bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒05‒29
28 papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Aryl hydrocarbon receptor blocks aging-induced senescence in the liver and fibroblast cells.
  2. S-adenosylhomocysteine induces cellular senescence in rat aorta vascular smooth muscle cells via NF-κB-SASP pathway.
  3. Cellular senescence.
  4. Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.
  5. Long-term consumption of green tea EGCG enhances murine healthspan by mitigating multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gut dysbiosis, and immunosenescence.
  6. p16INK4A dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors.
  7. Single-Cell Analysis Reveals Transcriptomic Reprogramming in Aging Cardiovascular Endothelial Cells.
  8. The heterogeneity of cellular senescence: insights at the single-cell level.
  9. Induction of ferroptosis selectively eliminates senescent tubular cells.
  10. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation.
  11. Berberine exerts protective effects on cardiac senescence by regulating the Klotho/SIRT1 signaling pathway.
  12. Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice.
  13. Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle.
  14. Accumulation of pTreg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis.
  15. Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
  16. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.
  17. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities.
  18. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
  19. Telomere length declines with age, but relates to immune function independent of age in a wild passerine.
  20. Protocol to induce and assess cGAS-STING pathway activation in vitro.
  21. Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues.
  22. miR-188-3p targets skeletal endothelium coupling of angiogenesis and osteogenesis during ageing.
  23. Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice.
  24. Modeling human gray hair by irradiation as a valuable tool to study aspects of tissue aging.
  25. Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice.
  26. Ferroptosis - A new target of osteoporosis.
  27. Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults.
  28. Nuclear mRNA Export and Aging.
  1. Aging (Albany NY). 2022 May 26. 14(undefined):
    Aryl hydrocarbon receptor blocks aging-induced senescence in the liver and fibroblast cells.
    Ana Nacarino-Palma, Eva M Rico-Leo, Judith Campisi, Arvind Ramanathan, Francisco J González-Rico, Claudia M Rejano-Gordillo, Ana Ordiales-Talavero, Jaime M Merino, Pedro M Fernández-Salguero.
      Aging impairs organismal homeostasis leading to multiple pathologies. Yet, the mechanisms and molecular intermediates involved are largely unknown. Here, we report that aged aryl hydrocarbon receptor-null mice (AhR-/-) had exacerbated cellular senescence and more liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16Ink4a and p21Cip1 and genes encoding senescence-associated secretory phenotype (SASP) factors TNF and IL1 were overexpressed in aged AhR-/- livers. Chromatin immunoprecipitation showed that AhR binding to those gene promoters repressed their expression, thus adjusting physiological levels in AhR+/+ livers. MCP-2, MMP12 and FGF secreted by senescent cells were overproduced in aged AhR-null livers. Supporting the relationship between senescence and stemness, liver progenitor cells were overrepresented in AhR-/- mice, probably contributing to increased hepatocarcinoma burden. These AhR roles are not liver-specific since adult and embryonic AhR-null fibroblasts underwent senescence in culture, overexpressing SA-β-Gal, p16Ink4a and p21Cip1. Notably, depletion of senescent cells with the senolytic agent navitoclax restored expression of senescent markers in AhR-/- fibroblasts, whereas senescence induction by palbociclib induced an AhR-null-like phenotype in AhR+/+ fibroblasts. AhR levels were downregulated by senescence in mouse lungs but restored upon depletion of p16Ink4a-expressing senescent cells. Thus, AhR restricts age-induced senescence associated to a differentiated phenotype eventually inducing resistance to liver tumorigenesis.
    Keywords:  aryl hydrocarbon receptor; hepatocarcinogenesis; metabolism; senescence
    DOI:  https://doi.org/10.18632/aging.204103
  2. J Nutr Biochem. 2022 May 21. pii: S0955-2863(22)00134-6. [Epub ahead of print] 109063
    S-adenosylhomocysteine induces cellular senescence in rat aorta vascular smooth muscle cells via NF-κB-SASP pathway.
    Jiaxin Mi, Xu Chen, Yi Tang, Yiran You, Qiannan Liu, Jinghe Xiao, Wenhua Ling.
