation; Senescence
    DOI:  https://doi.org/10.1186/s40659-022-00379-1
  22. Blood. 2022 Mar 01. pii: blood.2021012197. [Epub ahead of print]
    Age-dependent effects of Igf2bp2 on gene regulation, function, and aging of hematopoietic stem cells in mice.
    Miaomiao Suo, Megan K Rommelfanger, Yulin Chen, Elias Moris Amro, Bing Han, Zhiyang Chen, Karol Szafranski, Sundaram Reddy Chakkarappan, Bernhard Otto Boehm, Adam L MacLean, Karl Lenhard Rudolph.
      Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPC) during aging. The Lin28b/Hmga2 pathway controls tissue development and the postnatal downregulation of this pathway limits the self-renewal of adult vs. fetal hematopoietic stem cells (HSC). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates mRNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. Here, we show in an analysis of wildtype and Igf2bp2 knockout mice that Igf2bp2 regulates oxidative metabolism in HSPC and the expression of metabolism, protein synthesis, and stemness-related genes in HSC of young mice. Interestingly, Igf2bp2 expression and function strongly decline in HSC aging. In young mice, Igf2bp2-deletion mimics aging-related changes of HSC, including changes in Igf2bp2-target gene expression and the impairment in colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status has no effect on these parameters in HSC. Unexpectedly, Igf2bp2 deficient mice exhibit an amelioration of the aging-associated increase of HSC numbers and myeloid skewed differentiation. Together, Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSC, which is required for full HSC function at young adult age. However, Igf2bp2 gene function is lost during aging and it appears to contribute to HSC aging in two ways: (i) the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSC and (ii) the activity of Igf2bp2 at young age contributes to aging-associated HSC expansion and myeloid skewing.
    DOI:  https://doi.org/10.1182/blood.2021012197
  23. Oxid Med Cell Longev. 2022 ;2022 7295224
    Regulation of Cr(VI)-Induced Premature Senescence in L02 Hepatocytes by ROS-Ca2+-NF-κB Signaling.
    Yujing Zhang, Gang Yang, Shuai Huang, Xinyue Yang, Fengyan Yuan, Yinghui Song, Sulai Liu, Xing Yu.
      Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.
    DOI:  https://doi.org/10.1155/2022/7295224
  24. Nat Neurosci. 2022 Mar 03.
    Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine.
    Omar Mossad, Bérénice Batut, Bahtiyar Yilmaz, Nikolaos Dokalis, Charlotte Mezö, Elisa Nent, Lara Susann Nabavi, Melanie Mayer, Feres José Mocayar Maron, Joerg M Buescher, Mercedes Gomez de Agüero, Antal Szalay, Tim Lämmermann, Andrew J Macpherson, Stephanie C Ganal-Vonarburg, Rolf Backofen, Daniel Erny, Marco Prinz, Thomas Blank.
      Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.
    DOI:  https://doi.org/10.1038/s41593-022-01027-3
  25. Elife. 2022 Mar 04. pii: e57393. [Epub ahead of print]11
    In vivo transcriptomic profiling using cell encapsulation identifieseffector pathways of systemic aging.
    Omid Mashinchian, Xiaotong Hong, Joris Michaud, Eugenia Migliavacca, Gregory Lefebvre, Christophe Boss, Filippo De Franceschi, Emmeran Le Moal, Jasmin Collerette-Tremblay, Joan Isern, Sylviane Metairon, Frederic Raymond, Patrick Descombes, Nicolas Bouche, Pura Muñoz-Cánoves, Jerome N Feige, C Florian Bentzinger.
      Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.57393
  26. EMBO Rep. 2022 Mar 01. e54262
    NPM1 ablation induces HSC aging and inflammation to develop myelodysplastic syndrome exacerbated by p53 loss.
    Claudia Morganti, Kyoko Ito, Chie Yanase, Amit Verma, Julie Teruya-Feldstein, Keisuke Ito.
      Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with morphologic dysplasia and a propensity to transform into overt acute myeloid leukemia (AML). Our analysis of two cohorts of 20 MDS and 49 AML with multi-lineage dysplasia patients shows a reduction in Nucleophosmin 1 (NPM1) expression in 70% and 90% of cases, respectively. A mouse model of Npm1 conditional knockout (cKO) in hematopoietic cells reveals that Npm1 loss causes premature aging of hematopoietic stem cells (HSCs). Mitochondrial activation in Npm1-deficient HSCs leads to aberrant activation of the NLRP3 inflammasome, which correlates with a developing MDS-like phenotype. Npm1 cKO mice exhibit shortened survival times, and expansion of both the intra- and extra-medullary myeloid populations, while evoking a p53-dependent response. After transfer into a p53 mutant background, the resulting Npm1/p53 double KO mice develop fatal leukemia within 6 months. Our findings identify NPM1 as a regulator of HSC aging and inflammation and highlight the role of p53 in MDS progression to leukemia.
    Keywords:  HSC aging; MDS; Nlrp3; Npm1; Tp53
    DOI:  https://doi.org/10.15252/embr.202154262
  27. Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11
    Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
    Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.
      Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.75658
  28. Hepatology. 2022 Mar 04.
    Improving the repopulation capacity of elderly human hepatocytes by decoding aging-associated hepatocyte plasticity.
    Yun-Zhong Nie, Yun-Wen Zheng, Hideki Taniguchi.
       BACKGROUND & AIMS: The loss of liver regenerative capacity is the most dramatic age-associated alteration. Because of an incomplete mechanistic understanding of the liver aging process, a successful therapeutic strategy to improve liver regeneration in the elderly has not been developed so far. Hepatocyte plasticity is a principal mechanism for producing new hepatocytes and cholangiocytes during regeneration. This study aims to promote the repopulation capacity of elderly hepatocytes by decoding the underlying mechanism about the regulation of aging on human hepatocyte plasticity.
    APPROACH & RESULTS: To understand the age-related mechanisms, we established a hepatocyte aging model from human induced pluripotent stem cells and developed a method for ex vivo characterization of hepatocyte plasticity. We found that hepatocyte plasticity was gradually diminished with aging, and the impaired plasticity was caused by aging-induced histone hypoacetylation. Notably, selective inhibition of histone deacetylases could markedly restore aging-impaired plasticity. Based on these findings, we successfully improved the plasticity of elderly PHHs that enhanced their repopulation capacity in the liver injury model.
    CONCLUSIONS: This study suggests that aging-induced histone hypoacetylation impairs hepatocyte plasticity, and hepatocyte plasticity might be a therapeutic target for promoting the regenerative capacity of the elderly liver.
    Keywords:  FGF2; Hepatic aging model; Hepatic progenitor cells; Histone acetylation; hiPSC
    DOI:  https://doi.org/10.1002/hep.32443
  29. Peptides. 2022 Feb 26. pii: S0196-9781(22)00041-9. [Epub ahead of print] 170775
    Angiotensin-(1-7), a protective peptide against vascular aging.
    Valencia, F Shamoon, A Romero, F De la Cuesta, C F Sánchez-Ferrer, C Peiró.
      Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound aging alterations make arteries more prone to vascular disease, including hypertension, atherosclerosis and other arterial complications that impact the organism beyond the cardiovascular system and accelerate frailty. For these reasons, preventing or delaying the hallmarks of vascular aging is nowadays a major health goal, especially in our aged societies. In this context, angiotensin(Ang)-(1-7), a major player of the protective branch of the renin-angiotensin system, has gained relevance over recent years as growing knowledge on its anti-aging properties is being unveiled. Here, we briefly review the main actions of Ang-(1-7) against vascular aging. These include protection against vascular cell senescence, anti-inflammatory and antioxidant effects together with the induction of cytoprotective systems. Ang-(1-7) further ameliorates endothelial dysfunction, a hallmark of vascular aging and disease, attenuates fibrosis and calcification and promotes protective angiogenesis and repair. Although further research is needed to better understand the anti-aging properties of Ang-(1-7) on the vasculature, this heptapeptide arises as a promising pharmacological tool for preventing vascular aging and frailty.
