bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒11‒15
38 papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Aging Cell. 2020 Nov 09. e13270
    Kowald A, Passos JF, Kirkwood TBL.
      The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age-related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti-cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).
    Keywords:  aging; anti-aging; cellular senescence; evolution; senolytics
  2. Aging Cell. 2020 Nov 09. e13272
    Covre LP, De Maeyer RPH, Gomes DCO, Akbar AN.
      The development of senescence in tissues of different organs and in the immune system are usually investigated independently of each other although during ageing, senescence in both cellular systems develop concurrently. Senescent T cells are highly inflammatory and secrete cytotoxic mediators and express natural killer cells receptors (NKR) that bypass their antigen specificity. Instead they recognize stress ligands that are induced by inflammation or infection of different cell types in tissues. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.
    Keywords:  T cell; aging; senescence
  3. Cancer Cell. 2020 Oct 26. pii: S1535-6108(20)30543-2. [Epub ahead of print]
    Guccini I, Revandkar A, D'Ambrosio M, Colucci M, Pasquini E, Mosole S, Troiani M, Brina D, Sheibani-Tezerji R, Elia AR, Rinaldi A, Pernigoni N, Rüschoff JH, Dettwiler S, De Marzo AM, Antonarakis ES, Borrelli C, Moor AE, Garcia-Escudero R, Alajati A, Attanasio G, Losa M, Moch H, Wild P, Egger G, Alimonti A.
      Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
    Keywords:  FGF1; GDF-15; MMPs; PTEN; TIMP1; docetaxel; prostate cancer metastasis; senescence; senescence-associated secretory phenotype (SASP); senolytic therapy
  4. Trends Neurosci. 2020 Nov 10. pii: S0166-2236(20)30239-3. [Epub ahead of print]
    Paul BD, Snyder SH, Bohr VA.
      Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities. When cytosolic DNA is sensed, a signal is relayed via the cGAS-STING pathway: this involves the activation of cyclic GMP-AMP (cGMP-AMP) synthase (cGAS) and generation of the cyclic dinucleotide cGAMP, followed by the induction of stimulator of interferon genes (STING). The cGAS-STING pathway responds to viral, bacterial, and self-DNA. Whereas it generally mediates immune surveillance and is often neuroprotective, excessive engagement of the system can be deleterious. This is relevant in aging and age-related neurological diseases, where neuroinflammation contributes to disease progression. This review focuses on cGAS-STING signaling in aging, neurodegeneration, and neuroinflammation, and on therapeutic implications.
    Keywords:  Huntington’s disease; ataxia telangiectasia; cyclic GAMP; innate immune system; interferon-stimulated genes; senescence
  5. Biomater Sci. 2020 Nov 11.
    Pauty J, Nakano S, Usuba R, Nakajima T, Johmura Y, Omori S, Sakamoto N, Kikuchi A, Nakanishi M, Matsunaga YT.
      All human tissues experience aging that eventually causes organ dysfunction and disease. Cellular senescence was discovered in fibroblasts cultured in vitro. In adults, it is a primary defense mechanism against cancer, but also a major contributor to lifespan limits and disorders associated with aging. To assess how human blood vessels change in an aged environment, we developed an elementary tissue model-on-a-chip that comprises an in vitro three-dimensional model of a blood vessel embedded in a collagen gel with young or senescent skin fibroblasts. We found that senescent fibroblasts mechanically altered the surrounding extracellular matrix by exerting excessive traction stress. We then found that senescent fibroblasts induced sprouting angiogenesis of a microvessel via their senescence-associated secretory phenotype (SASP). Finally, we gathered evidence that the mechanical changes of the microenvironment play a role in sustaining SASP-induced angiogenesis. The model proved useful in monitoring morphological changes in blood vessels induced by senescent fibroblasts while controlling the proportion of senescent cells, and enabled the study of SASP inhibitors, a class of drugs useful in aging and cancer research.
  6. Aging (Albany NY). 2020 11 10. 12
    Lee OH, Woo YM, Moon S, Lee J, Park H, Jang H, Park YY, Bae SK, Park KH, Heo JH, Choi Y.
      Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.
    Keywords:  FOXM1; SIRT6; cell cycle; endothelial cell; senescence
  7. Aging Cell. 2020 Nov 11. e13274
    Battilana F, Steurer S, Rizzi G, Delgado AC, Tan KR, Handschin C.
