bims-senagi 2021-03-21 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–03–21
33 papers selected by
Maria Grazia Vizioli, Mayo Clinic

NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.
Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging.
Cellular Senescence in Brain Aging.
The elevated level of IL-1α in the bone marrow of aged mice leads to MSC senescence partly by down-regulating Bmi-1.
The struggle of a good friend getting old: cellular senescence in viral responses and therapy.
PPARα Targeting GDF11 Inhibits Vascular Endothelial Cell Senescence in an Atherosclerosis Model.
Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.
p53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells.
Senolytic targets and new strategies for clearing senescent cells.
COX2 regulates senescence secretome composition and senescence surveillance through PGE2.
Beyond DNA repair and chromosome instability-Fanconi anaemia as a cellular senescence-associated syndrome.
Caffeine promotes the expression of telomerase reverse transcriptase to regulate cellular senescence and aging.
PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons.
Growth differentiation factor-15 is associated with age-related monocyte dysfunction.
β-catenin-promoted cholesterol metabolism protects against cellular senescence in naked mole-rat cells.
Decreased autophagy of vascular smooth muscle cells was involved in hyperhomocysteinemia-induced vascular ageing.
Identification of SRY-box 30 as an age-related essential gatekeeper for male germ-cell meiosis and differentiation.
Fluorescent nanocarriers targeting VCAM-1 for early detection of senescent endothelial cells.
Senescent accelerated prone 8 (SAMP8) mice as a model of age dependent neuroinflammation.
Elimination of Senescent Endothelial Cells: Good or Bad Idea?
PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.
Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke.
Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction.
PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury.
Proteomics in aging research: A roadmap to clinical, translational research.
The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress.
SIRT1-induced deacetylation of Akt expedites platelet phagocytosis and delays HEMEC aging.
Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.
A ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice.
Aging: All roads lead to mitochondria.
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.
The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing.
Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis.

Aging Cell. 2021 Mar 18. e13329

NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.

Beimeng Yang, Xiuli Dan, Yujun Hou, Jong-Hyuk Lee, Noah Wechter, Sudarshan Krishnamurthy, Risako Kimura, Mansi Babbar, Tyler Demarest, Ross McDevitt, Shiliang Zhang, Yongqing Zhang, Mark P Mattson, Deborah L Croteau, Vilhelm A Bohr.

  Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A-T). Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in A-T patient fibroblasts, and in ATM-deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1-dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm-/- mice. Our findings suggest a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.

Keywords:  Ataxia Telangiectasia; Nicotinamide riboside; SASP; mitophagy; senescence

DOI:  https://doi.org/10.1111/acel.13329
Aging Cell. 2021 Mar 16. e13337

Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging.

Akaitz Dorronsoro, Fernando E Santiago, Diego Grassi, Tianpeng Zhang, Ruenn Chai Lai, Sara J McGowan, Luise Angelini, Mitra Lavasani, Lana Corbo, Aiping Lu, Robert W Brooks, Marta Garcia-Contreras, Donna B Stolz, Antonio Amelio, Siddaraju V Boregowda, Mohammad Fallahi, Adrian Reich, Camillo Ricordi, Donald G Phinney, Johnny Huard, Sai Kiang Lim, Laura J Niedernhofer, Paul D Robbins.

  Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1-/- mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.

Keywords:  aging; extracellular vesicles; mesenchymal stem cells; senescence; stem cells

DOI:  https://doi.org/10.1111/acel.13337
Front Aging Neurosci. 2021 ;13 646924

Cellular Senescence in Brain Aging.

Ewa Sikora, Anna Bielak-Zmijewska, Magdalena Dudkowska, Adam Krzystyniak, Grazyna Mosieniak, Malgorzata Wesierska, Jakub Wlodarczyk.

  Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Keywords:  autophagy; brain aging; cellular senescence; cognitive impairment; neuroinflammation; neuronal plasticity

DOI:  https://doi.org/10.3389/fnagi.2021.646924
Exp Gerontol. 2021 Mar 16. pii: S0531-5565(21)00088-7. [Epub ahead of print]148 111313

The elevated level of IL-1α in the bone marrow of aged mice leads to MSC senescence partly by down-regulating Bmi-1.

