bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒10‒02
forty-four papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation.
  2. Recent Advances in Strategies for Imaging Detection and Intervention of Cellular Senescence.
  3. Upregulation of PD-L1 in Senescence and Aging.
  4. Cellular Senescence is Increased in Airway Smooth Muscle Cells of Elderly Asthmatics.
  5. Cellular Senescence in Aging, Tissue Repair, and Regeneration.
  6. Targeting Cellular Senescence with Senotherapeutics: Development of New Approaches for Skin Care.
  7. Targeted delivery strategy: A beneficial partner for emerging senotherapy.
  8. Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis.
  9. Transcriptional regulation of CDKN2A/p16 by sirtuin 7 in senescence.
  10. Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
  11. Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging - from theory to practice.
  12. DNA damage, inflammation and aging: Insights from mice.
  13. DNA damage response and GATA4 signaling in cellular senescence and aging-related pathology.
  14. Evidence of sex differences in cellular senescence.
  15. Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells.
  16. Frailty biomarkers under the perspective of geroscience: A narrative review.
  17. Nucleosome disruption by 5-bromodeoxyuridine leads to senescence.
  18. Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α.
  19. Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans.
  20. Immunosenescence profiles of lymphocyte compartments and multiple long-term conditions (multimorbidity) in very old adults: The Newcastle 85+ Study.
  21. The epigenetic aging, obesity, and lifestyle.
  22. Single-cell analysis reveals transcriptomic reprogramming in aging primate entorhinal cortex and the relevance with Alzheimer's disease.
  23. Nicotinamide riboside kinase 1 protects against diet and age-induced pancreatic β-cell failure.
  24. Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy.
  25. Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice.
  26. Healthspan Extension through Innovative Genetic Medicines.
  27. Growth hormone/IGF-I-dependent signaling restores decreased expression of the myokine SPARC in aged skeletal muscle.
  28. The molecular architecture of cell cycle arrest.
  29. Riboflavin depletion promotes longevity and metabolic hormesis in Caenorhabditis elegans.
  30. Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.
  31. Tumor necrosis factor-α mediated inflammation versus apoptosis in age-related hearing loss.
  32. Reprograming of proteasomal degradation by branched chain amino acid metabolism.
  33. Single-cell RNA-seq reveals early heterogeneity during aging in yeast.
  34. The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging.
  35. Bmi1 suppresses protein synthesis and promotes proteostasis in hematopoietic stem cells.
  36. Lotus germ extract rejuvenates aging fibroblasts via restoration of disrupted proteostasis by the induction of autophagy.
  37. Circulating miR-181a as a novel potential plasma biomarker for multimorbidity burden in the older population.
  38. The Role of NAD+ in Regenerative Medicine.
  39. RNA modifications in aging-associated cardiovascular diseases.
  40. Drosophila exercise, an emerging model bridging the fields of exercise and aging in human.
  41. Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles.
  42. Circular RNA expression profiles of ovarian granulosa cells in advanced-age women explain new mechanisms of ovarian aging.
  43. Sirt3 mediates the benefits of exercise on bone in aged mice.
  44. Identification of a hippocampal lncRNA-regulating network in a natural aging rat model.
  1. Plast Reconstr Surg. 2022 Oct 01. 150 20S-26S
    Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation.
    Saranya P Wyles, Tamara Tchkonia, James L Kirkland.
      SUMMARY: Beyond the palliative reach of today's medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging.
    DOI:  https://doi.org/10.1097/PRS.0000000000009669
  2. Chembiochem. 2022 Sep 26.
    Recent Advances in Strategies for Imaging Detection and Intervention of Cellular Senescence.
    Jili Li, Zhengyan Bi, Linlin Wang, Yinghao Xia, Yuqi Xie, Yanlan Liu.
      Cellular senescence is a stable cell cycle arrest state that can be triggered by a wide range of intrinsic or extrinsic stresses. Increased burden of senescent cells in various tissues is thought to contribute to aging and age-related diseases. Thus, the detection and interventions of senescent cells are critical for longevity and treatment of diseases. However, the highly heterogeneous feature of senescence makes it challenging for precise detection and selective clearance of senescent cells in different age-related diseases. To address this issue, considerable efforts have been devoted to developing senescence-targeting molecular theranostic strategies, based on the potential biomarkers of cellular senescence. Herein, we overview recent advances in the field of anti-senescence research with highlights of the specific visualization and elimination of senescent cells. Additionally, the challenges in this emerging field are further outlined.
    Keywords:  Age-related diseases; Cellular senescence; Molecular probes; Senescence imaging; Senescence intervention
    DOI:  https://doi.org/10.1002/cbic.202200364
  3. Mol Cell Biol. 2022 Sep 26. e0017122
    Upregulation of PD-L1 in Senescence and Aging.
    Angelique Onorati, Aaron P Havas, Brian Lin, Jayaraj Rajagopal, Payel Sen, Peter D Adams, Zhixun Dou.
      Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.
    Keywords:  PD-L1; SASP; aging; senescence
    DOI:  https://doi.org/10.1128/mcb.00171-22
  4. Am J Physiol Lung Cell Mol Physiol. 2022 Sep 27.
    Cellular Senescence is Increased in Airway Smooth Muscle Cells of Elderly Asthmatics.
    Arbi Aghali, Latifa Khalfaoui, Anthony B Lagnado, Li Drake, Jacob J Teske, Christina M Pabelick, João F Passos, Y S Prakash.
      Senescent cells can drive age-related tissue dysfunction partially via a senescence-associated secretory phenotype (SASP) involving pro-inflammatory and pro-fibrotic factors. Cellular senescence has been associated with a structural and functional decline during normal lung aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Asthma in the elderly (AIE) represents a major healthcare burden. AIE is associated with bronchial airway hyperresponsiveness and remodeling, which involves increased cell proliferation and higher rates of fibrosis, and resistant to standard therapy. Airway smooth muscle (ASM) cells play a major role in asthma such as remodeling via modulation of inflammation and the extracellular matrix (ECM) environment. Whether senescent ASM accumulate in AIE and contribute to airway structural or functional changes is unknown. Lung tissues from elderly asthmatics showed greater airway fibrosis compared to age-matched non-asthmatics and young age controls. Isolated ASM from elderly asthmatics showed increased expression of multiple senescent markers including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP components. Senescence and SASP components were also increased with aging per se. These data highlight the presence of cellular senescence in AIE that may contribute to airway remodeling.
    Keywords:  Aging; Airway remodeling; Asthma; Lung; fibrosis
    DOI:  https://doi.org/10.1152/ajplung.00146.2022
  5. Plast Reconstr Surg. 2022 Oct 01. 150 4S-11S
    Cellular Senescence in Aging, Tissue Repair, and Regeneration.
    Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Elizabeth L Thompson, Laura J Niedernhofer, Daniel S Roh.
      SUMMARY: Society and our healthcare system are facing unprecedented challenges due to the expansion of the older population. As plastic surgeons, we can improve care of our older patients through understanding the mechanisms of aging that inevitably impact their outcomes and well-being. One of the major hallmarks of aging, cellular senescence, has recently become the focus of vigorous research in academia and industry. Senescent cells, which are metabolically active but in a state of stable cell cycle arrest, are implicated in causing aging and numerous age-related diseases. Further characterization of the biology of senescence revealed that it can be both detrimental and beneficial to organisms depending on tissue context and senescence chronicity. Here, we review the role of cellular senescence in aging, wound healing, tissue regeneration, and other domains relevant to plastic surgery. We also review the current state of research on therapeutics that modulate senescence to improve conditions of aging.
