Aging, Lifespan & Longevity

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.

1 month 1 week ago
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Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.

Genome Res. 2021 Jan 13;:

Authors: Yang SY, Castellani CA, Longchamps RJ, Pillalamarri VK, O'Rourke B, Guallar E, Arking DE

Abstract
Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In non-blood tissues, there were more significantly associated genes than expected in 30 tissues, suggesting that global gene expression in those tissues is correlated with blood-derived mtDNA-CN. Neurodegenerative disease pathways were significantly associated in multiple tissues, and in an independent dataset, the UK Biobank we observed that higher mtDNA-CN was significantly associated with lower rates of both prevalent (OR=0.89, CI=0.83;0.96) and incident neurodegenerative disease (HR=0.95, 95% CI= 0.91;0.98). The observation that mtDNA-CN measured in blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Identification of key pathways including splicing, RNA binding, and catalysis reinforces the importance of mitochondria in maintaining cellular homeostasis. Finally, validation of the role of mtDNA CN in neurodegenerative disease in a large independent cohort study solidifies the link between blood-derived mtDNA-CN, altered gene expression in multiple tissues, and aging-related disease.

PMID: 33441415 [PubMed - as supplied by publisher]

m6A RNA methylation regulates the fate of endogenous retroviruses.

1 month 1 week ago
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m6A RNA methylation regulates the fate of endogenous retroviruses.

Nature. 2021 Jan 13;:

Authors: Chelmicki T, Roger E, Teissandier A, Dura M, Bonneville L, Rucli S, Dossin F, Fouassier C, Lameiras S, Bourc'his D

Abstract
Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that affect genome regulation and cell physiology throughout their RNA-centred life cycle1. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases2,3. Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m6A RNA methylation as a way to restrict ERVs. Methylation of ERV mRNAs is catalysed by the complex of methyltransferase-like METTL3-METTL144 proteins, and we found that depletion of METTL3-METTL14, along with their accessory subunits WTAP and ZC3H13, led to increased mRNA abundance of intracisternal A-particles (IAPs) and related ERVK elements specifically, by targeting their 5' untranslated region. Using controlled auxin-dependent degradation of the METTL3-METTL14 enzymatic complex, we showed that IAP mRNA and protein abundance is dynamically and inversely correlated with m6A catalysis. By monitoring chromatin states and mRNA stability upon METTL3-METTL14 double depletion, we found that m6A methylation mainly acts by reducing the half-life of IAP mRNA, and this occurs by the recruitment of the YTHDF family of m6A reader proteins5. Together, our results indicate that RNA methylation provides a protective effect in maintaining cellular integrity by clearing reactive ERV-derived RNA species, which may be especially important when transcriptional silencing is less stringent.

PMID: 33442060 [PubMed - as supplied by publisher]

Chaperone-mediated autophagy sustains haematopoietic stem-cell function.

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Chaperone-mediated autophagy sustains haematopoietic stem-cell function.

Nature. 2021 Jan 13;:

Authors: Dong S, Wang Q, Kao YR, Diaz A, Tasset I, Kaushik S, Thiruthuvanathan V, Zintiridou A, Nieves E, Dzieciatkowska M, Reisz JA, Gavathiotis E, D'Alessandro A, Will B, Cuervo AM

Abstract
The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells1. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division2-4. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)5, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.

PMID: 33442062 [PubMed - as supplied by publisher]

Genome-wide surveillance of transcription errors in response to genotoxic stress.

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Genome-wide surveillance of transcription errors in response to genotoxic stress.

Proc Natl Acad Sci U S A. 2021 Jan 05;118(1):

Authors: Fritsch C, Gout JF, Haroon S, Towheed A, Chung C, LaGosh J, McGann E, Zhang X, Song Y, Simpson S, Danthi PS, Benayoun BA, Wallace D, Thomas K, Lynch M, Vermulst M

Abstract
Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

PMID: 33443141 [PubMed - in process]

R-spondin substitutes for neuronal input for taste cell regeneration in adult mice.

1 month 1 week ago
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R-spondin substitutes for neuronal input for taste cell regeneration in adult mice.

Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):