Xueling Zheng, Qianxing Wang, Zhuo Xie, Jiao Li.

  Osteoporosis is becoming increasingly prevalent with individual aging. Recent studies found that bone marrow mesenchymal stem cells (MSCs) undergo senescence along with the progression of age-related osteoporosis, leading to a decreased rate of new bone formation and fracture repair. The underlying mechanism of MSC senescence in the aged bone marrow has not been clarified yet. Here we found that MSCs from aged mice (12-month-old, O-MSCs) exhibited apparent senescent phenotypes compared with those from young controls (2-month-old, Y-MSCs), including lower proliferation rate, impaired self-renewal capacity, increased p16Ink4a expression and shifted differentiation balance to favor adipocytes over osteoblasts. Bmi-1, one of the main factors that regulate stem cell self-renewal, is dramatically decreased in O-MSCs. Knocking-down of Bmi-1 in Y-MSCs lead to cellular senescence, while over-expression of it rejuvenated O-MSCs. We further showed that the level of IL-1α is much higher in the bone marrow fluid of aged mice, which significantly inhibited Bmi-1 expression in MSCs. Our present study indicated that IL-1α, a key component of the senescence-associated secretory phenotype (SASP), is elevated in the aged bone marrow microenvironment, leading to decreased Bmi-1 expression in MSCs and consequently, MSC senescence.

Keywords:  Aging; Bmi-1; IL-1α; MSC senescence; Osteoporosis

DOI:  https://doi.org/10.1016/j.exger.2021.111313
EMBO Rep. 2021 Mar 18. e52243

The struggle of a good friend getting old: cellular senescence in viral responses and therapy.

Jaskaren Kohli, Iris Veenstra, Marco Demaria.

  Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of pro-inflammatory cytokines and molecules. Senescence-associated phenotypes restrict damage propagation and activate immune responses, two essential processes involved in response to viral infections. However, excessive accumulation and persistence of senescent cells can become detrimental and promote pathology and dysfunctions. Various pharmacological interventions, including antiviral therapies, lead to aberrant and premature senescence. Here, we review the molecular mechanisms by which viral infections and antiviral therapy induce senescence. We highlight the importance of these processes in attenuating viral dissemination and damage propagation, but also how prematurely induced senescent cells can promote detrimental adverse effects in humans. We describe which sequelae due to viral infections and treatment can be partly due to excessive and aberrant senescence. Finally, we propose that pharmacological strategies which eliminate senescent cells or suppress their secretory phenotype could mitigate side effects and alleviate the onset of additional morbidities. These strategies can become extremely beneficial in patients recovering from viral infections or undergoing antiviral therapy.

Keywords:  ageing; antiretroviral therapy; cellular senescence; immunosenescence; viral infection

DOI:  https://doi.org/10.15252/embr.202052243
Oxid Med Cell Longev. 2021 ;2021 2045259

PPARα Targeting GDF11 Inhibits Vascular Endothelial Cell Senescence in an Atherosclerosis Model.

Fangfang Dou, Beiling Wu, Jiulin Chen, Te Liu, Zhihua Yu, Chuan Chen.

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Using molecular biology and cell biology approaches to detect senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe -/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11). GDF11 levels declined with age in several organs including the myocardium, bone, central nervous system, liver, and spleen in mice and participated in the regulation of aging. Our results showed that PPARα inhibited vascular endothelial cell senescence and apoptosis and promoted vascular endothelial cell proliferation and angiogenesis by increasing GDF11 production. Taken together, these results demonstrated that PPARα inhibited vascular endothelial cell aging by promoting the expression of the aging-related protein GDF11, thereby delaying the occurrence of AS.

DOI: https://doi.org/10.1155/2021/2045259
Aging Cell. 2021 Mar 20. e13345

Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.

Ziqian Shen, Abby Hinson, Richard A Miller, Gonzalo G Garcia.