    DOI:  https://doi.org/10.1097/PRS.0000000000009667
  6. Plast Reconstr Surg. 2022 Oct 01. 150 12S-19S
    Targeting Cellular Senescence with Senotherapeutics: Development of New Approaches for Skin Care.
    Elizabeth L Thompson, Louise E Pitcher, Laura J Niedernhofer, Paul D Robbins.
      SUMMARY: Aging of the skin is evidenced by increased wrinkles, age spots, dryness, and thinning with decreased elasticity. Extrinsic and intrinsic factors including UV, pollution, and inflammation lead to an increase in senescent cells (SnCs) in skin with age that contribute to these observed pathological changes. Cellular senescence is induced by multiple types of damage and stress and is characterized by the irreversible exit from the cell cycle with upregulation of cell cycle-dependent kinase inhibitors p16INK4a and p21CIP1. Most SnCs also developed an inflammatory senescence-associated secretory phenotype (SASP) that drives further pathology through paracrine effects on neighboring cells and endocrine effects on cells at a distance. Recently, compounds able to kill senescent cells specifically, termed senolytics, or suppress the SASP, termed senomorphics, have been developed that have the potential to improve skin aging as well as systemic aging in general. Here, we provide a summary of the evidence for a key role in cellular senescence in driving skin aging. In addition, the evidence for the potential application of senotherapeutics for skin treatments is presented. Overall, topical, and possibly oral senotherapeutic treatments have tremendous potential to eventually become a standard of care for skin aging and related skin disorders.
    DOI:  https://doi.org/10.1097/PRS.0000000000009668
  7. Biomed Pharmacother. 2022 Sep 23. pii: S0753-3322(22)01126-X. [Epub ahead of print]155 113737
    Targeted delivery strategy: A beneficial partner for emerging senotherapy.
    Qixiong Zhang, Shanshan Li, Fengyu Chen, Rui Zeng, Rongsheng Tong.
      Numerous cutting-edge studies have confirmed that the slow accumulation of cell cycle arrested and secretory cells, called senescent cells (SCs), in tissues is an important negative factor, or even the culprit, in age- associated diseases such as non-alcoholic fatty liver, Alzheimer's disease, type 2 diabetes, atherosclerosis, and malignant tumors. With further understanding of cellular senescence, SCs are important effective targets for the treatment of senescence-related diseases, called the Senotherapy. However, existing therapies, including Senolytics (which lyse SCs) and Senostatic (which regulate senescence-associated secretory phenotype), do not have the properties to target SCs, and side effects due to non-specific distribution are one of the hindrances to clinical use of Senotherapy. In the past few decades, targeted delivery has attracted much attention and been developed as a recognized diagnostic and therapeutic novel tool, due to the advantages of visualization of targets, more accurate drug/gene delivery, and ultimately "reduced toxicity and enhanced efficacy". Despite considerable advances in achieving targeted delivery, it has not yet been widely used in Senotherapy. In this review, we clarify the challenge for Senotherapy, then discuss how different targeted strategies contribute to imaging or therapy for SCs in terms of different biomarkers of SCs. Finally, the emerging nano-Senotherapy is prospected.
    Keywords:  Senescence-associated diseases; Senotherapy; Targeted delivery
    DOI:  https://doi.org/10.1016/j.biopha.2022.113737
  8. Acta Pharm Sin B. 2022 Sep;12(9): 3618-3638
    Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis.
    Feixia Wang, Zhanghao Li, Li Chen, Ting Yang, Baoyu Liang, Zili Zhang, Jiangjuan Shao, Xuefen Xu, Guoping Yin, Shijun Wang, Hai Ding, Feng Zhang, Shizhong Zheng.
      Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.
    Keywords:  ASCT2; Atractylenolide III; Hepatic stellate cells; Liver fibrosis; NF-κB; Precursor IL-1α; SASP; Senescence
    DOI:  https://doi.org/10.1016/j.apsb.2022.03.014
  9. Mol Med Rep. 2022 Nov;pii: 345. [Epub ahead of print]26(5):
    Transcriptional regulation of CDKN2A/p16 by sirtuin 7 in senescence.
    Sergio Rodríguez, Litzy Gisella Bermúdez, Daniel González, Camila Bernal, Alejandra Cañas, Teresa Morales-Ruíz, Berta Henríquez, Adriana Rojas.
      Cell senescence is a state of limited cell proliferation during a stress response or as part of a programmed process. When a senescent cell stops dividing, maintaining metabolic activity contributes to cellular homeostasis maintenance. In this process, the cell cycle is arrested at the G0/G1 phase. p16INK4A protein is a key regulator of this process via its cyclin‑dependent kinase inhibitor (CDKI) function. CDKI 2A (CDKN2A)/p16 gene expression is regulated by DNA methylation and histone acetylation. Sirtuins (SIRTs) are nicotinamide dinucleotide (NAD+)‑dependent deacetylases that have properties which prevent diseases and reverse certain aspects of aging (such as immune, metabolic and cardiovascular diseases). By performing quantitative PCR, Western blot, ChIP, and siRNAs assays, in this study it was demonstrated that CDKN2A/p16 gene transcriptional activation and repression were accompanied by selective deposition and elimination of histone acetylation during the senescence of MRC5 cells. Specifically, significant H3K9Ac and H3K18Ac enrichment in cells with a senescent phenotype concomitant with CDKN2A/p16 gene overexpression was demonstrated compared with the non‑senescent phenotype. Furthermore, the presence of H3K18Ac in deacetyl‑transferase SIRT7 knockdown MRC5 cells allowed CDKN2A/p16 promoter activation. These results suggested that SIRT7 served as a critical component of an epigenetic mechanism involved in senescence mediated by the CDKN2A/p16 gene.
    Keywords:  aging; cyclin‑dependent kinase inhibitor 2A/p16; epigenetics; senescence; sirtuin 7
    DOI:  https://doi.org/10.3892/mmr.2022.12861
  10. Nat Commun. 2022 Sep 27. 13(1): 5671
    Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
    Xu Zhang, Vesselina M Pearsall, Chase M Carver, Elizabeth J Atkinson, Benjamin D S Clarkson, Ethan M Grund, Michelle Baez-Faria, Kevin D Pavelko, Jennifer M Kachergus, Thomas A White, Renee K Johnson, Courtney S Malo, Alan M Gonzalez-Suarez, Katayoun Ayasoufi, Kurt O Johnson, Zachariah P Tritz, Cori E Fain, Roman H Khadka, Mikolaj Ogrodnik, Diana Jurk, Yi Zhu, Tamara Tchkonia, Alexander Revzin, James L Kirkland, Aaron J Johnson, Charles L Howe, E Aubrey Thompson, Nathan K LeBrasseur, Marissa J Schafer.
      Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.
    DOI:  https://doi.org/10.1038/s41467-022-33226-8
  11. Front Nutr. 2022 ;9 958563
    Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging - from theory to practice.
    Carla Luís, Ana T Maduro, Paula Pereira, José João Mendes, Raquel Soares, Renata Ramalho.