Authors: Lin X, Lu C, Ohmoto M, Choma K, Margolskee RF, Matsumoto I, Jiang P

Abstract
Taste bud cells regenerate throughout life. Taste bud maintenance depends on continuous replacement of senescent taste cells with new ones generated by adult taste stem cells. More than a century ago it was shown that taste buds degenerate after their innervating nerves are transected and that they are not restored until after reinnervation by distant gustatory ganglion neurons. Thus, neuronal input, likely via neuron-supplied factors, is required for generation of differentiated taste cells and taste bud maintenance. However, the identity of such a neuron-supplied niche factor(s) remains unclear. Here, by mining a published RNA-sequencing dataset of geniculate ganglion neurons and by in situ hybridization, we demonstrate that R-spondin-2, the ligand of Lgr5 and its homologs Lgr4/6 and stem-cell-expressed E3 ligases Rnf43/Znrf3, is expressed in nodose-petrosal and geniculate ganglion neurons. Using the glossopharyngeal nerve transection model, we show that systemic delivery of R-spondin via adenovirus can promote generation of differentiated taste cells despite denervation. Thus, exogenous R-spondin can substitute for neuronal input for taste bud cell replenishment and taste bud maintenance. Using taste organoid cultures, we show that R-spondin is required for generation of differentiated taste cells and that, in the absence of R-spondin in culture medium, taste bud cells are not generated ex vivo. Thus, we propose that R-spondin-2 may be the long-sought neuronal factor that acts on taste stem cells for maintaining taste tissue homeostasis.

PMID: 33443181 [PubMed - in process]

Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus.

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Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus.

Aging Cell. 2021 Jan 14;:e13277

Authors: Kodali M, Attaluri S, Madhu LN, Shuai B, Upadhya R, Gonzalez JJ, Rao X, Shetty AK

Abstract
Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive impairment. However, metformin's therapeutic use as an anti-aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen-month-old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate-activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.

PMID: 33443781 [PubMed - as supplied by publisher]

Ecd promotes U5 snRNP maturation and Prp8 stability.

1 month 1 week ago
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Ecd promotes U5 snRNP maturation and Prp8 stability.

Nucleic Acids Res. 2021 Jan 14;:

Authors: Erkelenz S, Stanković D, Mundorf J, Bresser T, Claudius AK, Boehm V, Gehring NH, Uhlirova M

Abstract
Pre-mRNA splicing catalyzed by the spliceosome represents a critical step in the regulation of gene expression contributing to transcriptome and proteome diversity. The spliceosome consists of five small nuclear ribonucleoprotein particles (snRNPs), the biogenesis of which remains only partially understood. Here we define the evolutionarily conserved protein Ecdysoneless (Ecd) as a critical regulator of U5 snRNP assembly and Prp8 stability. Combining Drosophila genetics with proteomic approaches, we demonstrate the Ecd requirement for the maintenance of adult healthspan and lifespan and identify the Sm ring protein SmD3 as a novel interaction partner of Ecd. We show that the predominant task of Ecd is to deliver Prp8 to the emerging U5 snRNPs in the cytoplasm. Ecd deficiency, on the other hand, leads to reduced Prp8 protein levels and compromised U5 snRNP biogenesis, causing loss of splicing fidelity and transcriptome integrity. Based on our findings, we propose that Ecd chaperones Prp8 to the forming U5 snRNP allowing completion of the cytoplasmic part of the U5 snRNP biogenesis pathway necessary to meet the cellular demand for functional spliceosomes.

PMID: 33444449 [PubMed - as supplied by publisher]

Orthogonal immunoassays for IgG antibodies to SARS-CoV-2 antigens reveal that immune response lasts beyond 4 mo post illness onset.

1 month 1 week ago
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Orthogonal immunoassays for IgG antibodies to SARS-CoV-2 antigens reveal that immune response lasts beyond 4 mo post illness onset.

Proc Natl Acad Sci U S A. 2021 02 02;118(5):

Authors: Sasisekharan V, Pentakota N, Jayaraman A, Tharakaraman K, Wogan GN, Narayanasami U

Abstract
Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the current pandemic remains a field of immense interest and active research worldwide. Although the severity of acute infection may depend on the intensity of innate and adaptive immunity, leading to higher morbidity and mortality, the longevity of IgG antibodies, including neutralizing activity to SARS-CoV-2, is viewed as a key correlate of immune protection. Amid reports and concern that there is a rapid decay of IgG antibody levels within 1 mo to 2 mo after acute infection, we set out to study the pattern and duration of IgG antibody response to various SARS-CoV-2 antigens in asymptomatic and symptomatic patients in a community setting. Herein, we show the correlation of IgG anti-spike protein S1 subunit, receptor binding domain, nucleocapsid, and virus neutralizing antibody titers with each other and with clinical features such as length and severity of COVID-19 illness. More importantly, using orthogonal measurements, we found the IgG titers to persist for more than 4 mo post symptom onset, implying that long-lasting immunity to COVID-19 from infection or vaccination might be observed, as seen with other coronaviruses such as SARS and Middle East respiratory syndrome.

PMID: 33446512 [PubMed - indexed for MEDLINE]

Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders.

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Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders.

Science. 2021 01 15;371(6526):265-270

Authors: Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, Suzuki N, Kumamoto S, Yamaguchi K, Hatakeyama S, Takami T, Yamaguchi R, Shimizu E, Ikeda K, Okahashi N, Mikawa R, Suematsu M, Arita M, Sugimoto M, Nakayama KI, Furukawa Y, Imoto S, Nakanishi M

Abstract
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.