      Vascular aging plays an important role in the development and progression of atherosclerosis (AS) , and one-carbon metabolism dysfunction will lead to Vascular Smooth Muscle Cells (VSMCs) senescence, which contributes to vascular senescence. However, the mechanisms underlying the role of VSMCs senescence in AS remain unclear. This study aimed to evaluate S-adenosyl-homocysteine (SAH) as a one-carbon metabolite that affects VSMCs senescence. We treated Rat Aorta Smooth Muscle Cells (RASMCs) with S-adenosylhomocysteine Hydrolase (SAHH) inhibitor, adenosine-2,3-dialdehyde (ADA) and SAHH siRNA to examine the effect of elevated SAH levels on RASMCs phenotypes. SAHH inhibition induced RASMCs senescence, as demonstrated by the manifestation of senescence-associated secretory phenotype in cells and induction of senescence in pre-senescent RASMCs. Furthermore, we found that SAHH inhibition induced CpG island demethylation in the promoter of NF-κB, a molecule that drives the pro-inflammatory response of the cells manifesting the senescence-associated secretory phenotype (SASP). Overall, these findings indicate that the elevated intracellular SAH levels could be targeted to ameliorate vascular aging.
    Keywords:  CpG islands; DNA methylation; NF-κB; S-adenosyl-homocysteine; rat aorta vascular smooth muscle cells; senescence-associated secretory phenotype; vascular aging
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109063
  3. Curr Biol. 2022 May 23. pii: S0960-9822(22)00568-1. [Epub ahead of print]32(10): R448-R452
    Cellular senescence.
    Marta Varela-Eirín, Marco Demaria.
      Cellular senescence defines a state of stable and generally irreversible proliferative arrest associated with various morphological, structural and functional changes (Figure 1), including enhanced expression and secretion of pro-inflammatory and tissue-remodelling mediators. This state is crucial in tissue physiology and pathology and arises as a response to potentially damaging stress signals. Whether the activation of a senescence state provides benefits or detriments for tissue function and homeostasis is strictly dependent on the context. Cell senescence acts as a potent tumour-suppressive mechanism limiting the proliferation of cells at risk of malignant transformation and supports the repair of acute tissue damage, but also represents a key driver of ageing and age-related diseases.
    DOI:  https://doi.org/10.1016/j.cub.2022.04.003
  4. Genes Dev. 2022 May 26.
    Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.
    Kelvin Yin, Daniel Patten, Sarah Gough, Susana de Barros Gonçalves, Adelyne Chan, Ioana Olan, Liam Cassidy, Marta Poblocka, Haoran Zhu, Aaron Lun, Martijn Schuijs, Andrew Young, Celia Martinez-Jimenez, Timotheus Y F Halim, Shishir Shetty, Masashi Narita, Matthew Hoare.
      Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
    Keywords:  NF-κB; SASP; endothelium; immune surveillance; liver; senescence
    DOI:  https://doi.org/10.1101/gad.349585.122
  5. J Nutr Biochem. 2022 May 23. pii: S0955-2863(22)00139-5. [Epub ahead of print] 109068
    Long-term consumption of green tea EGCG enhances murine healthspan by mitigating multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gut dysbiosis, and immunosenescence.
    Rohit Sharma, Ravi Kumar, Anamika Sharma, Abhishek Goel, Yogendra Padwad.
      Cellular senescence is emerging as a major hallmark of aging, and its modulation presents an effective anti-aging strategy. This study attempted to understand the progression of cellular senescence in vivo, and whether it can be mitigated by chronic consumption of green tea catechin epigallocatechin gallate (EGCG). We profiled cellular senescence in various organs of mice at four different time-points of lifespan, and then explored the influence of EGCG consumption in impacting markers of cellular senescence, inflamm-aging, immunosenescence, and gut dysbiosis. We report that visceral adipose and intestinal tissues are highly vulnerable to cellular senescence due to an increase in DNA damage response, activation of cell cycle inhibitors, and SASP regulators. With advancing age, dysregulation in nutrient signaling mediators (AMPK/AKT/SIRT3/5), and a decrease in autophagy was also observed. Inflamm-aging markers (TNF-α/IL-1β) and splenic CD4/CD8 T cell ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed an age-related decrease in the diversity of microbial species and an increase in the abundance of various pathogenic bacterial species. On the other hand, long-term EGCG consumption significantly attenuated markers of DNA damage, cell cycle inhibitors, SASP regulators, AMPK/AKT signaling, and enhanced SIRT3/5 expression and autophagy. Systemic inflamm-aging indicators decreased, while early T cell activation increased in EGCG fed animals. EGCG also suppressed the abundance of pathogenic bacteria and preserved microbial diversity. Our results suggest that adipose and intestine tissues are prone to cellular senescence and that chronic consumption of EGCG can attenuate several deleterious aspects of aging which could be implicated in developing anti-aging strategies.
    Keywords:  Autophagy; EGCG; Microbiota; Nutrient signaling; SASP; Senescence
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109068
  6. Blood Adv. 2022 May 27. pii: bloodadvances.2022007033. [Epub ahead of print]
    p16INK4A dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors.