      Aging is a natural physiological process, but one that poses major challenges in an increasingly aging society prone to greater health risks such as diabetes, cardiovascular disease, cancer, frailty, increased susceptibility to infection, and reduced response to vaccine regimens. The loss of capacity for cell regeneration and the surrounding tissue microenvironment itself is conditioned by genetic, metabolic, and even environmental factors, such as nutrition. The senescence of the immune system (immunosenescence) represents a challenge, especially when associated with the presence of age-related chronic inflammation (inflammaging) and affecting the metabolic programming of immune cells (immunometabolism). These aspects are linked to poorer health outcomes and therefore present an opportunity for host-directed interventions aimed at both eliminating senescent cells and curbing the underlying inflammation. Senotherapeutics are a class of drugs and natural products that delay, prevent, or reverse the senescence process - senolytics; or inhibit senescence-associated secretory phenotype - senomorphics. Natural senotherapeutics from food sources - nutritional senotherapeutics - may constitute an interesting way to achieve better age-associated outcomes through personalized nutrition. In this sense, the authors present herein a framework of nutritional senotherapeutics as an intervention targeting immunosenescence and immunometabolism, identifying research gaps in this area, and gathering information on concluded and ongoing clinical trials on this subject. Also, we present future directions and ideation for future clinical possibilities in this field.
    Keywords:  aging; immunometabolism; immunosenescence; inflammaging; nutritional senolytics; nutritional senomorphics; precision nutrition
    DOI:  https://doi.org/10.3389/fnut.2022.958563
  12. Front Aging. 2022 ;3 973781
    DNA damage, inflammation and aging: Insights from mice.
    Ermioni S Arvanitaki, Kalliopi Stratigi, George A Garinis.
      Persistent DNA lesions build up with aging triggering inflammation, the body's first line of immune defense strategy against foreign pathogens and irritants. Once established, DNA damage-driven inflammation takes on a momentum of its own, due to the amplification and feedback loops of the immune system leading to cellular malfunction, tissue degenerative changes and metabolic complications. Here, we discuss the use of murine models with inborn defects in genome maintenance and the DNA damage response for understanding how irreparable DNA lesions are functionally linked to innate immune signaling highlighting their relevance for developing novel therapeutic strategies against the premature onset of aging-associated diseases.
    Keywords:  DNA damage; DNA repair; aging; diseases; inflammation
    DOI:  https://doi.org/10.3389/fragi.2022.973781
  13. Front Aging Neurosci. 2022 ;14 933015
    DNA damage response and GATA4 signaling in cellular senescence and aging-related pathology.
    Hao Xiong, Fuzhou Hua, Yao Dong, Yue Lin, Jun Ying, Jie Liu, Xifeng Wang, Lieliang Zhang, Jing Zhang.
      Aging is the continuous degradation of biological function and structure with time, and cellular senescence lies at its core. DNA damage response (DDR) can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that plays an important role in the development of many organs, such as the heart, testis, ovary, foregut, liver, and ventral pancreas. Studies have shown that GATA4 can also contribute to the DDR, leading to aging. Consistently, there is also evidence that the GATA4 signaling pathway is associated with aging-related diseases, including atherosclerosis and heart failure. This paper reviews the relationship between GATA4, DDR, and cellular senescence, as well as its effect on aging-related diseases.
    Keywords:  CGATA4; DNA damage response; atherosclerosis; cellular senescence; heart failure
    DOI:  https://doi.org/10.3389/fnagi.2022.933015
  14. Neurobiol Aging. 2022 Sep 02. pii: S0197-4580(22)00195-6. [Epub ahead of print]120 88-104
    Evidence of sex differences in cellular senescence.
    Mitchell Ng, Lili-Naz Hazrati.
      Biological sex is a factor in many conditions, including aging, neurodegenerative disease, cancer, and more. For each of these, men and women display distinct differences in disease development and progression. To date, studies on the molecular basis of such differences have largely focused on sex hormones, typically highlighting their neuroprotective benefits. However, new research suggests that cellular senescence may underlie sex differences in both neurological and non-neurological pathologies. Cellular senescence-stable proliferative arrest with a unique pro-inflammatory phenotype-occurs in response to persistent DNA damage signaling, safeguarding against tissue-level consequences of DNA damage (e.g., tumorigenesis). Though critical for maintaining tissue health, senescence has also been implicated in disease. Indeed, senescent cell accumulation occurs in multiple disease contexts, and the elimination of such cells (via senolytic therapies) alleviates associated disease hallmarks. If cell senescence is a driver of pathophysiology, sex differences in cellular senescence may underlie sex-specific disease outcomes. This review summarizes evidence of sex differences in cellular senescence-highlighting findings from both human and animal studies-and briefly discusses the potential relevance of sex chromosome epigenetics and mosaicism. Current studies show that female sex is associated with greater susceptibility to DNA damage and greater likelihood of senescence onset, despite additional evidence that estrogen protects against genotoxic insult and inhibits senescence regulatory proteins. Further studies on sex differences in cellular senescence are needed, both to verify whether findings from animal studies hold true in human contexts and to validate whether senescence manifests differently between men and women following comparable senescence-inducing stimuli.
    Keywords:  Aging; Cellular senescence; DNA damage; DNA repair; Neurodegeneration; Sex differences; X Chromosome inactivation
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.08.014
  15. Aging (Albany NY). 2022 Sep 24. 14(undefined):
    Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells.
    Lars Erichsen, James Adjaye.
      The aging process is manifested by a multitude of inter-linked biological processes. These processes contribute to genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, de-regulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mammalian ortholog of the yeast silent information regulator (Sir2) SIRT1 is a NAD+-dependent class III histone deacetylase and has been recognized to be involved in many of the forementioned processes. Furthermore, the physiological activity of several Sirtuin family members has been connected to the regulation of life span of lower organisms (Caenorhabditis elegans and Drosophila melanogaster) as well as mammals. In the present study, we provide evidence that SIX2-positive urine derived renal progenitor cells-UdRPCs isolated directly from human urine show typical hallmarks of aging. This includes the subsequent transcriptional downregulation of SIRT1 and its downstream targets AKT and GSK3ß with increased donor age. This transcriptional downregulation is accompanied by an increase in DNA damage and transcriptional levels of several cell cycle inhibitors such as P16. We provide evidence that the renal progenitor transcription factor SIX2 binds to the coding sequence of SIRT1. Furthermore, we show that the SIRT1 promoter region is methylation sensitive and becomes methylated during aging, dividing them into SIRT1-high and -low expressing UdRPCs. Our results highlight the importance of SIRT1 in DNA damage repair recognition in UdRPCs and the control of differentiation by regulating the activation of GSK3β through AKT.
    Keywords:  DNA-damage; SIRT1; aging; renal differentiation
    DOI:  https://doi.org/10.18632/aging.204300
  16. Ageing Res Rev. 2022 Sep 23. pii: S1568-1637(22)00179-9. [Epub ahead of print]81 101737
    Frailty biomarkers under the perspective of geroscience: A narrative review.
    Rafaella Silva Dos Santos Aguiar Gonçalves, Álvaro Campos Cavalcanti Maciel, Yves Rolland, Bruno Vellas, Philipe de Souto Barreto.
      Cellular and molecular aging biomarkers might contribute to identify at-risk individuals for frailty before overt clinical manifestations appear. Although studies on the associations of aging biomarkers and frailty exist, no investigation has gathered this information using a structured framework for identifying aging biomarkers; as a result, the evidence on frailty and aging biomarkers is diffuse and incomplete. Therefore, this narrative review aimed to gather information on the associations of the hallmarks of aging and frailty under the perspective of geroscience. The literature on human studies on this topic is sparse and mainly composed of cross-sectional investigations performed in small study samples. The main putative aging biomarkers associated to frailty were: mitochondrial DNA copy number (genomic instability and mitochondrial dysfunction), telomere length (telomere attrition), global DNA methylation (epigenetic alterations), Hsp70 and Hsp72 (loss of proteostasis), IGF-1 and SIRT1 (deregulated nutrient-sensing), GDF-15 (mitochondrial dysfunction, cellular senescence and altered intercellular communication), CD4 + and CD8 + cell percentages (cellular senescence), circulating osteogenic progenitor (COP) cells (stem cell exhaustion), and IL-6, CRP and TNF-alpha (altered intercellular communication). IGF-1, SIRT1, GDF-15, IL-6, CRP and TNF-alpha presented more evidence among these biomarkers, highlighting the importance of inflammation and nutrient sensing on frailty. Further longitudinal studies investigating biomarkers across the hallmarks of aging would provide valuable information on this topic.