    Keywords:  Angiotensin-(1-7); aging; protection; vascular
    DOI:  https://doi.org/10.1016/j.peptides.2022.170775
  30. Med Mol Morphol. 2022 Mar 03.
    Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation.
    Yudai Nakajima, Yuto Yamazaki, Xin Gao, Masatoshi Hashimoto, Masaki Nio, Motoshi Wada, Fumiyoshi Fujishima, Hironobu Sasano.
      Biliary atresia (BA) is a cholestatic disease with extrahepatic bile duct obstruction that requires early surgical intervention and occasionally liver transplantation (LT). Accumulation of toxic bile acids induces oxidative stress that results in cell damage, such as cell senescence, mitochondrial dysfunction and others. However, details of their reciprocal association and clinical significance are unexplored. Therefore, we used immuno-localization of markers for cell senescence (p16 and p21), nuclear double-strand DNA damage (γH2AX), autophagy (p62), and mtDNA damage (mtDNA copy number) in patients with BA who underwent Kasai portoenterostomy (KP) and LT. We studied liver biopsy specimens from 54 patients with BA, 14 who underwent LT and 11 from the livers of neonates and infants obtained at autopsy. In hepatocytes, p21 expression was significantly increased in KP. In cholangiocytes, p16 expression was significantly increased in LT, and p21 expression was significantly increased in KP. p62 expression was significantly increased in the KP hepatocytes and LT cholangiocytes. Furthermore, mtDNA copy number significantly decreased in KP and LT compared with the control. Cell senescence and mitochondrial DNA damage progression were dependent on the BA clinical stages and could possibly serve as the markers of indication of LT.
    Keywords:  Biliary atresia; DNA damage; Kasai portoenterostomy; Liver; Mitochondrial damage; Senescence
    DOI:  https://doi.org/10.1007/s00795-022-00314-z
  31. J Cardiovasc Transl Res. 2022 Mar 02.
    SIRT6 Protects Against Myocardial Ischemia-Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation.
    Xiaokang Li, Lin Liu, Wenhua Jiang, Manling Liu, Yishi Wang, Heng Ma, Nan Mu, Haiyan Wang.
      Impaired autophagic flux induces aging-related ischemia vulnerability, which is the hallmark pathology in cardiac aging. Our previous work has confirmed that the accumulation of charged multivesicular body protein 2B (CHMP2B), a subunit of the ESCRT-III complex, in the heart can impair autophagy flux. However, whether CHMP2B accumulation contributes to aging-related intolerance to ischemia/reperfusion (I/R) injury and the regulatory mechanism for CHMP2B in aged heart remain elusive. The cardiac CHMP2B level was significantly higher in aged human myocardium than that in young myocardium. Increased CHMP2B were shown to inhibit autophagic flux leading to the deterioration of MI/R injury in aged mice hearts. Interestingly, a negative correlation was observed between SIRT6 and CHMP2B expression in human heart samples. Specific activation of SIRT6 suppressed CHMP2B accumulation and ameliorated autophagy flux in aged hearts. Using myocardial-specific SIRT6 heterozygous knockout mice and recovery experiments confirmed that SIRT6 regulated myocardial CHMP2B levels. Finally, activation of SIRT6 decreased acetylation of FoxO1 to promote its transcriptional function on Atrogin-1, a muscle-specific ubiquitin ligase, which subsequently enhanced the degradation of CHMP2B by Atrogin-1. This is a novel mechanism for SIRT6 against aging-related myocardial ischemia vulnerability, particularly by preventing excessive accumulation of autophagy key factors.