    Charlotte Hellmich, Edyta Wojtowicz, Jamie A Moore, Jayna J Mistry, Aisha Jibril, Benjamin B Johnson, James Gw Smith, Naiara Beraza, Kristian M Bowles, Stuart A Rushworth.
      Rapid and effective leucocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the bone marrow niche on this phenotype. We found that, in response to LPS induced stress, HPC mitochondrial function is impaired and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared to young animals. Furthermore, aged mesenchymal stromal cells (MSC) of the BM niche, but not HPCs, exhibit a senescent phenotype and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with LPS. In summary, age related HPC metabolic dysfunction occurs indirectly as a 'bystander phenomenon' in the aging BM niche and can be restored by targeting senescent MSCs.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007033
  7. Front Cardiovasc Med. 2022 ;9 900978
    Single-Cell Analysis Reveals Transcriptomic Reprogramming in Aging Cardiovascular Endothelial Cells.
    Bo Gou, Xiaojing Chu, Yi Xiao, Pinxuan Liu, Hao Zhang, Zeyu Gao, Moshi Song.
      The senescence of cardiovascular endothelial cells (ECs) is a major risk factor in the development of aging-related cardiovascular diseases. However, the molecular dynamics in cardiovascular EC aging are poorly understood. Here, we characterized the transcriptomic landscape of cardiovascular ECs during aging and observed that ribosome biogenesis, inflammation, apoptosis and angiogenesis-related genes and pathways changed with age. We also highlighted the importance of collagen genes in the crosstalk between ECs and other cell types in cardiovascular aging. Moreover, transcriptional regulatory network analysis revealed Jun as a candidate transcription factor involved in murine cardiovascular senescence and we validated the upregulation of Jun in aged cardiovascular ECs both in vitro and in vivo. Altogether, our study reveals the transcriptomic reprogramming in the aging murine cardiovascular ECs, which deepens the understanding of the molecular mechanisms of cardiovascular aging and provides new insights into potential therapeutic targets against age-related cardiovascular diseases.
    Keywords:  age-dependent genes; cardiovascular endothelial cells; scRNA-seq; senescence; transcriptomic reprogramming
    DOI:  https://doi.org/10.3389/fcvm.2022.900978
  8. Trends Cell Biol. 2022 May 20. pii: S0962-8924(22)00116-7. [Epub ahead of print]
    The heterogeneity of cellular senescence: insights at the single-cell level.
    Rachel L Cohn, Nathan S Gasek, George A Kuchel, Ming Xu.
      Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process. One commonly used marker to examine senescent cells in vivo is p16, which has led to important discoveries. Recent studies have also described new senescence markers beyond p16 and have highlighted the importance of investigating senescence heterogeneity in cell types and tissues. With the development of high-throughput technologies, such as single-cell RNA-seq and single-nucleus RNA-seq, we can examine senescent cells at the single-cell level and potentially uncover new markers. This review emphasizes that there is an urgent need to investigate senescence heterogeneity and discuss how this could be accomplished by using advanced technologies and sequencing datasets.
    Keywords:  RNA-sequencing; aging; p16; p21; senolytics
    DOI:  https://doi.org/10.1016/j.tcb.2022.04.011
  9. Am J Transplant. 2022 May 23.
    Induction of ferroptosis selectively eliminates senescent tubular cells.
    Chieh M Liao, Vera C Wulfmeyer, Rongjun Chen, Zulrahman Erlangga, Julius Sinning, A von Mässenhausen, Inga Sörensen-Zender, Kristina Beer, Sibylle von Vietinghoff, Hermann Haller, Andreas Linkermann, Anette Melk, Roland Schmitt.
      The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies to improve marginal organs. While most existing senolytics induce senescent cell clearance by apoptosis, we observed that ferroptosis, an iron catalyzed subtype of regulated necrosis, might serve as an alternative way to ablate senescent cells. We found that murine kidney tubular epithelial cells became sensitized to ferroptosis when turning senescent. This was linked to increased expression of pro-ferroptotic lipoxygenase-5 and reduced expression of anti-ferroptotic glutathione peroxidase 4 (GPX4). In tissue slice cultures from aged kidneys low dose application of the ferroptosis-inducer RSL3 selectively eliminated senescent cells while leaving healthy tubular cells unaffected. Similar results were seen in a transplantation model, in which RSL3 reduced the senescent cell burden of aged donor kidneys and caused a reduction of damage and inflammatory cell infiltration during the early post-transplantation period. In summary, these data reveal an increased susceptibility of senescent tubular cells to ferroptosis with the potential to be exploited for selective reduction of renal senescence in aged kidney transplants.