    Keywords:  Aging; Biomarkers; Frailty
    DOI:  https://doi.org/10.1016/j.arr.2022.101737
  17. FEBS J. 2022 Sep 26.
    Nucleosome disruption by 5-bromodeoxyuridine leads to senescence.
    Ana Guerrero.
      5-Bromodeoxyuridine (BrdU) exposure leads to senescence, but the mechanistic details remain elusive. In this issue, En A et al. unveil a role of the HBR domain in histone H2B as a potential mediator of the effects of BrdU both in yeast and in human cells. Comment on: https://doi.org/10.1111/febs.16584.
    Keywords:  BrdU; SASP; cellular senescence; epigenetics; nucleosomes
    DOI:  https://doi.org/10.1111/febs.16630
  18. Life Sci. 2022 Sep 21. pii: S0024-3205(22)00680-4. [Epub ahead of print] 120980
    Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α.
    Geum-Lan Hong, Kyung-Hyun Kim, Yae-Ji Kim, Hui-Ju Lee, Hyun-Tae Kim, Ju-Young Jung.
      Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.
    Keywords:  Aging; Autophagy; Benign prostate hyperplasia; Estrogen receptor; Mitophagy
    DOI:  https://doi.org/10.1016/j.lfs.2022.120980
  19. Aging Cell. 2022 Sep 29. e13716
    Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans.
    Julia A Loose, Francis R G Amrit, Thayjas Patil, Judith L Yanowitz, Arjumand Ghazi.
      An expanding body of evidence, from studies in model organisms to human clinical data, reveals that reproductive health influences organismal aging. However, the impact of germline integrity on somatic aging is poorly understood. Moreover, assessing the causal relationship of such an impact is challenging to address in human and vertebrate models. Here, we demonstrate that disruption of meiosis, a germline restricted process, shortened lifespan, impaired individual aspects of healthspan, and accelerated somatic aging in Caenorhabditis elegans. Young meiotic mutants exhibited transcriptional profiles that showed remarkable overlap with the transcriptomes of old worms and shared similarities with transcriptomes of aging human tissues as well. We found that meiosis dysfunction caused increased expression of functionally relevant longevity determinants whose inactivation enhanced the lifespan of normal animals. Further, meiotic mutants manifested destabilized protein homeostasis and enhanced proteasomal activity partially rescued the associated lifespan defects. Our study demonstrates a role for meiotic integrity in controlling somatic aging and reveals proteostasis control as a potential mechanism through which germline status impacts overall organismal health.
    Keywords:   C. elegans ; aging; germ cells; germline; healthspan; lifespan; meiosis; proteostasis; reproduction; soma-germline signaling
    DOI:  https://doi.org/10.1111/acel.13716
  20. Mech Ageing Dev. 2022 Sep 21. pii: S0047-6374(22)00121-X. [Epub ahead of print]208 111739
    Immunosenescence profiles of lymphocyte compartments and multiple long-term conditions (multimorbidity) in very old adults: The Newcastle 85+ Study.
    Antoneta Granic, Carmen Martin-Ruiz, Lucy Rimmer, Richard M Dodds, Louise A Robinson, Ioakim Spyridopoulos, Thomas B L Kirkwood, Thomas von Zglinicki, Avan A Sayer.
      Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and ageing syndromes. Very old adults (aged ≥ 85 years) live with multiple long-term conditions (MLTC, also known as multimorbidity)-a complex phenomenon of poor health defined by either counts, indices, or patterns, but little is known about the relationship between an ageing immune system and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the associations between previously defined immunosenescence profiles of lymphocyte compartments and MLTC counts and patterns (from 16 chronic diseases/ageing syndromes). Seven hundred and three participants had MLTC and complete data for all 16 conditions, a median and mean of 5 (range 2-11) and 62.2% had ≥ 5 conditions. Three distinct MLTC patterns emerged by clustering: Cluster 1 ('Low frequency cardiometabolic-cerebrovascular diseases', n = 209), Cluster 2 ('High ageing syndromes-arthritis', n = 240), and Cluster 3 ('Hypertensive-renal impairment', n = 254). Although having a more senescent phenotype, characterised by higher frequency of CD4 and CD8 senescence-like effector memory cells and lower CD4/CD8 ratio, was not associated with MLTC compared with less senescent phenotype, the results warrant further investigation, including whether immunosenescence drives change in MLTC and influences MLTC severity in late adulthood.
    Keywords:  Immunosenescence; Lymphocyte compartments; Multimorbidity; Multiple long-term conditions; Very old adults
    DOI:  https://doi.org/10.1016/j.mad.2022.111739
  21. Front Cell Dev Biol. 2022 ;10 985274
    The epigenetic aging, obesity, and lifestyle.
    Marica Franzago, Lucrezia Pilenzi, Sara Di Rado, Ester Vitacolonna, Liborio Stuppia.
      The prevalence of obesity has dramatically increased worldwide over the past decades. Aging-related chronic conditions, such as type 2 diabetes and cardiovascular disease, are more prevalent in individuals with obesity, thus reducing their lifespan. Epigenetic clocks, the new metrics of biological age based on DNA methylation patterns, could be considered a reflection of the state of one's health. Several environmental exposures and lifestyle factors can induce epigenetic aging accelerations, including obesity, thus leading to an increased risk of age-related diseases. The insight into the complex link between obesity and aging might have significant implications for the promotion of health and the mitigation of future disease risk. The present narrative review takes into account the interaction between epigenetic aging and obesity, suggesting that epigenome may be an intriguing target for age-related physiological changes and that its modification could influence aging and prolong a healthy lifespan. Therefore, we have focused on DNA methylation age as a clinical biomarker, as well as on the potential reversal of epigenetic age using a personalized diet- and lifestyle-based intervention.
    Keywords:  BMI; DNA methylation; DNAm age; epigenetics; lifestyle; obesity
    DOI:  https://doi.org/10.3389/fcell.2022.985274
  22. Aging Cell. 2022 Sep 27. e13723
    Single-cell analysis reveals transcriptomic reprogramming in aging primate entorhinal cortex and the relevance with Alzheimer's disease.
    Ming-Li Li, Shi-Hao Wu, Bo Song, Jing Yang, Li-Yuan Fan, Yang Yang, Yun-Chao Wang, Jing-Hua Yang, Yuming Xu.
      The entorhinal cortex is of great importance in cognition and memory, its dysfunction causes a variety of neurological diseases, particularly Alzheimer's disease (AD). Yet so far, research on entorhinal cortex is still limited. Here, we provided the first single-nucleus transcriptomic map of primate entorhinal cortex aging. Our result revealed that synapse signaling, neurogenesis, cellular homeostasis, and inflammation-related genes and pathways changed in a cell-type-specific manner with age. Moreover, among the 7 identified cell types, we highlighted the neuronal lineage that was most affected by aging. By integrating multiple datasets, we found entorhinal cortex aging was closely related to multiple neurodegenerative diseases, particularly for AD. The expression levels of APP and MAPT, which generate β-amyloid (Aβ) and neurofibrillary tangles, respectively, were increased in most aged entorhinal cortex cell types. In addition, we found that neuronal lineage in the aged entorhinal cortex is more prone to AD and identified a subpopulation of excitatory neurons that are most highly associated with AD. Altogether, this study provides a comprehensive cellular and molecular atlas of the primate entorhinal cortex at single-cell resolution and provides new insights into potential therapeutic targets against age-related neurodegenerative diseases.