    Keywords:  Aging; Atrogin-1; Autophagic flux; CHMP2B; Myocardial ischemia–reperfusion; SIRT6
    DOI:  https://doi.org/10.1007/s12265-021-10184-y
  32. Nat Metab. 2022 Feb;4(2): 269-283
    mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1.
    Dandan Zhong, Zhikang Wan, Jie Cai, Lingling Quan, Rumeng Zhang, Tian Teng, Hang Gao, Chenyu Fan, Meng Wang, Dong Guo, Hongxing Zhang, Zhanjun Jia, Ying Sun.
      β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through unknown mechanisms. Here we show better β-cell identity, less β-cell senescence, enhanced glucose-stimulated insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/db mice). Furthermore, the function of mPGES-2 in β-cells is validated using mice with β-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing β-cell senescence via interference of the PGE2-EP3-NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against β-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated β-cell senescence and dysfunction via the PGE2-EP3-NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated β-cell dysfunction and diabetes.
    DOI:  https://doi.org/10.1038/s42255-022-00536-6
  33. Trends Immunol. 2022 Feb 11. pii: S1471-4906(22)00025-4. [Epub ahead of print]
    NAD+ in COVID-19 and viral infections.
    Minyan Zheng, Michael B Schultz, David A Sinclair.
      NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.
    Keywords:  COVID-19; NAD(+); immune responses; inflammation
    DOI:  https://doi.org/10.1016/j.it.2022.02.001
  34. Front Med (Lausanne). 2022 ;9 844266
    Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue.
    Maddalena Conte, Laura Petraglia, Paolo Poggio, Vincenza Valerio, Serena Cabaro, Pasquale Campana, Giuseppe Comentale, Emilio Attena, Vincenzo Russo, Emanuele Pilato, Pietro Formisano, Dario Leosco, Valentina Parisi.
      Human aging is a complex phenomenon characterized by a wide spectrum of biological changes which impact on behavioral and social aspects. Age-related changes are accompanied by a decline in biological function and increased vulnerability leading to frailty, thereby advanced age is identified among the major risk factors of the main chronic human diseases. Aging is characterized by a state of chronic low-grade inflammation, also referred as inflammaging. It recognizes a multifactorial pathogenesis with a prominent role of the innate immune system activation, resulting in tissue degeneration and contributing to adverse outcomes. It is widely recognized that inflammation plays a central role in the development and progression of numerous chronic and cardiovascular diseases. In particular, low-grade inflammation, through an increased risk of atherosclerosis and insulin resistance, promote cardiovascular diseases in the elderly. Low-grade inflammation is also promoted by visceral adiposity, whose accumulation is paralleled by an increased inflammatory status. Aging is associated to increase in epicardial adipose tissue (EAT), the visceral fat depot of the heart. Structural and functional changes in EAT have been shown to be associated with several heart diseases, including coronary artery disease, aortic stenosis, atrial fibrillation, and heart failure. EAT increase is associated with a greater production and secretion of pro-inflammatory mediators and neuro-hormones, so that thickened EAT can pathologically influence, in a paracrine and vasocrine manner, the structure and function of the heart and is associated to a worse cardiovascular outcome. In this review, we will discuss the evidence underlying the interplay between inflammaging, EAT accumulation and cardiovascular diseases. We will examine and discuss the importance of EAT quantification, its characteristics and changes with age and its clinical implication.
    Keywords:  aortic stenosis; atrial fibrillation; cardiovascular diseases; coronary artery disease; elderly; epicardial adipose tissue; heart failure; inflammation
    DOI:  https://doi.org/10.3389/fmed.2022.844266
  35. Bioengineered. 2022 Mar;13(3): 6196-6207
    Nintedanib ameliorates oxidized low-density lipoprotein -induced inflammation and cellular senescence in vascular endothelial cells.
    Ling Li, Yudan Chen, Chang Shi.