    DOI:  https://doi.org/10.1111/ajt.17102
  10. Aging Cell. 2022 May 22. e13622
    Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation.
    Weizhe Zhong, Zhuqing Rao, Jian Xu, Yu Sun, Haoran Hu, Ping Wang, Yongxiang Xia, Xiongxiong Pan, Weiwei Tang, Ziyi Chen, Haoming Zhou, Xuehao Wang.
      Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.
    Keywords:  aging; macrophage; mitochondrial DNA; mitophagy; sterile inflammation; stimulator of interferon genes
    DOI:  https://doi.org/10.1111/acel.13622
  11. Biomed Pharmacother. 2022 May 24. pii: S0753-3322(22)00486-3. [Epub ahead of print]151 113097
    Berberine exerts protective effects on cardiac senescence by regulating the Klotho/SIRT1 signaling pathway.
    Cong Li, Shuang Jiang, Hengfei Wang, Yuhong Wang, Yanxing Han, Jiandong Jiang.
      Berberine (BBR), an isoquinoline alkaloid, exerts protective effects on various cardiac injuries, and also extends the lifespan of individuals. However, the cardioprotective effect of BBR on cardiac senescence remains unknown. This study investigated the effects of BBR on cardiac senescence and its underlying mechanism. Senescent H9c2 cells induced by doxorubicin (DOX) and naturally aged rats were used to evaluate the protective effects of BBR on cardiac senescence. The results showed that BBR protected H9c2 cells against DOX-induced senescence. Exogenous Klotho (KL) exerts similar effects to those of BBR. BBR significantly increased in protein expression of KL, while transfection with KL-specific siRNA (siKL) inhibited the protective effect of BBR against senescence. Both BBR and exogenous KL decreased the levels of reactive oxygen species, inhibited apoptosis, and alleviated mitochondrial dysfunction in these cells; and transfection with siKL attenuated these effects of BBR. In naturally aged rats, BBR indeed protected the animals from cardiac aging, at least partially, through lowering the levels of cardiac hypertrophy markers, and increased the expression of KL in cardiac tissue. Additionally, BBR markedly reversed downregulation of sirtuin1 (SIRTI) in the aged heart. In vitro experiments revealed that BBR and exogenous KL also increased the expression of SIRT1, whereas siKL limited this effect of BBR in senescent H9c2 cell. In summary, BBR upregulated KL expression and prevented heart from cardiac senescence through anti-oxidative and anti-apoptotic effects, as well as alleviation of mitochondrial dysfunction. These effects may be mediated via regulation of the Klotho/SIRT1 signaling pathway.
    Keywords:  Apoptosis; Berberine; Cardiac senescence; Klotho; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2022.113097
  12. Int J Mol Sci. 2022 May 17. pii: 5609. [Epub ahead of print]23(10):
    Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice.
    Philipp Kasper, Jaco Selle, Christina Vohlen, Rebecca Wilke, Celien Kuiper-Makris, Oleksiy Klymenko, Inga Bae-Gartz, Charlotte Schömig, Alexander Quaas, Björn Schumacher, Münevver Demir, Martin Bürger, Sonja Lang, Anna Martin, Hans-Michael Steffen, Tobias Goeser, Jörg Dötsch, Miguel A Alejandre Alcazar.
      Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.
    Keywords:  aging; cellular senescence; liver; maternal obesity; metabolic programming
    DOI:  https://doi.org/10.3390/ijms23105609
  13. Exp Gerontol. 2022 May 24. pii: S0531-5565(22)00149-8. [Epub ahead of print] 111841
    Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle.
    Melissa C Orenduff, Michael F Coleman, Elaine M Glenny, Kim M Huffman, Erika T Rezeli, Akshay Bareja, Carl F Pieper, Virginia B Kraus, Stephen D Hursting.
      Aging is a multifactorial process associated with progressive degradation of physiological integrity and function. One of the greatest factors contributing to the deleterious effects of aging is the decline of functional ability due to loss of muscle mass, strength, and function, a condition termed sarcopenia. Calorie restriction (CR) has consistently been shown to extend lifespan and delay the onset and progression of various age-related diseases, including sarcopenia. Additional anti-aging interventions that are receiving scientific attention are CR mimetics. Of these pharmacological compounds, rapamycin has shown similar CR-related longevity benefits without the need for diet restrictions. To investigate the potential role of rapamycin as an anti-sarcopenic alternative to CR, we conducted a study in male and female C57BL/6 J mice to assess the effects of rapamycin on age-related gene expression changes in skeletal muscle associated with loss of muscle mass, strength, and function, relative to control. We hypothesize that the effects of rapamycin will closely align with CR with respect to physical function and molecular indices associated with muscle quality. Our results indicate CR and rapamycin provide partial protection against age-related decline in muscle, while engaging uniquely different molecular pathways in skeletal muscle. Our preclinical findings of the therapeutic potential of rapamycin or a CR regimen on geroprotective benefits in muscle should be extended to translational studies towards the development of effective strategies for the prevention and management of sarcopenia.