    Keywords:  aging; alzheimer’s disease; entorhinal cortex; primate; single cell
    DOI:  https://doi.org/10.1111/acel.13723
  23. Mol Metab. 2022 Sep 20. pii: S2212-8778(22)00174-0. [Epub ahead of print] 101605
    Nicotinamide riboside kinase 1 protects against diet and age-induced pancreatic β-cell failure.
    Angelique Cercillieux, Joanna Ratajczak, Magali Joffraud, José Luis Sanchez-Garcia, Guillaume Jacot, Alix Zollinger, Sylviane Métairon, Judith Giroud-Gerbetant, Marie Rumpler, Eleonora Ciarlo, Miriam Valera-Alberni, Audrey Sambeat, Carles Canto.
      OBJECTIVE: Disturbances in NAD + metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic β-cell function in pathophysiological conditions.METHODS: Whole body and pancreatic β-cell-specific NRK1 knockout (KO) mice were metabolically phenotyped in situations of high-fat feeding and aging. We also analyzed pancreatic β-cell function and gene expression.
    RESULTS: We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is abundantly expressed in pancreatic β-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised β-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, β cells dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in β-cells did not show altered glucose homeostasis.
    CONCLUSIONS: This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic β-cell function in high-fat feeding or aging conditions.
    Keywords:  Metabolic disease; NAD(+); Nicotinamide riboside; Nicotinamide riboside kinase 1 (NRK1)
    DOI:  https://doi.org/10.1016/j.molmet.2022.101605
  24. MedComm (2020). 2022 Dec;3(4): e173
    Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy.
    Su Zhang, Yang Meng, Lian Zhou, Lei Qiu, Heping Wang, Dan Su, Bo Zhang, Kui-Ming Chan, Junhong Han.
      Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor-κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation-associated diseases to improve therapeutic outcomes.
    Keywords:  epigenetic regulator; immune; inflammation; posttranslational modification (PTM)
    DOI:  https://doi.org/10.1002/mco2.173
  25. Aging Cell. 2022 Sep 30. e13724
    Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice.
    Randy Strong, Richard A Miller, Catherine J Cheng, James F Nelson, Jonathan Gelfond, Shailaja Kesaraju Allani, Vivian Diaz, Angela Olsen Dorigatti, Jonathan Dorigatti, Elizabeth Fernandez, Andrzej Galecki, Brett Ginsburg, Karyn L Hamilton, Martin A Javors, Kerry Kornfeld, Matt Kaeberlein, Suja Kumar, David B Lombard, Marisa Lopez-Cruzan, Benjamin F Miller, Peter Rabinovitch, Peter Reifsnyder, Nadia A Rosenthal, Molly A Bogue, Adam B Salmon, Yousin Suh, Eric Verdin, Herbert Weissbach, John Newman, Francesca Maccchiarini, David E Harrison.
      Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
    Keywords:  acarbose plus rapamycin; captopril; survival
    DOI:  https://doi.org/10.1111/acel.13724
  26. Plast Reconstr Surg. 2022 Oct 01. 150 49S-57S
    Healthspan Extension through Innovative Genetic Medicines.
    Henry Garcia, Douglas Brown, Matthew Scholz, John D Lewis.
      SUMMARY: Genetic medicine has emerged as an innovative class of therapeutics, allowing the development of new and powerful approaches to address a myriad of diseases that were previously untreatable. At the same time, our improved understanding of the mechanisms underlying aging has created novel opportunities to intervene therapeutically in the aging process itself through the targeting of key pathways driving this process. As individuals age, the onset of a multitude of age-related diseases can significantly impact lifespan. The ultimate goal of their treatment is the maximization of healthy, disease-free years, or healthspan. Here, we discuss a number of promising genetic medicine approaches to target both general and specific mechanisms of age-related disease, and their potential impact on healthspan extension. Essential to this topic is the challenge of nucleic acid delivery, and we discuss the technologies that have been developed to address this challenge in highly promising preclinical and clinical development efforts. In particular, we describe a next-generation delivery technology for healthspan applications called proteo-lipid vehicles.
    DOI:  https://doi.org/10.1097/PRS.0000000000009674
  27. J Mol Med (Berl). 2022 Sep 30.
    Growth hormone/IGF-I-dependent signaling restores decreased expression of the myokine SPARC in aged skeletal muscle.
    Sebastian Mathes, Alexandra Fahrner, Edlira Luca, Jan Krützfeldt.
      Skeletal muscle exerts many beneficial effects on the human body including the contraction-dependent secretion of peptides termed myokines. We have recently connected the myokine secreted protein acidic and rich in cysteine (SPARC) to the formation of intramuscular adipose tissue (IMAT) in skeletal muscle from aged mice and humans. Here, we searched for inducers of SPARC in order to uncover novel treatment approaches for IMAT. Endurance exercise in mice as well as forskolin treatment in vitro only modestly activated SPARC levels. However, through pharmacological treatments in vitro, we identified IGF-I as a potent inducer of SPARC expression in muscle cells, likely through a direct activation of its promoter via phosphatidylinositol 4,5-bisphospate 3-kinase (PI3K)-dependent signaling. We employed two different mouse models of growth hormone (GH)/IGF-I deficiency to solidify our understanding of the relationship between IGF-I and SPARC in vivo. GH administration robustly increased intramuscular SPARC levels (3.5-fold) in GH releasing hormone receptor-deficient mice and restored low intramuscular SPARC expression in skeletal muscle from aged mice. Intramuscular glycerol injections induced higher levels of adipocyte markers (adiponectin, perilipin) in aged compared to young mice, which was not prevented by GH treatment. Our study provides a roadmap for the study of myokine regulation during aging and demonstrates that the GH/IGF-I axis is critical for SPARC expression in skeletal muscle. Although GH treatment did not prevent IMAT formation in the glycerol model, targeting SPARC by exercise or by activation of IGF-I signaling might offer a novel therapeutic strategy against IMAT formation during aging. KEY MESSAGES : IGF-I regulates the myokine SPARC in muscle cells directly at the promoter level. GH/IGF-I is able to restore the decreased SPARC levels in aged skeletal muscle. The glycerol model induces higher adipocyte markers in aged compared to young muscle. GH treatment does not prevent IMAT formation in the glycerol model.
    Keywords:  Aging; Growth hormone; IGF-I; IMAT; SPARC; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00109-022-02260-w
  28. Mol Syst Biol. 2022 Sep;18(9): e11087
    The molecular architecture of cell cycle arrest.
    Wayne Stallaert, Sovanny R Taylor, Katarzyna M Kedziora, Colin D Taylor, Holly K Sobon, Catherine L Young, Juanita C Limas, Jonah Varblow Holloway, Martha S Johnson, Jeanette Gowen Cook, Jeremy E Purvis.
      The cellular decision governing the transition between proliferative and arrested states is crucial to the development and function of every tissue. While the molecular mechanisms that regulate the proliferative cell cycle are well established, we know comparatively little about what happens to cells as they diverge into cell cycle arrest. We performed hyperplexed imaging of 47 cell cycle effectors to obtain a map of the molecular architecture that governs cell cycle exit and progression into reversible ("quiescent") and irreversible ("senescent") arrest states. Using this map, we found multiple points of divergence from the proliferative cell cycle; identified stress-specific states of arrest; and resolved the molecular mechanisms governing these fate decisions, which we validated by single-cell, time-lapse imaging. Notably, we found that cells can exit into senescence from either G1 or G2; however, both subpopulations converge onto a single senescent state with a G1-like molecular signature. Cells can escape from this "irreversible" arrest state through the upregulation of G1 cyclins. This map provides a more comprehensive understanding of the overall organization of cell proliferation and arrest.