      Age-associated loss of muscle function is exacerbated by a concomitant reduction in balance, leading to gait abnormalities and falls. Even though balance defects can be mitigated by exercise, the underlying neural mechanisms are unknown. We now have investigated components of the proprioceptive and vestibular systems in specific motor neuron pools in sedentary and trained old mice, respectively. We observed a strong age-linked deterioration in both circuits, with a mitigating effect of exercise on vestibular synapse numbers on motor neurons, closely associated with an improvement in gait and balance in old mice. Our results thus describe how the proprioceptive and vestibular systems are modulated by age and exercise, and how these changes affect their input to motor neurons. These findings not only make a strong case for exercise-based interventions in elderly individuals to improve balance, but could also lead to targeted therapeutic interventions aimed at the respective neuronal circuitry.
    Keywords:  aging; balance; exercise; motor control; motor neurons; proprioceptive system; training; vestibular system
  8. Cureus. 2020 Oct 04. 12(10): e10794
    Dhalla PS, Kaul A, Garcia J, Bapatla A, Khalid R, Armenta-Quiroga AS, Khan S.
      Aging is defined as progressive physiological alterations in an organism that lead to senescence. In response to stress, when proliferative-competent cells undergo permanent, irreversible growth arrest (like replicative dividing limit, oncogene activation, oxidative stress, or deoxyribonucleic acid (DNA) damage), it is termed as cellular senescence. Biomarkers p53, telomerase, and other inflammatory cytokines have a vital link with senescence, and directed use of these markers might be useful in manipulating cancer and the aging process. We included studies related to topics ' accelerated aging due to cancer', telomerase's relation to Aging and Cancer, p53's relation to Aging and Cancer, Atherosclerosis and Cancer from Search databases like PubMed and Google Scholar. We relied on peer-reviewed articles and included literature from the last 10 years written in the English language. Degenerative diseases in humans are usually linked to atherosclerosis, and atherosclerosis is associated with short leukocyte telomere length. Cancer itself and its treatment are linked with accelerated aging by causing progressive shortening of telomeres during cell replication, resulting in cell death. Gene p53 is known to have a dual effect that works as a tumor suppressor and has pro-aging side effects. In experimental studies, when p53 overcomes multiple regulatory mechanisms controlling its activity, then only the pro-aging side effects of p53 manifested. This might be a potential key for treating cancer without causing the side-effects of aging. In this review, we aim to explain and summarize the interdependent nature of p53, telomeres, and other conventional mechanisms of aging and cancer like inflammation, oxidative stress, uncontrolled proliferation, angiogenesis, micro ribonucleic acids (RNAs), and apoptosis, with a more synergistic approach that can help in developing new therapeutics and play a potential role in shaping modern human lifespan and revolutionize cancer treatment.
    Keywords:  aging; atherosclerosis; cancer; metformin; p16ink4a; p53; progeria; sasp; statin; telomerase
  9. J Hematol Oncol. 2020 Nov 10. 13(1): 151
    Lian J, Yue Y, Yu W, Zhang Y.
      Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell-output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.
    Keywords:  Aging; Cancer immunotherapy; Immunosenescence; Tumor microenvironment; Tumor progression
  10. Exp Cell Res. 2020 Nov 07. pii: S0014-4827(20)30614-5. [Epub ahead of print] 112361
    Boniewska-Bernacka E, Pańczyszyn A, Klinger M.
      Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.
    Keywords:  Cardiovascular diseases; Senescence; Telomerase; Telomeres
  11. Cell Biochem Funct. 2020 Nov 08.
    Ahmadi M, Rezaie J.
      Ageing induces a great risk factor that participates in progressing various degenerative diseases morbidities. The main characteristic of ageing is the failure in maintaining homeostasis in the organs with a cellular senescence. Senescence is characterized by reduced cell growth, evade cellular death, and acquiring a senescence-associated secretory phenotype (SASP). Mesenchymal stem cells (MSCs) are advantageous cells in regenerative medicine, exerting pleiotropic functions by producing soluble factors, such as exosomes. MSCs and their exosomes (MSCs-Exo) kinetic are affected by ageing and other aged exosomes. Exosomes biogenesis from aged MSCs is accelerated and their exosomal cargoes, such as miRNAs, vary as compared to those of normal cells. Besides, exosomes from aged MSCs loss their regenerative potential and may negatively influence the function of recipient cells. MSCs-Exo can improve ageing and age-related diseases; however, the detailed mechanisms remain yet elusive. Although exosomes-therapy may serve as a new approach to combat ageing, the translation of preclinical results to clinic needs more extensive investigation on exosomes both on their biology and related techniques. Overall, scrutiny on the effect of ageing on MSCs and vice versa is vital for designing novel therapy using MSCs with focus on the management of older individuals.
    Keywords:  ageing; exosomes; mesenchymal stem cells; senescence
  12. Front Immunol. 2020 ;11 583019
    Pereira B, Xu XN, Akbar AN.