    Keywords:  Calorie restriction; Rapamycin; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2022.111841
  14. Aging Cell. 2022 May 26. e13630
    Accumulation of pTreg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis.
    Weikan Wang, Rachel Thomas, Jiyoung Oh, Dong-Ming Su.
      Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks the elderly, which is termed late-onset MS. The disease can be recapitulated and studied in a mouse model, experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but disease severity is increased relative to young EAE mice. Given that CD4+ FoxP3+ regulatory T (Treg) cells play an ameliorative role in MS/EAE severity, and the aged immune system accumulates peripheral Treg (pTreg) cells, failure of these cells to prevent or ameliorate EAE disease is enigmatic. When analyzing the distribution of Treg cells in EAE mice, the aged mice exhibited a higher proportion of polyclonal (pan-) pTreg cells and a lower proportion of antigen-specific pTreg cells in the periphery but lower proportions of both pan- and antigen-specific Treg cells in the central nervous system (CNS). Furthermore, in the aged inflamed CNS, CNS-Treg cells exhibited a higher plasticity, and T effector (CNS-Teff) cells exhibited greater clonal expansion, disrupting the Treg/Teff balance. Transiently inhibiting FoxP3 or depleting pTreg cells partially corrected Treg distribution and restored the Treg/Teff balance in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS.
    Keywords:  aging; autoimmunity; negative selection; regulatory T cell generation; thymic atrophy
    DOI:  https://doi.org/10.1111/acel.13630
  15. Front Aging Neurosci. 2022 ;14 845330
    Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases.
    Wei Wan, Fuzhou Hua, Pu Fang, Chang Li, Fumou Deng, Shoulin Chen, Jun Ying, Xifeng Wang.
      Sirtuins are protein factors that can delay aging and alleviate age-related diseases through multiple molecular pathways, mainly by promoting DNA damage repair, delaying telomere shortening, and mediating the longevity effect of caloric restriction. In the last decade, sirtuins have also been suggested to exert mitochondrial quality control by mediating mitophagy, which targets damaged mitochondria and delivers them to lysosomes for degradation. This is especially significant for age-related diseases because dysfunctional mitochondria accumulate in aging organisms. Accordingly, it has been suggested that sirtuins and mitophagy have many common and interactive aspects in the aging process. This article reviews the mechanisms and pathways of sirtuin family-mediated mitophagy and further discusses its role in aging and age-related diseases.
    Keywords:  age-related disease; aging; mitochondria; mitophagy; neurodegenerative diseases; sirtuins
    DOI:  https://doi.org/10.3389/fnagi.2022.845330
  16. Dev Cell. 2022 May 19. pii: S1534-5807(22)00332-X. [Epub ahead of print]
    Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.
    Zunpeng Liu, Qianzhao Ji, Jie Ren, Pengze Yan, Zeming Wu, Si Wang, Liang Sun, Zehua Wang, Jiaming Li, Guoqiang Sun, Chuqian Liang, Run Sun, Xiaoyu Jiang, Jianli Hu, Yingjie Ding, Qiaoran Wang, Shijia Bi, Gang Wei, Gang Cao, Guoguang Zhao, Hongmei Wang, Qi Zhou, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Guang-Hui Liu.
      Nuclear deformation, a hallmark frequently observed in senescent cells, is presumed to be associated with the erosion of chromatin organization at the nuclear periphery. However, how such gradual changes in higher-order genome organization impinge on local epigenetic modifications to drive cellular mechanisms of aging has remained enigmatic. Here, through large-scale epigenomic analyses of isogenic young, senescent, and progeroid human mesenchymal progenitor cells (hMPCs), we delineate a hierarchy of integrated structural state changes that manifest as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. We found that the epigenetic de-repression unlocks the expression of pregnancy-specific beta-1 glycoprotein (PSG) genes that exacerbate hMPC aging and serve as potential aging biomarkers. Our analyses provide a rich resource for uncovering the principles of epigenomic landscape organization and its changes in cellular aging and for identifying aging drivers and intervention targets with a genome-topology-based mechanism.
    Keywords:  3D genome; aging biomarker; chromomatin entropy; epigenome; placenta-specific genes; pregnancy-specific beta-1 glycoprotein (PSG); progeria; senesence; stem cell aging
    DOI:  https://doi.org/10.1016/j.devcel.2022.05.004
  17. J Pers Med. 2022 Apr 29. pii: 716. [Epub ahead of print]12(5):
    Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities.