    Keywords:  cell cycle; proliferation; quiescence; senescence; single-cell
    DOI:  https://doi.org/10.15252/msb.202211087
  29. Aging Cell. 2022 Sep 30. e13718
    Riboflavin depletion promotes longevity and metabolic hormesis in Caenorhabditis elegans.
    Armen Yerevanian, Luke M Murphy, Sinclair Emans, Yifei Zhou, Fasih M Ahsan, Daniel Baker, Sainan Li, Adebanjo Adedoja, Lucydalila Cedillo, Nicole L Stuhr, Einstein Gnanatheepam, Khoi Dao, Mohit Jain, Sean P Curran, Irene Georgakoudi, Alexander A Soukas.
      Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here, we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent upon AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and FOXO/daf-16. Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin-depleted animals also exhibit the activation of caloric restriction reporters without any reduction in caloric intake. Our findings indicate that riboflavin depletion activates an integrated hormetic response that promotes lifespan and healthspan in C. elegans.
    Keywords:   C. elegans ; rft-1 riboflavin transporter ; AMPK; FOXO; UPRmt; dietary restriction; longevity; riboflavin
    DOI:  https://doi.org/10.1111/acel.13718
  30. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01274-8. [Epub ahead of print]40(13): 111433
    Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.
    Margarita Brilkova, Martina Nigri, Harshitha Santhosh Kumar, James Moore, Matilde Mantovani, Claudia Keller, Amandine Grimm, Anne Eckert, Dimitri Shcherbakov, Rashid Akbergenov, Petra Seebeck, Stefanie D Krämer, David P Wolfer, Thomas C Gent, Erik C Böttger.
      Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.
    Keywords:  Alzheimer; CP: Neuroscience; error-prone translation; neurodegenerative diseases; pathogenesis; protein misfolding; synaptic homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111433
  31. Front Aging Neurosci. 2022 ;14 956503
    Tumor necrosis factor-α mediated inflammation versus apoptosis in age-related hearing loss.
    Ting Wu, Jiamin Zhou, Jingjing Qiu, Yuwan Song, Wentao Guo, Limei Cui, Xicheng Song, Yan Sun.
      An almost universal phenomenon occurring during aging is a state of chronic, low-grade, sterile inflammation. Inflammation is a crucial contributor to various age-related pathologies and natural processes in aging tissues. Tumor necrosis factor-α (TNF-α), a master regulator of the immune system, plays an important role in the propagation of inflammation. Recent research has found correlations between hearing loss and markers such as TNF-α. However, the intrinsic molecular mechanism by which TNF-α influences aging individuals' increased risk of hearing loss remains unclear. In this study, we found that TNF-α expression gradually increased with age in DBA/2J mice. We then used recombinant TNF-α to upregulate TNF-α levels in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and found that low concentrations of TNF-α could activate the nuclear factor kappa B (NF-κB) transcriptional response to mediate hair cell survival, while high concentrations of TNF-α could activate the Caspase-3 cascade to mediate hair cell apoptosis, which preliminarily confirmed that a TNF-α mediated signaling pathway plays an important role in the pathogenesis of age-related hearing loss.
    Keywords:  NF-κB; TNF-α; age; inflammation response; presbycusis
    DOI:  https://doi.org/10.3389/fnagi.2022.956503
  32. Aging Cell. 2022 Sep 27. e13725
    Reprograming of proteasomal degradation by branched chain amino acid metabolism.
    Sonia Ravanelli, Qiaochu Li, Andrea Annibal, Aleksandra Trifunovic, Adam Antebi, Thorsten Hoppe.
      Branched-chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi-omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin-proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP-based proteasome substrate, which is suppressed by loss-of-function of the first BCAA catabolic enzyme, the branched-chain aminotransferase BCAT-1. The exogenous supply of BCAA-derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.
    Keywords:   Caenorhabditis elegans ; aging; branched-chain amino acid; branched-chain aminotransferase; metabolism; proteasome; proteostasis; ubiquitin
    DOI:  https://doi.org/10.1111/acel.13725
  33. Aging Cell. 2022 Oct 01. e13712
    Single-cell RNA-seq reveals early heterogeneity during aging in yeast.
    Jincheng Wang, Yuchen Sang, Shengxian Jin, Xuezheng Wang, Gajendra Kumar Azad, Mark A McCormick, Brian K Kennedy, Qing Li, Jianbin Wang, Xiannian Zhang, Yi Zhang, Yanyi Huang.
      The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has relatively short lifespan and is genetically tractable, making it a widely used model organism in aging research. Here, we carried out a systematic and quantitative investigation of yeast aging with single-cell resolution through transcriptomic sequencing. We optimized a single-cell RNA sequencing (scRNA-seq) protocol to quantitatively study the whole transcriptome profiles of single yeast cells at different ages, finding increased cell-to-cell transcriptional variability during aging. The single-cell transcriptome analysis also highlighted key biological processes or cellular components, including oxidation-reduction process, oxidative stress response (OSR), translation, ribosome biogenesis and mitochondrion that underlie aging in yeast. We uncovered a molecular marker of FIT3, indicating the early heterogeneity during aging in yeast. We also analyzed the regulation of transcription factors and further characterized the distinctive temporal regulation of the OSR by YAP1 and proteasome activity by RPN4 during aging in yeast. Overall, our data profoundly reveal early heterogeneity during aging in yeast and shed light on the aging dynamics at the single cell level.
    Keywords:  early heterogeneity; iron transport; mitochondrial dysfunction; single cell RNA sequencing; yeast aging
    DOI:  https://doi.org/10.1111/acel.13712
  34. Biochemistry (Mosc). 2022 Sep;87(9): 995-1014
    The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging.
    Dzhuliia Sh Dzhalilova, Olga V Makarova.
      Aging is accompanied by a reduction in the oxygen delivery to all organs and tissues and decrease in the oxygen partial pressure in them, resulting in the development of hypoxia. The lack of oxygen activates cell signaling pathway mediated by the hypoxia-inducible transcription factor (HIF), which exists in three isoforms - HIF-1, HIF-2, and HIF-3. HIF regulates expression of several thousand genes and is a potential target for the development of new drugs for the treatment of many diseases, including those associated with age. Human organism and organisms of laboratory animals differ in their tolerance to hypoxia and expression of HIF and HIF-dependent genes, which may contribute to the development of inflammatory, tumor, and cardiovascular diseases. Currently, the data on changes in the HIF expression with age are contradictory, which is mostly due to the fact that such studies are conducted in different age groups, cell types, and model organisms, as well as under different hypoxic conditions and mainly in vitro. Furthermore, the observed discrepancies can be due to the individual tolerance of the studied organisms to hypoxia, which is typically not taken into account. Therefore, the purpose of this review was to analyze the published data on the connection between the mechanisms of aging, basal tolerance to hypoxia, and changes in the level of HIF expression with age. Here, we summarized the data on the age-related changes in the hypoxia tolerance, HIF expression and the role of HIF in aging, which is associated with its involvement in the molecular pathways mediated by insulin and IGF-1 (IIS), sirtuins (SIRTs), and mTOR. HIF-1 interacts with many components of the IIS pathway, in particular with FOXO, the activation of which reduces production of reactive oxygen species (ROS) and increases hypoxia tolerance. Under hypoxic conditions, FOXO is activated via both HIF-dependent and HIF-independent pathways, which contributes to a decrease in the ROS levels. The activity of HIF-1 is regulated by all members of the sirtuin family, except SIRT5, while the mechanisms of SIRT interaction with HIF-2 and HIF-3 are poorly understood. The connection between HIF and mTOR and its inhibitor, AMPK, has been identified, but its exact mechanism has yet to be studied. Understanding the role of HIF and hypoxia in aging and pathogenesis of age-associated diseases is essential for the development of new approaches to the personalized therapy of these diseases, and requires further research.