      One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during aging and certainly affect vaccination. Likewise, age-related changes in the innate immune system may have important consequences on antigen presentation and priming of adaptive immune responses. Importantly, a low-level chronic inflammatory status known as inflammaging has been shown to inhibit immune responses to vaccination and pharmacological strategies aiming at blocking baseline inflammation can be potentially used to boost vaccine responses. Yet current strategies aiming at improving immunogenicity in the elderly have mainly focused on the use of adjuvants to promote local inflammation. More research is needed to understand the role of inflammation in vaccine responses and to reconcile these seemingly paradoxical observations. Alternative approaches to improve vaccine responses in the elderly include the use of higher vaccine doses or alternative routes of vaccination showing only limited benefits. This review will explore novel targets and potential new strategies for enhancing vaccine responses in older adults, including the use of anti-inflammatory drugs and immunomodulators.
    Keywords:  T lymphocytes; aging; anti-inflammatories; immunosenescence and inflammaging; vaccine
  13. Cell Mol Gastroenterol Hepatol. 2020 Nov 05. pii: S2352-345X(20)30179-X. [Epub ahead of print]
    Cai Q, Shi P, Yuan Y, Peng J, Ou X, Zhou W, Li J, Su T, Lin L, Cai S, He Y, Xu J.
      BACKGROUND & AIMS: The association between cellular senescence and Helicobacter pylori (H. pylori)-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H. pylori-induced atrophic gastritis and the underlying mechanism.METHODS: C57BL/6J mice were infected with H. pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using SA-β-gal, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H. pylori infection. Chromatin immunoprecipitation, luciferase reporter assays and other techniques were used to explore the underlying mechanism in vitro.
    RESULTS: Gastric mucosa atrophy was highly associated with cellular senescence. H. pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H. pylori infection not only upregulated the expression of CXCR2 ligands, C-X-C motif chemokine ligand 1 (CXCL1) and 8 (CXCL8), but also transcriptionally upregulated the expression of CXCR2 via nuclear factor-kappa B subunit 1 (NFKB1) directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H. pylori-infected mouse model attenuated mucosal senescence and atrophy and delayed further precancerous lesion progression.
    CONCLUSIONS: Our study demonstrated a new mechanism of H. pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H. pylori-induced atrophic gastritis.
    Keywords:  C-X-C motif chemokine receptor 2; H. pylori; mucosa atrophy; senescent cell
  14. Insect Biochem Mol Biol. 2020 Nov 07. pii: S0965-1748(20)30184-3. [Epub ahead of print] 103495
    Liao S, Amcoff M, Nässel DR.
      Excess consumption of high-fat diet (HFD) is likely to result in obesity and increases the predisposition to associated health disorders. Drosophila melanogaster has emerged as an important model to study the effects of HFD on metabolism, gut function, behavior, and ageing. In this study, we investigated the effects of HFD on physiology and behavior of female flies at different time-points over several weeks. We found that HFD decreases lifespan, and also with age leads to accelerated decline of climbing ability in both virgins and mated flies. In virgins HFD also increased sleep fragmentation with age. Furthermore, long-term exposure to HFD results in elevated adipokinetic hormone (AKH) transcript levels and an enlarged crop with increased lipid stores. We detected no long-term effects of HFD on body mass, or levels of triacylglycerides (TAG), glycogen or glucose, although fecundity was diminished. However, one week of HFD resulted in decreased body mass and elevated TAG levels in mated flies. Finally, we investigated the role of AKH in regulating effects of HFD during aging. Both with normal diet (ND) and HFD, Akh mutant flies displayed increased longevity compared to control flies. However, both mutants and controls showed shortened lifespan on HFD compared to ND. In flies exposed to ND, fecundity is decreased in Akh mutants compared to controls after one week, but increased after three weeks. However, HFD leads to a similar decrease in fecundity in both genotypes after both exposure times. Thus, long-term exposure to HFD increases AKH signaling, impairs lifespan and fecundity and augments age-related behavioral senescence.
  15. Semin Immunopathol. 2020 Oct;42(5): 559-572
    Xu W, Wong G, Hwang YY, Larbi A.
      From a holistic point of view, aging results from the cumulative erosion of the various systems. Among these, the immune system is interconnected to the rest as immune cells are present in all organs and recirculate through bloodstream. Immunosenescence is the term used to define the remodelling of immune changes during aging. Because immune cells-and particularly lymphocytes-can further differentiate after their maturation in response to pathogen recognition, it is therefore unclear when senescence is induced in these cells. Additionally, it is also unclear which signals triggers senescence in immune cells (i) aging per se, (ii) specific response to pathogens, (iii) underlying conditions, or (iv) inflammaging. In this review, we will cover the current knowledge and concepts linked to immunosenescence and we focus this review on lymphocytes and T cells, which represent the typical model for replicative senescence. With the evidence presented, we propose to disentangle the senescence of immune cells from chronological aging.