    Paola Fernanda Ruiz-Aparicio, Jean-Paul Vernot.
      Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
    Keywords:  AML; B-ALL; BM aging; MSCs senescence; leukaemia; leukemic microenvironment
    DOI:  https://doi.org/10.3390/jpm12050716
  18. Signal Transduct Target Ther. 2022 May 25. 7(1): 162
    Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
    Xin Li, Jiaqiang Wang, LeYun Wang, Yuanxu Gao, Guihai Feng, Gen Li, Jun Zou, Meixin Yu, Yu Fei Li, Chao Liu, Xue Wei Yuan, Ling Zhao, Hong Ouyang, Jian-Kang Zhu, Wei Li, Qi Zhou, Kang Zhang.
      Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. Furthermore, restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells; this indicates a conservative mechanism in both human and mouse. Taken together, we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies.
    DOI:  https://doi.org/10.1038/s41392-022-00964-6
  19. R Soc Open Sci. 2022 Apr;9(4): 212012
    Telomere length declines with age, but relates to immune function independent of age in a wild passerine.
    Michael J Roast, Justin R Eastwood, Nataly Hidalgo Aranzamendi, Marie Fan, Niki Teunissen, Simon Verhulst, Anne Peters.
      Telomere length (TL) shortens with age but telomere dynamics can relate to fitness components independent of age. Immune function often relates to such fitness components and can also interact with telomeres. Studying the link between TL and immune function may therefore help us understand telomere-fitness associations. We assessed the relationships between erythrocyte TL and four immune indices (haptoglobin, natural antibodies (NAbs), complement activity (CA) and heterophil-lymphocyte (HL) ratio; n = 477-589), from known-aged individuals of a wild passerine (Malurus coronatus). As expected, we find that TL significantly declined with age. To verify whether associations between TL and immune function were independent of parallel age-related changes (e.g. immunosenescence), we statistically controlled for sampling age and used within-subject centring of TL to separate relationships within or between individuals. We found that TL positively predicted CA at the between-individual level (individuals with longer average TL had higher CA), but no other immune indices. By contrast, age predicted the levels of NAbs and HL ratio, allowing inference that respective associations between TL and age with immune indices are independent. Any links existing between TL and fitness are therefore unlikely to be strongly mediated by innate immune function, while TL and immune indices appear independent expressions of individual heterogeneity.
    Keywords:  ageing; avian; constitutive; immune; quality; senescence
    DOI:  https://doi.org/10.1098/rsos.212012
  20. STAR Protoc. 2022 Jun 17. 3(2): 101384
    Protocol to induce and assess cGAS-STING pathway activation in vitro.
    Hanane Chamma, Soumyabrata Guha, Nadine Laguette, Isabelle K Vila.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in several cellular processes including pathogen recognition and inflammatory responses. We describe a protocol to activate the cGAS-STING pathway in murine cells using nucleic acids transfection. We describe how to prepare the nucleic acid probes and validate activation of the pathway by western blot and gene expression analysis. The protocol can be applied to investigate cGAS-STING signaling in both murine and human cell lines. For complete details on the use and execution of this protocol, please refer to Vila et al. (2022).
    Keywords:  Cell Biology; Gene Expression; Immunology; Molecular Biology; Molecular/Chemical Probes; Signal Transduction
    DOI:  https://doi.org/10.1016/j.xpro.2022.101384
  21. Cell Stem Cell. 2022 May 19. pii: S1934-5909(22)00170-9. [Epub ahead of print]
    Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues.
    Shuai Ma, Si Wang, Yanxia Ye, Jie Ren, Ruiqing Chen, Wei Li, Jiaming Li, Liyun Zhao, Qian Zhao, Guoqiang Sun, Ying Jing, Yuesheng Zuo, Muzhao Xiong, Yuanhan Yang, Qiaoran Wang, Jinghui Lei, Shuhui Sun, Xiao Long, Moshi Song, Shuyang Yu, Piu Chan, Jianwei Wang, Qi Zhou, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Guang-Hui Liu.
      The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.
    Keywords:  aging; hematopoietic stem and progenitor cell; heterochronic parabiosis; single-cell sequencing; stem cell
    DOI:  https://doi.org/10.1016/j.stem.2022.04.017
  22. Cell Death Dis. 2022 May 25. 13(5): 494
    miR-188-3p targets skeletal endothelium coupling of angiogenesis and osteogenesis during ageing.