PMID: 33446552 [PubMed - indexed for MEDLINE]

Mtor inhibition by INK128 extends functions of the ovary reconstituted from germline stem cells in aging and premature aging mice.

1 month 1 week ago
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Mtor inhibition by INK128 extends functions of the ovary reconstituted from germline stem cells in aging and premature aging mice.

Aging Cell. 2021 Jan 14;:e13304

Authors: Heng D, Sheng X, Tian C, Li J, Liu L, Gou M, Liu L

Abstract
Stem cell transplantation has been generally considered as promising therapeutics in preserving or recovering functions of lost, damaged, or aging tissues. Transplantation of primordial germ cells (PGCs) or oogonia stem cells (OSCs) can reconstitute ovarian functions that yet sustain for only short period of time, limiting potential application of stem cells in preservation of fertility and endocrine function. Here, we show that mTOR inhibition by INK128 extends the follicular and endocrine functions of the reconstituted ovaries in aging and premature aging mice following transplantation of PGCs/OSCs. Follicular development and endocrine functions of the reconstituted ovaries by transplanting PGCs into kidney capsule of the recipient mice were maintained by INK128 treatment for more than 12 weeks, in contrast to the controls for only about 4 weeks without receiving the mTOR inhibitors. Comparatively, rapamycin also can prolong the ovarian functions but for limited time. Furthermore, our data reveal that INK128 promotes mitochondrial function in addition to its known function in suppression of immune response and inflammation. Taken together, germline stem cell transplantation in combination with mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice.

PMID: 33448083 [PubMed - as supplied by publisher]

Age-related changes in hippocampal-dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor.

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Age-related changes in hippocampal-dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor.

Aging Cell. 2021 Jan 15;:e13305

Authors: Wong LW, Chong YS, Lin W, Kisiswa L, Sim E, Ibáñez CF, Sajikumar S

Abstract
The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal-dependent long-term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age-related decline. The p75 neurotrophin receptor (p75NTR ) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age-related alterations. However, the mechanisms by which p75NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75NTR were resistant to age-associated changes in long-term plasticity, associative plasticity, and associative memory. Our study shows that p75NTR is responsible for age-dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA-ROCK2-LIMK1-cofilin. p75NTR may thus represent an important therapeutic target for limiting the age-related memory and cognitive function deficits.

PMID: 33448137 [PubMed - as supplied by publisher]

Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay.

1 month 1 week ago
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Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay.

Nucleic Acids Res. 2021 Jan 15;:

Authors: Wencker FDR, Marincola G, Schoenfelder SMK, Maaß S, Becher D, Ziebuhr W

Abstract
In Staphylococcus aureus, de novo methionine biosynthesis is regulated by a unique hierarchical pathway involving stringent-response controlled CodY repression in combination with a T-box riboswitch and RNA decay. The T-box riboswitch residing in the 5' untranslated region (met leader RNA) of the S. aureus metICFE-mdh operon controls downstream gene transcription upon interaction with uncharged methionyl-tRNA. met leader and metICFE-mdh (m)RNAs undergo RNase-mediated degradation in a process whose molecular details are poorly understood. Here we determined the secondary structure of the met leader RNA and found the element to harbor, beyond other conserved T-box riboswitch structural features, a terminator helix which is target for RNase III endoribonucleolytic cleavage. As the terminator is a thermodynamically highly stable structure, it also forms posttranscriptionally in met leader/ metICFE-mdh read-through transcripts. Cleavage by RNase III releases the met leader from metICFE-mdh mRNA and initiates RNase J-mediated degradation of the mRNA from the 5'-end. Of note, metICFE-mdh mRNA stability varies over the length of the transcript with a longer lifespan towards the 3'-end. The obtained data suggest that coordinated RNA decay represents another checkpoint in a complex regulatory network that adjusts costly methionine biosynthesis to current metabolic requirements.

PMID: 33450025 [PubMed - as supplied by publisher]

α-ketoglutarate delays age-related fertility decline in mammals.

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α-ketoglutarate delays age-related fertility decline in mammals.

Aging Cell. 2021 Jan 15;:e13291

Authors: Zhang Z, He C, Gao Y, Zhang L, Song Y, Zhu T, Zhu K, Lv D, Wang J, Tian X, Ma T, Ji P, Cui W, Liu G

Abstract
The fecundity reduction with aging is referred as the reproductive aging which comes earlier than that of chronological aging. Since humans have postponed their childbearing age, to prolong the reproductive age becomes urgent agenda for reproductive biologists. In the current study, we examined the potential associations of α-ketoglutarate (α-KG) and reproductive aging in mammals including mice, swine, and humans. There is a clear tendency of reduced α-KG level with aging in the follicle fluids of human. To explore the mechanisms, mice were selected as the convenient animal model. It is observed that a long term of α-KG administration preserves the ovarian function, the quality and quantity of oocytes as well as the telomere maintaining system in mice. α-KG suppresses ATP synthase and alterations of the energy metabolism trigger the nutritional sensors to down-regulate mTOR pathway. These events not only benefit the general aging process but also maintain ovarian function and delay the reproductive decline. Considering the safety of the α-KG as a naturally occurring molecule in energy metabolism, its utility in reproduction of large mammals including humans deserves further investigation.