  16. Exp Gerontol. 2020 Nov 07. pii: S0531-5565(20)30495-2. [Epub ahead of print] 111147
    Moreno-Fernández Ayala DJ, Navas P, López-Lluch G.
      SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.
    Keywords:  COVID-19; Cytokine storm; Inflammaging; Inflammation; Mitochondria; Mitochondrial health; Mitochondrial nutrients; Mitochondrial turnover; SARS-CoV-2
  17. BMC Mol Cell Biol. 2020 Nov 07. 21(1): 79
    Gottwald D, Putz F, Hohmann N, Büttner-Herold M, Hecht M, Fietkau R, Distel L.
      BACKGROUND: Non-professional phagocytosis is usually triggered by stimuli such as necrotic cell death. In tumor therapy, the tumors often disappear slowly and only long time after the end of therapy. Here, tumor therapy inactivates the cells by inducing senescence. Therefore, study focused whether senescence is a stimulus for non-professional phagocytosis or whether senescent cells themselves phagocytize non-professionally.RESULTS: Senescence was induced in cell lines by camptothecin and a phagocytosis assay was performed. In tissue of a cohort of 192 rectal cancer patients senescence and non-professional phagocytosis was studied by anti-histone H3K9me3 and anti-E-cadherin staining. Senescent fibroblasts and pancreas carcinoma cells phagocytize necrotic cells but are not phagocytized. In the tissue of rectal carcinoma, senescent cells can phagocytize and can be phagocytized. A high number of senescent cells and, at the same time, high numbers of non-professional phagocytizing cells in the rectal carcinoma tissue lead to an extremely unfavorable prognosis regarding overall survival.
    CONCLUSION: Senescent cells can be non-professionally phagocytized and at the same time they can non-professionally phagocytize in vivo. In vitro experiments indicate that it is unlikely that senescence is a strong trigger for non-professional phagocytosis. Combined high rates of non-professional phagocytosis and high rates of senescence are an extremely poor prognostic factor for overall survival.
    Keywords:  Camptothecin; Cannibalism; Cell-in-cell; Entosis; Non-professional phagocytosis; Prognostic factor and survival; Rectal cancer; Senescence
  18. Pharmacol Res. 2020 Nov 06. pii: S1043-6618(20)31586-3. [Epub ahead of print] 105278
    Du S, Ling H, Guo Z, Cao Q, Song C.
      Aging is a major risk factor for human diseases. As global average life expectancy has lengthened, delaying or reducing aging and age-related diseases has become an urgent issue for improving the quality of life. The vascular aging process represents an important link between aging and age-related diseases. Exosomes are small extracellular vesicles (EV) that can be secreted by almost all eukaryotic cells, and they deliver characteristic biological information about donor cells to regulate the cellular microenvironment, mediate signal transmission between neighboring or distant cells, and affect the expression of target genes in recipient cells. Many recent studies have shown that exosomal microribonucleic acids (miRNA) are involved in the regulation of vascular aging by participating in the physiological functions of vascular cells and the destruction and remodeling of the extracellular matrix (ECM). This review summarizes the regulatory functions of exosomal miRNA in vascular aging because they interact with the ECM, and participate in vascular cell senescence, and the regulation of senescence-related functions such as proliferation, migration, apoptosis, inflammation, and differentiation.
    Keywords:  Angiotensin II (PubChem CID:172198); Calcium phosphate (PubChem CID: 24456); Cobalt chloride (PubChem CID: 24288); HSP (PubChem CID: 127339120) TNF-alpha (PubChem CID: 317231557); Iron citrate (PubChem CID: 4989393); Nicotine (PubChem CID:89594); Nitric oxide (PubChem CID: 145068); Reactive Oxygen Species (PubChem CID: 135292933); TGF-beta (PubChem CID: 56842206); exosomes; miRNA; vascular aging
  19. Cells. 2020 Nov 05. pii: E2420. [Epub ahead of print]9(11):
    Santin Y, Lluel P, Rischmann P, Gamé X, Mialet-Perez J, Parini A.
      Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases.
    Keywords:  SASP; aging; chronic kidney disease; senescence; urogenital disorders
  20. Elife. 2020 11 10. pii: e62420. [Epub ahead of print]9
    Drijvers JM, Sharpe AH, Haigis MC.