    Wen-Zhen He, Mi Yang, Yangzi Jiang, Chen He, Yu-Chen Sun, Ling Liu, Mei Huang, Yu-Rui Jiao, Kai-Xuan Chen, Jing Hou, Min Huang, Yi-Li Xu, Xu Feng, Ya Liu, Qi Guo, Hui Peng, Yan Huang, Tian Su, Ye Xiao, Yusheng Li, Chao Zeng, Guanghua Lei, Xiang-Hang Luo, Chang-Jun Li.
      A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin β3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.
    DOI:  https://doi.org/10.1038/s41419-022-04902-w
  23. EMBO Rep. 2022 May 27. e52990
    Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice.
    Immacolata Prevenzano, Alessia Leone, Michele Longo, Antonella Nicolò, Serena Cabaro, Francesca Collina, Iacopo Panarese, Gerardo Botti, Pietro Formisano, Raffaele Napoli, Francesco Beguinot, Claudia Miele, Cecilia Nigro.
      Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age-dependent impairment of glucose tolerance and glucose-stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80-positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP-1 and TNF-α), part of the senescence-activated secretory profile, in the pancreas from 10-month-old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 β-cells to MGO confirms its casual role on β-cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.
    Keywords:  aging; dicarbonyl stress; glyoxalase 1; insulin secretion; methylglyoxal
    DOI:  https://doi.org/10.15252/embr.202152990
  24. Geroscience. 2022 May 25.
    Modeling human gray hair by irradiation as a valuable tool to study aspects of tissue aging.
    Da-Mao Dai, Ye He, Qing Guan, Zhe-Xiang Fan, Yunmin Zhu, Jin Wang, Shulian Wu, Jian Chen, Demengjie Le, Zhi-Qi Hu, Qian Qu, Yong Miao.
      As one of the earliest and most visible phenomenon of aging, gray hair makes it a unique model system for investigating the mechanism of aging. Ionizing radiation successfully induces gray hair in mice, and also provides a venue to establish an organ-cultured human gray hair model. To establish a suitable organ-cultured human gray HF model by IR, which imitates gray hair in the elderly, and to explore the mechanisms behind the model. By detecting growth parameters, melanotic and senescence markers of the model, we found that the model of 5 Gy accords best with features of elderly gray hair. Then, we investigated the formation mechanisms of the model by RNA-sequencing. We demonstrated that the model of organ-cultured gray HFs after 5 Gy irradiation is closest to the older gray HFs. Moreover, the 5 Gy inhibited the expression of TRP-1, Tyr, Pmel17, and MITF in hair bulbs/ORS of HFs. The 5 Gy also significantly induced ectopically pigmented melanocytes and increased the expression of DNA damage and senescence in HFs. Finally, RNA-seq analysis of the model suggested that IR resulted in cell DNA damage, and the accumulation of oxidative stress in the keratinocytes. Oxidative stress and DNA damage caused cell dysfunction and decreased melanin synthesis in the gray HFs. We found that HFs irradiated at 5 Gy successfully constructed an appropriate aging HF model. This may provide a useful model for cost-effective and predictable treatment strategies to human hair graying and the process of aging.
    Keywords:  Gray hair; Hair follicle; Irradiation; RNA-seq; Senescence
    DOI:  https://doi.org/10.1007/s11357-022-00592-6
  25. Front Endocrinol (Lausanne). 2022 ;13 896356
    Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice.
    Mirella L Meyer-Ficca, Alexie E Zwerdling, Corey A Swanson, Abby G Tucker, Sierra A Lopez, Miles K Wandersee, Gina M Warner, Katie L Thompson, Claudia C S Chini, Haolin Chen, Eduardo N Chini, Ralph G Meyer.
      Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD+ levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD+ decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD+ levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD+ levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD+ levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD+ decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD+ synthesis, similar to humans. NAD+-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD+-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD+ is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD+ in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD+-deficient mice.
    Keywords:  aging; male fertility; niacin; nicotinamide; retinoic acid; spermatogonia; testis; vitamin B3
    DOI:  https://doi.org/10.3389/fendo.2022.896356
  26. Exp Gerontol. 2022 May 19. pii: S0531-5565(22)00144-9. [Epub ahead of print]165 111836
    Ferroptosis - A new target of osteoporosis.
    Zhonghua Gao, Zhuoying Chen, Zhifan Xiong, Xiangjie Liu.