      Atherosclerosis (AS) is a life-threatening cardiovascular disease and it has been reported that endothelial dysfunction is the initial inducer of AS. Recent reports suggest that inflammation and oxidative stress-induced cell senescence are main inducers of endothelial dysfunction. Nintedanib is an effective inhibitor of multityrosine kinase receptors developed for the treatment of fibrosis, which was recently reported to exert inhibitory effects against inflammation and oxidative stress. The present study plans to study the effect and mechanism of Nintedanib on endothelial dysfunction. We found that in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), the increased production of total cholesterol (TC), free cholesterol (FC), and pro-inflammatory cytokines were observed, reversed by 10 μM and 25 μM Nintedanib. The elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as the declined activity of glutathione peroxidase (GSH-Px) in ox-LDL-treated HUVECs, were significantly abolished by 10 μM and 25 μM Nintedanib. Increased proportion of senescence-associated β-galactosidase (SA-β-gal) positive staining cells, activated p53/p21 pathway, and promoted cell fraction in the G0/G1 phase were observed in ox-LDL-treated HUVECs, all of which were dramatically reversed by 10 μM and 25 μM Nintedanib. Lastly, the increased expression level of Arginase-II (Arg-II) in HUVECs by ox-LDL was repressed by Nintedanib. The protective effects of Nintedanib on ox-LDL- induced cellular senescence were pronouncedly blocked by the overexpression of Arg-II. Collectively, our data suggest that Nintedanib mitigates ox-LDL-induced inflammation and cellular senescence in vascular endothelial cells by downregulating Arg-II.
    Keywords:  Arg‐II; Atherosclerosis; HUVECs; Nintedanib; cell senescence
    DOI:  https://doi.org/10.1080/21655979.2022.2036913
  36. Aging (Albany NY). 2022 Feb 27. 14(undefined):
    Telomere length in leucocytes and solid tissues of young and aged rats.
    M Donatella Semeraro, Gunter Almer, Wilfried Renner, Hans-Jürgen Gruber, Markus Herrmann.
       BACKGROUND: Telomeres are protective nucleoprotein structures at the end of chromosomes that shorten with age. Telomere length (TL) in peripheral blood mononuclear cells (PBMCs) has been proposed as surrogate marker for TL in the entire organism. Solid evidence that supports this concept is lacking.
    METHODS: Relative TL (RTL) was measured in PBMCS and multiple solid tissues from 24 young (4 months) and 24 aged (14 months) Sprague-Dawley (SD) rats. The mRNA expression of telomerase (TERT) and shelterin proteins TERF-1 and TERF-2 was also measured.
    RESULTS: Mean RTL in PBMCs and solid tissues of young rats ranged from 0.64 ± 0.26 in large intestine to 1.07 ± 0.22 in skeletal muscle. RTL in PBMCs correlated with that in kidney (r = 0.315, p = 0.008), skeletal muscle (r = 0.276, p = 0.022), liver (r = 0.269, p = 0.033), large intestine (r = -0.463, p = 7.035E-5) and aorta (r = -0.273, p = 0.028). A significant difference of RTL between young and aged animals was only observed in aorta (0.98 ± 0.15 vs. 0.76 ± 0.11, p = 1.987E-6), lung (0.76 ± 0.14 vs. 0.85 ± 0.14, p = 0.024) and visceral fat (0.83 ± 0.14 vs. 0.92 ± 0.15, p = 0.44). The expression of TERT significantly differed between the tested organs with highest levels in liver and kidney. Age-related differences in TERT expression were found in PBMCs, skeletal muscle, and visceral fat. mRNA expression of TERF-1 and TERF-2 was tissue-specific with the highest levels in liver. Age-related differences in TERF-1 and TERF-2 expression were inconsistent.
    CONCLUSIONS: The present study questions the utility of RTL in PBMCs as a biomarker for the individual assessment of aging.
    Keywords:  Sprague Dawley rats; aging; shelterin; telomerase; telomeres
    DOI:  https://doi.org/10.18632/aging.203922
  37. Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00074-0. [Epub ahead of print]
    The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.