PMID: 33450127 [PubMed - as supplied by publisher]

JUNB-FBXO21-ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy.

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JUNB-FBXO21-ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy.

Aging Cell. 2021 Jan 15;:e13306

Authors: Lin Z, Miao J, Zhang T, He M, Wang Z, Feng X, Bai L

Abstract
Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P-glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate-induced OA rats, and chondrocytes treated with interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA-related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA-related cartilage degeneration. In addition, using mass spectrometry and co-immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB-FBXO21-ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA.

PMID: 33450132 [PubMed - as supplied by publisher]

ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.

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ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.

Cell Stem Cell. 2021 02 04;28(2):331-342.e5

Authors: Wang C, Zhang M, Garcia G, Tian E, Cui Q, Chen X, Sun G, Wang J, Arumugaswami V, Shi Y

Abstract
ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

PMID: 33450186 [PubMed - indexed for MEDLINE]

Telomeres: history, health, and hallmarks of aging.

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Telomeres: history, health, and hallmarks of aging.

Cell. 2021 Jan 21;184(2):306-322

Authors: Chakravarti D, LaBella KA, DePinho RA

Abstract
The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.

PMID: 33450206 [PubMed - in process]

Physical activity and exercise in the context of SARS-Cov-2: A perspective from geroscience field.

1 month 1 week ago
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Physical activity and exercise in the context of SARS-Cov-2: A perspective from geroscience field.

Ageing Res Rev. 2021 03;66:101258

Authors: de Souto Barreto P, Vellas B, Rolland Y

Abstract
The recent pandemics of the SARS-Cov-2 has pushed physical activity (PA) and exercise at the forefront of the discussion, since PA is associated with a reduced risk of developing all the chronic diseases strongly associated with severe cases of SARS-Cov-2 and exercise is considered a complimentary therapeutics for the treatment of these age-related conditions. The mechanisms through which PA and exercise could contribute to reduce the severity of the SARS-Cov-2 infection would be multiple, including their capacity to boost the immune system, but also their global effect on slowing down the progression of the aging process. The present perspective presents a discussion on how PA and exercise might hypothetically be linked with SARS-Cov-2 infection, current scientific gaps and shortcomings as well as recommendations for advancing research in this area, placing the debate in the context of aging and gerosciences.

PMID: 33450400 [PubMed - indexed for MEDLINE]

Lycorine hydrochloride suppresses stress-induced premature cellular senescence by stabilizing the genome of human cells.

1 month 1 week ago
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Lycorine hydrochloride suppresses stress-induced premature cellular senescence by stabilizing the genome of human cells.

Aging Cell. 2021 Jan 17;:e13307

Authors: Zhang W, Yang J, Chen Y, Xue R, Mao Z, Lu W, Jiang Y

Abstract
Lycorine, a natural compound isolated from the traditional Chinese medicinal herb Lycoris radiata, exhibits multiple pharmacological effects, such as anti-inflammatory, antiviral, and anticancer effects. Accumulating evidence also indicates that lycorine might hold the potential to treat age-associated Alzheimer's disease. However, whether lycorine is involved in delaying the onset of cellular senescence and its underlying mechanisms has not been determined. Here, we demonstrate that the salt of lycorine, lycorine hydrochloride, significantly suppressed stress-induced premature cellular senescence (SIPS) by ~2-fold, as determined by senescence-associated beta-galactosidase (SA-β-gal) staining and the expression of p16 and p21. In addition, pretreating cells with lycorine hydrochloride significantly inhibited the expression of CXCL1 and IL1α, two factors of the senescence-associated secreted phenotype (SASP) in SIPS cells. Further experiments revealed that lycorine hydrochloride promoted both the homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways of DNA double-strand break (DSB) repair. Mechanistic studies suggested that lycorine hydrochloride treatment promoted the transcription of SIRT1 and SIRT6, critical longevity genes positively regulating both HR and NHEJ repair pathways, thereby stimulating DSB repair and stabilizing genomes. Inhibiting SIRT1 enzymatic activity abrogated the protective effect of lycorine hydrochloride on delaying the onset of SIPS, repairing DSBs, and restoring genome integrity. In summary, our work indicates that lycorine hydrochloride might hold therapeutic potential for treating age-associated diseases or promoting healthy aging by stabilizing genomes.

PMID: 33455051 [PubMed - as supplied by publisher]

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