      Osteoporosis is a bone metabolic disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture, leading to enhanced skeletal fragility and susceptibility to fracture. Unbalanced bone remodeling is the primary pathogenetic factor of osteoporosis, in which osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Bisphosphonates and calcitonin are among the drugs commonly used to treat osteoporosis, in addition to the bone nutrients vitamin D and calcium supplements. The current treatments effectively prevent further bone loss by inhibiting the excessive activation of osteoclasts, accompanied by various degrees of side effects. Iron, one of the trace elements essential for life activities, has recently been recognized as an independent risk factor for osteoporosis. Abnormal iron metabolism increases the incidence of many bone diseases, especially osteoporosis. Iron metabolism does play a key role in bone homeostasis. Ferroptosis is a novel form of cell death that has been discovered in recent years. Its main features include iron overload and the accumulation of ROS. And lipid peroxidation is the key. There are increasing shreds of evidence that ferroptosis is involved in the occurrence and development of osteoporosis, and its regulation can effectively prevent osteoporosis. Therefore, this review further elucidates the role of ferroptosis in osteoporosis based on the mechanism and its relationship with osteoporosis and provides a new idea for treating osteoporosis.
    Keywords:  Ferroptosis; Lipid peroxidation; Osteoporosis; ROS; iron metabolism
    DOI:  https://doi.org/10.1016/j.exger.2022.111836
  27. Front Cardiovasc Med. 2022 ;9 881703
    Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults.
    Kaitlin A Freeberg, Daniel H Craighead, Christopher R Martens, Zhiying You, Michel Chonchol, Douglas R Seals.
      Background: Aging is the primary risk factor for cardiovascular diseases, the leading cause of death worldwide. Age-related increases in systolic blood pressure (SBP) link advancing age to cardiovascular disease risk. A key mechanism mediating the increase in SBP with aging is stiffening of the large elastic arteries, which occurs due to increases in oxidative stress, inflammation, and vascular smooth muscle tone. Nicotinamide adenine dinucleotide (NAD+) is a key molecule in energy metabolism and cellular functioning which declines with advancing age and chronic disease. Dietary supplementation with NAD+ precursors, such as nicotinamide riboside, boosts NAD+ bioavailability and may improve cardiovascular health. Here, we present the protocol for a randomized, controlled trial investigating the efficacy of 3 months of oral supplementation with nicotinamide riboside for decreasing SBP and arterial stiffness in midlife and older adults with initial above-normal (120-159 mmHg) SBP (ClinicalTrials.gov Identifier: NCT03821623). The primary outcome is casual (resting) SBP and secondary outcomes include 24-h SBP and aortic stiffness. Other outcomes include assessment of safety; tolerability; adherence; diastolic BP; systemic NAD+ bioavailability; and circulating biomarkers of oxidative stress, inflammation, and sympathoadrenal activity.Methods: A randomized, double-blind, placebo-controlled, single-site parallel-group design clinical trial will be conducted in 94 (47/group) midlife and older (age ≥ 50 years) adults with initial above-normal SBP. Participants will complete baseline testing and then will be randomized to either nicotinamide riboside (500 mg, 2×/day, NIAGEN®; ChromaDex Inc.) or placebo supplementation. Outcome measures will be assessed again after 3 months of treatment.
    Discussion: This study is designed to establish the safety and efficacy of the NAD+ boosting compound, nicotinamide riboside, for reducing casual and 24-h SBP and aortic stiffness in midlife and older adults with above-normal SBP at baseline, a population at increased risk of cardiovascular diseases.
    Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03821623].
    Keywords:  NAD+; NMN; NR; aging; pulse wave velocity
    DOI:  https://doi.org/10.3389/fcvm.2022.881703
  28. Int J Mol Sci. 2022 May 13. pii: 5451. [Epub ahead of print]23(10):
    Nuclear mRNA Export and Aging.
    Hyun-Sun Park, Jongbok Lee, Hyun-Shik Lee, Seong Hoon Ahn, Hong-Yeoul Ryu.
      The relationship between transcription and aging is one that has been studied intensively and experimentally with diverse attempts. However, the impact of the nuclear mRNA export on the aging process following its transcription is still poorly understood, although the nuclear events after transcription are coupled closely with the transcription pathway because the essential factors required for mRNA transport, namely TREX, TREX-2, and nuclear pore complex (NPC), physically and functionally interact with various transcription factors, including the activator/repressor and pre-mRNA processing factors. Dysregulation of the mediating factors for mRNA export from the nucleus generally leads to the aberrant accumulation of nuclear mRNA and further impairment in the vegetative growth and normal lifespan and the pathogenesis of neurodegenerative diseases. The optimal stoichiometry and density of NPC are destroyed during the process of cellular aging, and their damage triggers a defect of function in the nuclear permeability barrier. This review describes recent findings regarding the role of the nuclear mRNA export in cellular aging and age-related neurodegenerative disorders.
    Keywords:  NPC; TREX; TREX-2; lifespan; mRNA export; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms23105451
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