      Average age and obesity prevalence are increasing globally. Both aging and obesity are characterized by profound systemic metabolic and immunologic changes and are cancer risk factors. The mechanisms linking age and body weight to cancer are incompletely understood, but recent studies have provided evidence that the anti-tumor immune response is reduced in both conditions, while responsiveness to immune checkpoint blockade, a form of cancer immunotherapy, is paradoxically intact. Dietary restriction, which promotes health and lifespan, may enhance cancer immunity. These findings illustrate that the systemic context can impact anti-tumor immunity and immunotherapy responsiveness. Here, we review the current knowledge of how age and systemic metabolic state affect the anti-tumor immune response, with an emphasis on CD8+ T cells, which are key players in anti-tumor immunity. A better understanding of the underlying mechanisms may lead to novel therapies enhancing anti-tumor immunity in the context of aging or metabolic dysfunction.
    Keywords:  aging; cancer biology; cancer metabolism; immunity; immunology; inflammation; metabolism; obesity
  21. Front Cell Dev Biol. 2020 ;8 564461
    Schroth J, Thiemermann C, Henson SM.
      Chronic kidney disease (CKD) presents an ever-growing disease burden for the world's aging population. It is characterized by numerous changes to the kidney, including a decrease in renal mass, renal fibrosis, and a diminished glomerular filtration rate. The premature aging phenotype observed in CKD is associated with cellular senescence, particularly of renal tubular epithelial cells (TECs), which contributes to chronic inflammation through the production of a proinflammatory senescence associated secretory phenotype (SASP). When coupled with changes in immune system composition and progressive immune dysfunction, the accumulation of senescent kidney cells acts as a driver for the progression of CKD. The targeting of senescent cells may well present an attractive therapeutic avenue for the treatment of CKD. We propose that the targeting of senescent cells either by direct inhibition of pro-survival pathways (senolytics) or through the inhibition of their proinflammatory secretory profile (senomorphics) together with immunomodulation to enhance immune system surveillance of senescent cells could be of benefit to patients with CKD.
    Keywords:  T cell; aging; immune system; kidney; senescence
  22. Elife. 2020 11 12. pii: e59201. [Epub ahead of print]9
    Levine M, McDevitt RA, Meer M, Perdue K, Di Francesco A, Meade T, Farrell C, Thrush K, Wang M, Dunn C, Pellegrini M, de Cabo R, Ferrucci L.
      Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats-a model with unique physical, physiological, and biochemical advantages-by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.
    Keywords:  DNA methylation; biological age; caloric restriction; computational biology; epigenetic clock; genetics; genomics; mouse; rat; systems biology
  23. Front Cell Dev Biol. 2020 ;8 582346
    Bhoopalam M, Garza LA, Reddy SK.
      Hair follicles are the signature dermal appendage of mammals. They can be thought of as mini-organs with defined polarity, distinct constituent cell types, dedicated neurovascular supply, and specific stem cell compartments. Strikingly, some mammals show a capacity for adult hair follicle regeneration in a phenomenon known as wound-induced hair neogenesis (WIHN). In WIHN functional hair follicles reemerge during healing of large cutaneous wounds, and they can be counted to provide an index of regeneration. While age-related decline in hair follicle number and cycling are widely appreciated in normal physiology, it is less clear whether hair follicle regeneration also diminishes with age. WIHN provides an extraordinary quantitative system to address questions of mammalian regeneration and aging. Here we review cellular and molecular underpinnings of WIHN, explore known age-related changes to these elements, and present unanswered questions for future exploration.
    Keywords:  STAT3; Wnt; aging; hair follicle neogenesis; hair follicle stem cells; regeneration; wound-induced hair follicle neogenesis
  24. Nucleic Acids Res. 2020 Nov 09. pii: gkaa965. [Epub ahead of print]
    Allmann S, Mayer L, Olma J, Kaina B, Hofmann TG, Tomicic MT, Christmann M.
      Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.
  25. Mol Neurobiol. 2020 Nov 09.
    Petralla S, Parenti C, Ravaioli V, Fancello I, Massenzio F, Virgili M, Monti B, Pena-Altamira E.
      Dementia is a pathological condition characterized by a decline in memory, as well as in other cognitive and social functions. The cellular and molecular mechanisms of brain damage in dementia are not completely understood; however, neuroinflammation is involved. Evidence suggests that chronic inflammation may impair cognitive performance and that dietary protein source may differentially influence this process. Dietary protein source has previously been shown to modify systemic inflammation in mouse models. Thus, we aimed to investigate the effect of chronic dietary protein source substitution in an ageing and dementia male mouse model, the senescence-accelerated mouse-prone 8 (SAMP8) model. We observed that dietary protein source differentially modified memory as shown by inhibitory avoidance testing at 4 months of age. Also, dietary protein source differentially modified neuroinflammation and gliosis in male SAMP8 mice. Our results suggest that chronic dietary protein source substitution may influence brain ageing and memory-related mechanisms in male SAMP8 mice. Moreover, the choice of dietary protein source in mouse diets for experimental purposes may need to be carefully considered when interpreting results.