  We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA-KO, and Ghr-/- mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT). Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.

Keywords:  17α-estradiol; acarbose; aging; protein translation; rapamycin; signal transduction

DOI:  https://doi.org/10.1111/acel.13345
Toxicol In Vitro. 2021 Mar 15. pii: S0887-2333(21)00071-0. [Epub ahead of print] 105146

p53-mediated ferroptosis is required for 1-methyl-4-phenylpyridinium-induced senescence of PC12 cells.

Shanshan Li, Meng Wang, Youlin Wang, Yuting Guo, Xiaoxiao Tao, Xuncui Wang, Yin Cao, Shasha Tian, Qinglin Li.

  Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and striatum. Aging is the most important risk factor of PD. Ferroptosis is an iron-dependent form of cell death associated with PD. However, it is not clear whether ferroptosis accelerates PD by promoting cellular senescence. This study investigated the mechanism of 1-methyl-4-phenylpyridinium (MPP+) -induced PC12 cells injury. We found that MPP+ induced cell senescence with increased β-galactosidase activity and the expression of p53, p21 and p16 activation in cells. In addition, MPP+ treatment showed smaller mitochondria and increased membrane density, downregulation of ferritin heavy chain 1 expression and upregulation of acyl-CoA synthetase long chain family member 4 expression, and enhanced levels of oxidative stress, which were important characteristics of ferroptosis. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was tested to eliminate MPP+-induced cell senescence. Fer-1 downregulated the expression of p53 and upregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase-4 (GPX4) in MPP+-induced ferroptosis. Inhibition of p53 eliminated cell senescence by upregulation the expression of of SLC7A11 and GPX4. Thus, these results suggest that MPP+ induces senescence in PC12 cells via the p53/ SLC7A11/ GPX4 signaling pathway in the ferroptosis regulation mechanism.

Keywords:  Ferroptosis; Parkinson's disease; Senescence

DOI:  https://doi.org/10.1016/j.tiv.2021.105146
Mech Ageing Dev. 2021 Mar 16. pii: S0047-6374(21)00040-3. [Epub ahead of print] 111468

Senolytic targets and new strategies for clearing senescent cells.

Mingxia Ge, Li Hu, Hongshun Ao, Meiting Zi, Qingpeng Kong, Yonghan He.

  Senescent cells (SCs) accumulate with age and cause various age-related diseases. Clearance of SCs by transgenic or pharmaceutical strategies has been demonstrated to delay aging, treat age-related diseases and extend healthspan. SCs are resistant to various stressors because they are protected from apoptosis by SC anti-apoptotic pathways (SCAPs). Targeting the proteins in the SCAPs with small molecules selectively kill SCs, the effector proteins are called senolytic targets and the small molecules are called senolytics. Until now, a series of senolytic targets, such as BCL-XL, heat shock protein 90 (HSP90), Na+/K+ ATPase, bromodomain containing 4 (BRD4), and oxidation resistance 1 (OXR1) have been identified. However, current senolytics targeting these proteins still have some limitations in killing SCs in terms of safety, specificity and broad-spectrum activity. To overcome the challenges, some new strategies, such as proteolysis-targeting chimera (PROTAC) technology, chimeric antigen receptor (CAR) T cells, and β-galactosidase-modified prodrugs, were developed to clear SCs and shown to have promising therapeutic potential. Here we review the significance of SCs in aging and age-related diseases, summarize the known senolytic targets and highlight the emerging new strategies for clearing SCs.

Keywords:  Chimeric antigen receptor (CAR) T cell; Prodrug; Proteolysis-targeting chimera; Senescent cells; Senolytic target

DOI:  https://doi.org/10.1016/j.mad.2021.111468
Cell Rep. 2021 Mar 16. pii: S2211-1247(21)00174-1. [Epub ahead of print]34(11): 108860

COX2 regulates senescence secretome composition and senescence surveillance through PGE2.