    Yihang Zhao, Mengzhen Jia, Weixuan Chen, Zhigang Liu.
      Intermittent fasting (IF) has been studied for its effects on lifespan and lifespan as well as the prevention or delay of age-related diseases upon the regulation of metabolic pathways. Mitochondria participate in key metabolic pathways and play important roles in maintaining intracellular signaling networks that modulate various cellular functions. Mitochondrial dysfunction has been described as an early feature of brain aging and neurodegeneration. Although IF has been shown to prevent brain aging and neurodegeneration, the mechanism is still unclear. This review focuses on the mechanisms by which IF improves mitochondrial function, which plays a central role in brain aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The cellular and molecular mechanisms of IF in brain aging and neurodegeneration involve activation of adaptive cellular stress responses and signaling- and transcriptional pathways, thereby enhancing mitochondrial function, by promoting energy metabolism and reducing oxidant production.
    Keywords:  Brain aging; Intermittent fasting; Mitochondrial dysfunction; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.021
  38. Asian J Androl. 2022 Feb 18.
    Modulation of SIRT1 expression improves erectile function in aged rats.
    Wen Yu, Jing Wang, Yu-Tian Dai, Bin Wang, Yang Xu, Qing-Qiang Gao, Zhi-Peng Xu.
      Silent information regulator 2-related enzyme 1 (SIRT1) is an aging-related protein activated with aging. Herein, we evaluated the role of SIRT1 in aging-related erectile dysfunction. The expression of SIRT1 was modulated in aged Sprague-Dawley rats following intragastric administration of resveratrol (Res; 5 mg kg-1), niacinamide (NAM; 500 mg kg-1) or Res (5 mg kg-1) + tadalafil (Tad; phosphodiesterase-5 [PDE5] inhibitor; 5 mg kg-1) for 8 weeks. Then, we determined erectile function by the ratio of intracavernosal pressure (ICP)/mean systemic arterial pressure (MAP). Cavernosal tissues were extracted to evaluate histological changes, cell apoptosis, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP), the superoxide dismutase (SOD)/3,4-methylenedioxyamphetamine (MDA) level, and the expression of SIRT1, p53, and forkhead box O3 (FOXO3a) using immunohistochemistry, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL), enzyme-linked immunosorbent assays, and western blot analysis. Compared with the control, Res treatment significantly improved erectile function, reflected by an increased content of smooth muscle and endothelium, NO/cGMP and SOD activity, and reduced cell apoptosis and MDA levels. The effect of Res was improved by adding Tad. In addition, the protein expression of SIRT1 was increased in the Res group, accompanied by decreased p53 and FOXO3a levels. In addition, inhibition of SIRT1 by NAM treatment resulted in adverse results compared with Res treatment. SIRT1 activation ameliorated aging-related erectile dysfunction, supporting the potential of SIRT1 as a target for erectile dysfunction treatment.
    Keywords:  SIRT1 expression; apoptosis; erectile function; nitric oxide/cyclic guanosine monophosphate signaling; oxidative stress
    DOI:  https://doi.org/10.4103/aja202199
  39. Sci Adv. 2022 Mar 04. 8(9): eabl9051
    Premature aging in mice with error-prone protein synthesis.
    Dimitri Shcherbakov, Martina Nigri, Rashid Akbergenov, Margarita Brilkova, Matilde Mantovani, Patricia Isnard Petit, Amandine Grimm, Agnieszka A Karol, Youjin Teo, Adrián Cortés Sanchón, Yadhu Kumar, Anne Eckert, Kader Thiam, Petra Seebeck, David P Wolfer, Erik C Böttger.