    Keywords:  Ageing; Dementia; Diet; Gliosis; Neuroinflammation
  26. J Biol Chem. 2020 Nov 09. pii: jbc.RA120.013500. [Epub ahead of print]
    Nagano T, Iwasaki T, Onishi K, Awai Y, Terachi A, Kuwaba S, Asano S, Katasho R, Nagai K, Nakashima A, Kikkawa U, Kamada S.
      Although senescent cells display various morphological changes including vacuole formation, it is still unclear how these processes are regulated. We have recently identified the gene, lymphocyte antigen 6 complex, locus D (LY6D), to be upregulated specifically in senescent cells. LY6D is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein whose function remains unknown. Here, we analyzed the functional relationship between LY6D and the senescence processes. We found that overexpression of LY6D induced vacuole formation, and knockdown of LY6D suppressed the senescence-associated vacuole formation. The LY6D-induced vacuoles were derived from macropinocytosis, a distinct form of endocytosis. Furthermore, Src family kinases and Ras were found to be recruited to membrane lipid rafts in an LY6D-dependent manner, and inhibition of their activity impaired the LY6D-induced macropinocytosis. Finally, reduction of senescent cell survival induced by glutamine deprivation was recovered by albumin supplementation to the culture media in an LY6D-dependent manner. Since macropinocytosis acts as an amino acid supply route, these results suggest that LY6D-mediated macropinocytosis contributes to senescent cell survival through the incorporation of extracellular nutrients.
    Keywords:  LY6D; Ras protein; cellular senescence; endocytosis; lipid raft; macropinocytosis; vacuole
  27. Metabolites. 2020 Nov 07. pii: E450. [Epub ahead of print]10(11):
    Błaszczyk JW.
      There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production-which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.
    Keywords:  brain aging; energy metabolism; neurodegeneration; neurodegenerative disorders
  28. Mol Med Rep. 2020 Dec;22(6): 5251-5261
    Liang D, Hong D, Tang F, Wang Y, Li J, Li L, Chen H.
      Intervertebral disc (IVD) degeneration is a complicated physiological change involving cellular senescence, inflammation and the degradation of the extracellular matrix. Long non‑coding RNAs (lncRNAs) have been identified as new players in IVD degeneration. The present study aimed to identify lncRNAs implicated in IVD degeneration via the regulation of cellular senescence. In the present study, nucleus pulposus (NP) cells isolated from moderately degenerated IVD tissues exhibited a senescent phenotype with increased senescence rates, detected by senescence‑associated β‑galactosidase (SA‑β‑gal) staining, and reduced growth and migratory abilities. Microarray and target prediction analyses identified 353 differentially expressed lncRNAs, and 251 cis‑ and 2,170 trans‑acting targets in degenerated NP cells. Bioinformatic analyses revealed that these predicted targets were enriched in the regulation of response to DNA damage stimulus, positive regulation of cell cycle processes and interferon‑β production. In addition, a network of the top 10 upregulated and top 10 downregulated lncRNA targets was constructed, and two trans‑acting targets, C‑C motif chemokine ligand 5 (CCL5) and polyribonucleotide nucleotidyltransferase 1 (PNPT1) involved in aging or senescence, and their corresponding lncRNAs, lnc‑ST8SIA5‑1:2 and lnc‑HRK‑2:1, were identified. Reverse transcription‑quantitative PCR validation demonstrated that the two targets and two candidate lncRNAs were significantly upregulated in degenerated NP cells. Overexpression of lnc‑HRK‑2:1, with validated higher expression levels, in normal NP cells induced a senescent phenotype, with enhanced rates of senescence detected by SA‑β‑gal staining in cells, decreased growth and migratory abilities and improved expression levels of CCL5 and PNPT1. Collectively, these results suggested that upregulation of lnc‑HRK‑2:1 prompted NP cell senescence in IVD degeneration, which may be associated with increased expression levels of CCL5 and PNPT1.
  29. Life Sci. 2020 Nov 05. pii: S0024-3205(20)31477-6. [Epub ahead of print] 118724
    Chen T, Ma C, Fan G, Liu H, Lin X, Li J, Li N, Wang S, Zeng M, Zhang Y, Bu P.