Susana Gonçalves, Kelvin Yin, Yoko Ito, Adelyne Chan, Ioana Olan, Sarah Gough, Liam Cassidy, Eva Serrao, Stephen Smith, Andrew Young, Masashi Narita, Matthew Hoare.

  Senescent cells trigger their own immune-mediated destruction, termed senescence surveillance. This is dependent on the inflammatory senescence-associated secretory phenotype (SASP), which includes COX2, an enzyme with complex roles in cancer. The role COX2 plays during senescence surveillance is unknown. Here, we show that during RAS-induced senescence (RIS), COX2 is a critical regulator of SASP composition and senescence surveillance in vivo. COX2 regulates the expression of multiple inflammatory SASP components through an autocrine feedback loop involving its downstream product, prostaglandin E2 (PGE2), binding to EP4. During in vivo hepatocyte RIS, Cox2 is critical to tumor suppression, Cxcl1 expression, and immune-mediated senescence surveillance, partially through PGE2. Loss of Cox2 in RIS dysregulates the intrahepatic immune microenvironment, with enrichment of immunosuppressive immature myeloid cells and CD4+ regulatory T lymphocytes. Therefore, COX2 and PGE2 play a critical role in senescence, shaping SASP composition, promoting senescence surveillance and tumor suppression in the earliest stages of tumorigenesis.

Keywords:  COX2; SASP; immune surveillance; liver; senescence

DOI:  https://doi.org/10.1016/j.celrep.2021.108860
Cell Death Differ. 2021 Mar 15.

Beyond DNA repair and chromosome instability-Fanconi anaemia as a cellular senescence-associated syndrome.

Anne Helbling-Leclerc, Cécile Garcin, Filippo Rosselli.

Fanconi anaemia (FA) is the most frequent inherited bone marrow failure syndrome, due to mutations in genes encoding proteins involved in replication fork protection, DNA interstrand crosslink repair and replication rescue through inducing double-strand break repair and homologous recombination. Clinically, FA is characterised by aplastic anaemia, congenital defects and cancer predisposition. In in vitro studies, FA cells presented hallmarks defining senescent cells, including p53-p21 axis activation, altered telomere length, mitochondrial dysfunction, chromatin alterations, and a pro-inflammatory status. Senescence is a programme leading to proliferation arrest that is involved in different physiological contexts, such as embryogenesis, tissue remodelling and repair and guarantees tumour suppression activity. However, senescence can become a driving force for developmental abnormalities, aging and cancer. Herein, we summarise the current knowledge in the field to highlight the mutual relationships between FA and senescence that lead us to consider FA not only as a DNA repair and chromosome fragility syndrome but also as a "senescence syndrome".

DOI: https://doi.org/10.1038/s41418-021-00764-5
Food Funct. 2021 Mar 15.

Caffeine promotes the expression of telomerase reverse transcriptase to regulate cellular senescence and aging.

Li Tao, Wei Zhang, Yaxin Zhang, Mei Zhang, Yueying Zhang, Xing Niu, Qing Zhao, Zhenxing Liu, Yuyin Li, Aipo Diao.

Telomere shortening is one of the main causes of cellular senescence. Caffeine is a natural stimulant most commonly found in coffee and tea. In this study, caffeine was found to promote the expression of telomerase reverse transcriptase (TERT) at both mRNA and protein levels, and consequently extended the telomere length and prevented cellular senescence. Knockdown of TERT eliminated the effect of caffeine on telomere elongation. Moreover, animal studies indicated that caffeine promoted the expression of TERT and extended the telomere length in the thymus and spleen of mice treated with caffeine for a long period of eight months. In addition, caffeine restored the decline of organ index and improved the histological structural change of the thymus, spleen and liver of mice due to aging. These results suggest that caffeine promotes the expression of TERT to delay cellular senescence and aging, which help to understand the mechanism for the beneficial effects of caffeine containing foods on health.

DOI: https://doi.org/10.1039/d0fo03246h
Aging (Albany NY). 2021 Mar 14. 13

PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons.

Marisa Ferreira-Marques, André Carvalho, Cláudia Cavadas, Célia A Aveleira.