    Keywords:  HIF; age; hypoxia tolerance; mechanisms of aging
    DOI:  https://doi.org/10.1134/S0006297922090115
  35. Genes Dev. 2022 Sep 27.
    Bmi1 suppresses protein synthesis and promotes proteostasis in hematopoietic stem cells.
    Rebecca J Burgess, Zhiyu Zhao, Daisuke Nakada, Sean J Morrison.
      The polycomb complex component Bmi1 promotes the maintenance of stem cells in multiple postnatal tissues, partly by negatively regulating the expression of p16Ink4a and p19Arf, tumor suppressors associated with cellular senescence. However, deficiency for p16Ink4a and p19Arf only partially rescues the function of Bmi1-deficient stem cells. We conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs). Rather than inducing senescence, Bmi1 deficiency increased HSC division. The increased cell division was caused partly by increased Aristaless-related homeobox (ARX) transcription factor expression, which also increased ribosomal RNA expression. However, ARX deficiency did not rescue HSC depletion. Bmi1 deficiency also increased protein synthesis, protein aggregation, and protein ubiquitylation independent of its effects on cell division and p16Ink4a, p19Arf, and ARX expression. Bmi1 thus promotes HSC quiescence by negatively regulating ARX expression and promotes proteostasis by suppressing protein synthesis. This highlights a new connection between the regulation of stem cell maintenance and proteostasis.
    Keywords:  polycomb; self-renewal; senescence; tissue regeneration; tumor suppressor
    DOI:  https://doi.org/10.1101/gad.349917.122
  36. Aging (Albany NY). 2022 Sep 26. 14(undefined):
    Lotus germ extract rejuvenates aging fibroblasts via restoration of disrupted proteostasis by the induction of autophagy.
    Kayo Machihara, Sou Kageyama, Shoma Oki, Hiroki Makino, Masamichi Sasaki, Hiroyasu Iwahashi, Takushi Namba.
      Cell aging attenuates cellular functions, resulting in time-dependent disruption of cellular homeostasis, which maintains the functions of proteins and organelles. Mitochondria are important organelles responsible for cellular energy production and various metabolic processes, and their dysfunction is strongly related to the progression of cellular aging. Here we demonstrate that disruption of proteostasis attenuates mitochondrial function before the induction of DNA damage signaling by proliferative and replicative cellular aging. We found that lotus (Nelumbo nucifera Gaertn.) germ extract clears abnormal proteins and agglutinates via autophagy-mediated restoration of mitochondrial function and cellular aging phenotypes. Pharmacological analyses revealed that DAPK1 expression was suppressed in aging cells, and lotus germ extract upregulated DAPK1 expression by stimulating the acetylation of histones and then induced autophagy by activating the DAPK1-Beclin1 signaling pathway. Furthermore, treatment of aging fibroblasts with lotus germ extract stimulated collagen production and increased contractile ability in three-dimensional cell culture. Thus, time-dependent accumulation of abnormal proteins and agglutinates suppressed mitochondrial function in cells in the early stage of aging, and reactivation of mitochondrial function by restoring proteostasis rejuvenated aging cells. Lotus germ extract rejuvenates aging fibroblasts via the DAPK1-Beclin1 pathway-induced autophagy to clear abnormal proteins and agglutinates.
    Keywords:  aging; autophagy; mitochondria; proteostasis
    DOI:  https://doi.org/10.18632/aging.204303
  37. BMC Geriatr. 2022 Sep 29. 22(1): 772
    Circulating miR-181a as a novel potential plasma biomarker for multimorbidity burden in the older population.
    Francesca Iannone, Paolina Crocco, Serena Dato, Giuseppe Passarino, Giuseppina Rose.
      BACKGROUND: Chronic low-level inflammation is thought to play a role in many age-related diseases and to contribute to multimorbidity and to the disability related to this condition. In this framework, inflamma-miRs, an important subset of miRNA able to regulate inflammation molecules, appear to be key players. This study aimed to evaluate plasma levels of the inflamma-miR-181a in relation to age, parameters of health status (clinical, physical, and cognitive) and indices of multimorbidity in a cohort of 244 subjects aged 65- 97.METHODS: MiR-181a was isolated from plasma according to standardized procedures and its expression levels measured by qPCR. Correlation tests and multivariate regression analyses were applied on gender-stratified groups.
    RESULTS: MiR-181a levels resulted increased in old men, and significantly correlated with worsened blood parameters of inflammation (such as low levels of albumin and bilirubin and high lymphocyte content), particularly in females. Furthermore, we found miR-181a positively correlated with the overall multimorbidity burden, measured by CIRS Comorbidity Score, in both genders.
    CONCLUSIONS: These data support a role of miR-181a in age-related chronic inflammation and in the development of multimorbidity in older adults and indicate that the routes by which this miRNA influence health status are likely to be gender specific. Based on our results, we suggest that miR-181a is a promising biomarker of health status of the older population.
    Keywords:  Aging; Inflamma-miRs; Inflammation; Multimorbidity; miR-181a; miRNA
    DOI:  https://doi.org/10.1186/s12877-022-03451-3
  38. Plast Reconstr Surg. 2022 Oct 01. 150 41S-48S
    The Role of NAD+ in Regenerative Medicine.
    Nichola J Conlon.
      SUMMARY: The understanding of the molecular and cellular basis of aging has grown exponentially over recent years, and it is now accepted within the scientific community that aging is a malleable process; just as it can be accelerated, it can also be slowed and even reversed. This has far-reaching implications for our attitude and approach toward aging, presenting the opportunity to enter a new era of cellular regenerative medicine to not only manage the external signs of aging but also to develop therapies that support the body to repair and restore itself back to a state of internal well-being. A wealth of evidence now demonstrates that a decline in cellular nicotinamide adenine dinucleotide (NAD+) is a feature of aging and may play a role in the process. NAD+ plays a pivotal role in cellular metabolism and is a co-substrate for enzymes that play key roles in pathways that modify aging. Thus, interventions that increase NAD+ may slow aspects of the aging trajectory, and there is great interest in methods for cellular NAD+ restoration. Given these recent advancements in understanding the cellular aging process, it is important that there is an integration between the basic scientists who are investigating the underlying mechanisms of cellular aging and the surgeons and aesthetic practitioners who are providing antiaging therapies. This will allow the effective translation of this vastly complex area of biology into clinical practice so that people can continue to not only stay looking younger for longer but also experience improved health and wellness.
    DOI:  https://doi.org/10.1097/PRS.0000000000009673
  39. Aging (Albany NY). 2022 Sep 29. 14(undefined):
    RNA modifications in aging-associated cardiovascular diseases.
    Xinyu Yang, Priyanka Gokulnath, H Immo Lehmann, Zhitao Hou, Sun Yang, Liangzhen You, Guoxia Zhang, Yanwei Xing, Ji Lei, Guoping Li, Shuwen Guo, Hongcai Shang.
      Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide that bears an enormous healthcare burden and aging is a major contributing factor to CVDs. Functional gene expression network during aging is regulated by mRNAs transcriptionally and by non-coding RNAs epi-transcriptionally. RNA modifications alter the stability and function of both mRNAs and non-coding RNAs and are involved in differentiation, development, and diseases. Here we review major chemical RNA modifications on mRNAs and non-coding RNAs, including N6-adenosine methylation, N1-adenosine methylation, 5-methylcytidine, pseudouridylation, 2' -O-ribose-methylation, and N7-methylguanosine, in the aging process with an emphasis on cardiovascular aging. We also summarize the currently available methods to detect RNA modifications and the bioinformatic tools to study RNA modifications. More importantly, we discussed the specific implication of the RNA modifications on mRNAs and non-coding RNAs in the pathogenesis of aging-associated CVDs, including atherosclerosis, hypertension, coronary heart diseases, congestive heart failure, atrial fibrillation, peripheral artery disease, venous insufficiency, and stroke.
    Keywords:  RNA modifications; aging; aging-related cardiovascular diseases; epitranscriptome
    DOI:  https://doi.org/10.18632/aging.204311
  40. Front Cell Dev Biol. 2022 ;10 966531
    Drosophila exercise, an emerging model bridging the fields of exercise and aging in human.
    Meng Ding, Hongyu Li, Lan Zheng.
      Exercise is one of the most effective treatments for the diseases of aging. In recent years, a growing number of researchers have used Drosophila melanogaster to study the broad benefits of regular exercise in aging individuals. With the widespread use of Drosophila exercise models and the upgrading of the Drosophila exercise apparatus, we should carefully examine the differential contribution of regular exercise in the aging process to facilitate more detailed quantitative measurements and assessment of the exercise phenotype. In this paper, we review some of the resources available for Drosophila exercise models. The focus is on the impact of regular exercise or exercise adaptation in the aging process in Drosophila and highlights the great potential and current challenges faced by this model in the field of anti-aging research.
    Keywords:  Drosophila; aging; cardiac aging; exercise; lipid metabolism; obesity
    DOI:  https://doi.org/10.3389/fcell.2022.966531
  41. Geroscience. 2022 Sep 30.
    Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles.
    Allen Herbst, Judd M Aiken, Chiye Kim, Danielle Gushue, Debbie McKenzie, Timothy M Moore, Jin Zhou, Austin N Hoang, Solbie Choi, Jonathan Wanagat.
      Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4 weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects.
    Keywords:  Aging; Creatine; Genetics; Guanidinopropionic acid; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-022-00667-4
  42. Epigenomics. 2022 Sep 26.
    Circular RNA expression profiles of ovarian granulosa cells in advanced-age women explain new mechanisms of ovarian aging.
    Peigen Chen, Wei Li, Xiaoping Liu, Yanfang Wang, Huisi Mai, Rui Huang.
      Aim: We aimed to determine the role of granulosa cells (GCs) circular RNA (circRNA) in ovarian aging. Methods: Nine women were recruited, including three diminished ovarian reserve young women, three advanced-aged women and three normal ovarian reserve young women. The circRNA expression profiles of GCs were characterized by CLEAR software. Key circRNA were validated by quantitative reverse transcription PCR. Results: GCs in advanced-age group females exhibited active MHC class II-related biological processes. A total of 3575 circRNAs were found in the advanced age group. Hsa-circ-0031584 appears to be one of the important molecules regulating the mitotic process of GCs. Conclusion: The expression profiles of circRNAs exhibited obvious stage specificity with age which might contribute to ovarian aging progression.
    Keywords:  circular RNA; granulosa cells; microRNA; ovarian aging
    DOI:  https://doi.org/10.2217/epi-2022-0211
  43. Cell Death Differ. 2022 Sep 24.
    Sirt3 mediates the benefits of exercise on bone in aged mice.
    Qiangqiang Li, Rongliang Wang, Zhe Zhang, Haixing Wang, Xiaomin Lu, Jiajun Zhang, Alice Pik-Shan Kong, Xiao Yu Tian, Hon-Fai Chan, Arthur Chi-Kong Chung, Jack Chun-Yiu Cheng, Qing Jiang, Wayne Yuk-Wai Lee.
      Exercise in later life is important for bone health and delays the progression of osteoporotic bone loss. Osteocytes are the major bone cells responsible for transforming mechanical stimuli into cellular signals through their highly specialized lacunocanalicular networks (LCN). Osteocyte activity and LCN degenerate with aging, thus might impair the effectiveness of exercise on bone health; however, the underlying mechanism and clinical implications remain elusive. Herein, we showed that deletion of Sirt3 in osteocytes could impair the formation of osteocyte dendritic processes and inhibit bone gain in response to exercise in vivo. Mechanistic studies revealed that Sirt3 regulates E11/gp38 through the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. Additionally, the Sirt3 activator honokiol enhanced the sensitivity of osteocytes to fluid shear stress in vitro, and intraperitoneal injection of honokiol reduced bone loss in aged mice in a dose-dependent manner. Collectively, Sirt3 in osteocytes regulates bone mass and mechanical responses through the regulation of E11/gp38. Therefore, targeting Sirt3 could be a novel therapeutic strategy to prevent age-related bone loss and augment the benefits of exercise on the senescent skeleton.
    DOI:  https://doi.org/10.1038/s41418-022-01053-5
  44. BMC Neurosci. 2022 Sep 28. 23(1): 56
    Identification of a hippocampal lncRNA-regulating network in a natural aging rat model.
    Li Qi, Xiao Li, Shi-Min Liu, Dan-Li Jiao, Dan Hu, Xin-Yao Ju, Shu-Yu Zhao, Shu-Han Si, Li Hu, Guo-Na Li, Bing-Zhe Ma, Shuang Zhou, Chen Zhao.
      BACKGROUND: Dysregulation of long noncoding RNA (lncRNA) expression is related to aging and age-associated neurodegenerative diseases, and the lncRNA expression profile in the aging hippocampus is not well characterized. In the present investigation, the changed mRNAs and lncRNAs were confirmed via deep RNA sequencing. GO and KEGG pathway analyses were conducted to investigate the principal roles of the clearly dysregulated mRNAs and lncRNAs. Subsequently, through the prediction of miRNAs via which mRNAs and lncRNAs bind together, a competitive endogenous RNA network was constructed.RESULTS: A total of 447 lncRNAs and 182 mRNAs were upregulated, and 385 lncRNAs and 144 mRNAs were downregulated. Real-time reverse transcription-polymerase chain reaction validated the reliability of mRNA and lncRNA sequencing. KEGG pathway and GO analyses revealed that differentially expressed (DE) mRNAs were associated with cell adhesion molecules (CAMs), the p53 signaling pathway (SP), phagosomes, PPAR SP and ECM-receptor interactions. KEGG pathway and GO analyses showed that the target genes of the DE lncRNAs were related to cellular senescence, the p53 signaling pathway, leukocyte transendothelial migration and tyrosine metabolism. Coexpression analyses showed that 561 DE lncRNAs were associated with DE mRNAs. A total of 58 lncRNA-miRNA-mRNA target pairs were confirmed in this lncRNA‒miRNA‒mRNA network, comprising 10 mRNAs, 13 miRNAs and 38 lncRNAs.
    CONCLUSIONS: We found specific lncRNAs and mRNAs in the hippocampus of natural aging model rats, as well as abnormal regulatory ceRNA networks. Our outcomes help explain the pathogenesis of brain aging and provide direction for further research.
    Keywords:  Aging; Hippocampus; lncRNAs; mRNAs
    DOI:  https://doi.org/10.1186/s12868-022-00743-7
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