      Hyperglycemia induces endothelial cells (ECs) dysfunction and vascular complications by accelerating ECs senescence. It also induces downregulation of sirtuins (SIRTs). However, the molecular mechanism involved in the regulation of ECs senescence by SIRT3 remains unclear. Here, we showed that high glucose (HG) decreased the expression level of SIRT3 in human umbilical vein endothelial cells (HUVECs), increased the proportion of cells expressing senescence-associated galactosidase (SA-gal), and HG damaged the cell's ability to form tubule networks on Matrigel. However, transfection with adenoviral construct including SIRT3 significantly inhibited HG-induced SA-gal activity, decreased p53 acetylation level at the site Lys 320 (k320), and overexpression of SIRT3 antagonized high glucose-induced angiogenic dysfunction. Our results suggested a possible molecular mechanism involving HG-SIRT3-p53 in ECs senescence.
    Keywords:  Endothelial senescence; High glucose; SIRT3; p53
  30. Exp Biol Med (Maywood). 2020 Nov 11. 1535370220968802
    He X, Liu J, Liu B, Shi J.
      One of the key characteristics of aging is a progressive loss of physiological integrity, which weakens bodily functions and increases the risk of death. A robust biomarker is important for the assessment of biological age, the rate of aging, and a person's health status. DNA methylation clocks, novel biomarkers of aging, are composed of a group of cytosine-phosphate-guanine dinucleotides, the DNA methylation status of which can be used to accurately measure subjective age. These clocks are considered accurate biomarkers of chronological age for humans and other vertebrates. Numerous studies have demonstrated these clocks to quantify the rate of biological aging and the effects of longevity and anti-aging interventions. In this review, we describe the purpose and use of DNA methylation clocks in aging research.
    Keywords:  Aging; DNA methylation; clock; epigenetic; intervention
  31. J Diabetes Complications. 2020 Oct 07. pii: S1056-8727(20)30539-0. [Epub ahead of print] 107758
    Al Dubayee M, Alshahrani A, Almalk M, Hakami A, Homoud B, Alzneidi N, Aldhalaan J, Aljbli G, Nasr A, Farahat AI, Aljada A.
      BACKGROUND: Although there is increasing evidence showing that cell senescence is increased in circulating PBMC in type 2 diabetes mellitus (T2DM), the data are contradictory. This study examined several senescence biomarkers, including LMNA/C transcript variants, p16INK4a, p53, and p21Cip1/WAF, in PBMC of T2DM patients and the effect of Metformin on these senescence markers.METHODS: Blood samples were obtained from 30 lean, 30 obese, 20 newly diagnosed type 2 diabetes mellitus (T2DM), and 30 T2DM on Metformin. PBMC were isolated and mRNA expression of the senescence biomarkers were quantified by RT-qPCR. The effect of ectopic expression of LMNA and LMNC in human monocytic cells lines (THP-1 and U937) on several inflammatory mediators were also examined.
    RESULTS: LMNA expression was significantly higher in PBMC of obese and T2DM patients. LMNC expression was significantly inhibited in T2DM patients. LMNAΔ10 and Progerin mRNA expression was not detected in PBMC of all groups. Expression of p16INK4a, p21Cip1/WAF and p53 were inhibited significantly in T2DM. Metformin treatment reverted LMNA, LMNC, and p53 expression levels to normal levels. Upregulation of LMNA in monocytic THP-1 and U937 cell lines induced CD68, TNFα, CCL2, IL-6 and NOS2.
    CONCLUSIONS: These data support the notion that LMNA may mediate senescence in PBMCs of T2DM by upregulating inflammatory pathways. Metformin may exert its anti-inflammatory property by modulation of senescence mediator LMNA.
    Keywords:  Inflammation and cellular senescence; Insulin resistance; LMNA/C transcript variants; Mononuclear cells; Type 2 diabetes mellitus
  32. Curr Opin Hematol. 2020 Nov 12.
    Adelman ER, Figueroa ME.
      PURPOSE OF REVIEW: Our understanding of the effects of aging on human hematopoiesis has advanced significantly in recent years, yet the full ramifications of these findings are not fully understood. This review summarizes these findings and discusses their implication as they relate to malignant hematopoiesis.RECENT FINDINGS: With human aging there is an impaired immune response, loss of hematopoietic stem cell (HSC) function, increase in clonal hematopoiesis, and higher frequency of myeloid malignancies. Although murine models have implicated abnormalities in DNA damage repair, autophagy, metabolism, and epigenetics, studies in primary human specimens are more limited. The development of age-related clonal hematopoiesis and the risk associated with this is one of the major findings in the field of recent years. This is accompanied by changes in bone marrow stem and progenitor composition, changes in the epigenetic program of stem cells and an inflammatory milieu in the bone marrow. The precise consequences of these changes for the development of age-related malignancies are still unclear.