      The main source of error in gene expression is messenger RNA decoding by the ribosome. Translational accuracy has been suggested on a purely correlative basis to positively coincide with maximum possible life span among different rodent species, but causal evidence that translation errors accelerate aging in vivo and limit life span is lacking. We have now addressed this question experimentally by creating heterozygous knock-in mice that express the ribosomal ambiguity mutation RPS9 D95N, resulting in genome-wide error-prone translation. Here, we show that Rps9 D95N knock-in mice exhibit reduced life span and a premature onset of numerous aging-related phenotypes, such as reduced weight, chest deformation, hunchback posture, poor fur condition, and urinary syndrome, together with lymphopenia, increased levels of reactive oxygen species-inflicted damage, accelerated age-related changes in DNA methylation, and telomere attrition. Our results provide an experimental link between translational accuracy, life span, and aging-related phenotypes in mammals.
    DOI:  https://doi.org/10.1126/sciadv.abl9051
  40. Food Funct. 2022 Mar 02.
    Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions.
    Yan Bian, Xingjie Wang, Zhaodi Zheng, Guanghui Ren, Hongyan Zhu, Mengxue Qiao, Guorong Li.
      Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. Resveratrol is gaining attention for its cancer preventive and suppressive properties. The mechanisms of resveratrol in cancer suppression by inducing cancer cell senescence are unclear. Our results showed that resveratrol induced cell senescence along with an increase of SA-β-Gal activity and inhibition of colony formation in breast and lung cancer cells. The underlying mechanisms were that resveratrol induced ER-stress by increasing SIRT1 to promote p38MAPK expression and by reducing NO level to up-regulate DLC1 expression, and ER-stress further resulted in DNA damage and mitochondrial dysfunction, eventually leading to cancer cell senescence. Our findings on resveratrol's induction of cancer cell senescence via activating ER-stress through the SIRT1/p38MAPK and NO/DLC1 pathways provide a solid base for its clinical application and its preventive application as a food additive.
    DOI:  https://doi.org/10.1039/d1fo02365a
  41. Cell Metab. 2022 Mar 01. pii: S1550-4131(22)00045-6. [Epub ahead of print]34(3): 396-407.e6
    The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
    Brage Brakedal, Christian Dölle, Frank Riemer, Yilong Ma, Gonzalo S Nido, Geir Olve Skeie, Alexander R Craven, Thomas Schwarzlmüller, Njål Brekke, Joseph Diab, Lars Sverkeli, Vivian Skjeie, Kristin Varhaug, Ole-Bjørn Tysnes, Shichun Peng, Kristoffer Haugarvoll, Mathias Ziegler, Renate Grüner, David Eidelberg, Charalampos Tzoulis.
      We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.
    Keywords:  NAD; NR; disease modifying; experimental therapy; mitochondria; neurodegeneration; neuroprotective; nicotinamide adenine dinucleotide; parkinsonism; treatment
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.001
  42. Cell Metab. 2022 Mar 01. pii: S1550-4131(22)00047-X. [Epub ahead of print]34(3): 378-395
    Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.
    Sofie Hedlund Møller, Pei-Chun Hsueh, Yi-Ru Yu, Lianjun Zhang, Ping-Chih Ho.
      Productive T cell responses to infection and cancer rely on coordinated metabolic reprogramming and epigenetic remodeling among the immune cells. In particular, T cell effector and memory differentiation, exhaustion, and senescence/aging are tightly regulated by the metabolism-epigenetics axis. In this review, we summarize recent advances of how metabolic circuits combined with epigenetic changes dictate T cell fate decisions and shape their functional states. We also discuss how the metabolic-epigenetic axis orchestrates T cell exhaustion and explore how physiological factors, such as diet, gut microbiota, and the circadian clock, are integrated in shaping T cell epigenetic modifications and functionality. Furthermore, we summarize key features of the senescent/aged T cells and discuss how to ameliorate vaccination- and COVID-induced T cell dysfunctions by metabolic modulations. An in-depth understanding of the unexplored links between cellular metabolism and epigenetic modifications in various physiological or pathological contexts has the potential to uncover novel therapeutic strategies for fine-tuning T cell immunity.
    Keywords:  CD8; COVID; aging; epigenetic; exhaustion; immunometabolism
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.003
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