    SUMMARY: Advances in the field have begun to reveal the mechanisms driving human HSC loss of function with age. It will be critical to delineate between normal and malignant aging in order to better prevent age-associated myeloid malignancies.
  33. Nat Commun. 2020 11 09. 11(1): 5661
    Lee SM, Lee SH, Jung Y, Lee Y, Yoon JH, Choi JY, Hwang CY, Son YH, Park SS, Hwang GS, Lee KP, Kwon KS.
      Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.
  34. Proc Natl Acad Sci U S A. 2020 Nov 09. pii: 202016064. [Epub ahead of print]
    Chatterjee N, Whitman MA, Harris CA, Min SM, Jonas O, Lien EC, Luengo A, Vander Heiden MG, Hong J, Zhou P, Hemann MT, Walker GC.
      REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
    Keywords:  Rev1; cell death; chemotherapy; senescence; translesion synthesis
  35. Rejuvenation Res. 2020 Nov 09.
    Tripathi SS, Kumar R, Arya J, Rizvi SI.
      An experimental novel anti-aging intervention strategy is based on the concept of parabiosis, which involves long term treatment with factors derived from young blood facilitating rejuvenation of old individuals. In this study, we employed blood plasma from young rats as an intervention strategy to evaluate whether this could impact aging biomarkers in aged rats. The biomarkers studied include: reactive oxygen species (ROS), the ferric reducing ability of plasma (FRAP), plasma membrane redox system (PMRS), reduced glutathione (GSH), malondialdehyde (MDA), protein carbonyl (PCO) and advanced oxidation protein products (AOPP) in blood. Additionally, the level of tumour necrosis factor-α and interleukin-6 were also estimated in blood. We found that old rats injected with plasma from young rats were protected from oxidative stress. Thus, this study provides some evidence of the rejuvenating effects of young plasma. We hypothesize that young plasma may contain certain 'factors' which may be responsible for the observed effects. The mechanism of action is not clearly understood and is open to further studies.
  36. Mol Metab. 2020 Nov 10. pii: S2212-8778(20)30189-7. [Epub ahead of print] 101115
    Mashek DG.
      BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply a depot for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made towards our understanding of factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved.SCOPE OF REVIEW: This review will cover many facets of LD biology. We will provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis, and how they are altered in NAFLD. The major focus will be on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction will be presented. Finally, we will discuss emerging areas of LD biology and future research directions that are needed to advance our understanding into the role of LDs in NAFLD etiology.
    MAJOR CONCLUSIONS: Impairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the commitment step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction will be important for the design of effective therapeutic approaches targeting NAFLD and its comorbidities.
    Keywords:  Lipid droplets; Lipotoxicity; NAFLD; NASH; Perilipins
  37. Front Aging Neurosci. 2020 ;12 572090
    Mayne K, White JA, McMurran CE, Rivera FJ, de la Fuente AG.
      Neurodegenerative diseases of the central nervous system (CNS) are characterized by progressive neuronal death and neurological dysfunction, leading to increased disability and a loss of cognitive or motor functions. Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis have neurodegeneration as a primary feature. However, in other CNS diseases such as multiple sclerosis, stroke, traumatic brain injury, and spinal cord injury, neurodegeneration follows another insult, such as demyelination or ischaemia. Although there are different primary causes to these diseases, they all share a hallmark of neuroinflammation. Neuroinflammation can occur through the activation of resident immune cells such as microglia, cells of the innate and adaptive peripheral immune system, meningeal inflammation and autoantibodies directed toward components of the CNS. Despite chronic inflammation being pathogenic in these diseases, local inflammation after insult can also promote endogenous regenerative processes in the CNS, which are key to slowing disease progression. The normal aging process in the healthy brain is associated with a decline in physiological function, a steady increase in levels of neuroinflammation, brain shrinkage, and memory deficits. Likewise, aging is also a key contributor to the progression and exacerbation of neurodegenerative diseases. As there are associated co-morbidities within an aging population, pinpointing the precise relationship between aging and neurodegenerative disease progression can be a challenge. The CNS has historically been considered an isolated, "immune privileged" site, however, there is mounting evidence that adaptive immune cells are present in the CNS of both healthy individuals and diseased patients. Adaptive immune cells have also been implicated in both the degeneration and regeneration of the CNS. In this review, we will discuss the key role of the adaptive immune system in CNS degeneration and regeneration, with a focus on how aging influences this crosstalk.
    Keywords:  adaptive immune system; aging; degeneration; neurodegenerative diseases; regeneration