  Caloric restriction has been shown to robustly ameliorate age-related diseases and to prolong lifespan in several model organisms, and these beneficial effects are dependent on the stimulation of autophagy. Autophagy dysfunction contributes to the accumulation of altered macromolecules, and is a key mechanism of promoting aging and age-related disorders, as neurodegenerative ones. We have previously shown that caloric restriction (CR), and CR mimetics Neuropeptide Y (NPY) and ghrelin, stimulate autophagy in rat cortical neurons, however by unknown molecular mechanisms. Overall, we show that CR, NPY, and ghrelin stimulate autophagy through PI3K/AKT/MTOR inhibition and ERK1/2-MAPK activation. The knowledge of these kinases in autophagy regulation and the contribution to the understanding of molecular mechanism facilitates the discovery of more targeted therapeutic strategies to stimulate autophagy, which is relevant in the context of age-related disorders.

Keywords:  aging; autophagy; caloric restriction mimetics; cortical neurons

DOI:  https://doi.org/10.18632/aging.202805
Aging Med (Milton). 2021 Mar;4(1): 47-52

Growth differentiation factor-15 is associated with age-related monocyte dysfunction.

Brandt D Pence, Johnathan R Yarbro, Russell S Emmons.

   Objective: Age-associated decreases in immune functions are precipitated by a variety of mechanisms and affect nearly every immune cell subset. In myeloid cells, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we described an aging effect on several functions in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide. We hypothesized that circulating factors altered by the aging process underly these changes. Growth differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-β superfamily that has known anti-inflammatory effects in macrophages and has been shown to be highly differentially expressed during aging.
Methods: We used biobanked plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 and monocyte function.
Results: Monocyte interleukin-6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF-15. Additionally, GDF-15 was positively correlated to circulating CD16 + monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity.
Conclusions: These results suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence and thus may be an attractive candidate for therapeutic intervention to ameliorate this.

Keywords:  immune function; inflammaging; senescence; senescence‐associated secretory phenotype

DOI:  https://doi.org/10.1002/agm2.12128
Commun Biol. 2021 Mar 19. 4(1): 357

β-catenin-promoted cholesterol metabolism protects against cellular senescence in naked mole-rat cells.

Woei-Yaw Chee, Yuriko Kurahashi, Junhyeong Kim, Kyoko Miura, Daisuke Okuzaki, Tohru Ishitani, Kentaro Kajiwara, Shigeyuki Nada, Hideyuki Okano, Masato Okada.

The naked mole-rat (NMR; Heterocephalus glaber) exhibits cancer resistance and an exceptionally long lifespan of approximately 30 years, but the mechanism(s) underlying increased longevity in NMRs remains unclear. In the present study, we report unique mechanisms underlying cholesterol metabolism in NMR cells, which may be responsible for their anti-senescent properties. NMR fibroblasts expressed β-catenin abundantly; this high expression was linked to increased accumulation of cholesterol-enriched lipid droplets. Ablation of β-catenin or inhibition of cholesterol synthesis abolished lipid droplet formation and induced senescence-like phenotypes accompanied by increased oxidative stress. β-catenin ablation downregulated apolipoprotein F and the LXR/RXR pathway, which are involved in cholesterol transport and biogenesis. Apolipoprotein F ablation also suppressed lipid droplet accumulation and promoted cellular senescence, indicating that apolipoprotein F mediates β-catenin signaling in NMR cells. Thus, we suggest that β-catenin in NMRs functions to offset senescence by regulating cholesterol metabolism, which may contribute to increased longevity in NMRs.

DOI: https://doi.org/10.1038/s42003-021-01879-8
Clin Exp Pharmacol Physiol. 2021 Apr;48(4): 524-533

Decreased autophagy of vascular smooth muscle cells was involved in hyperhomocysteinemia-induced vascular ageing.

Wenjing Yan, Yan Cao, Panpan Zhen, Dengyu Ji, Jiayin Chai, Ke Xue, Hongyan Dai, Wen Wang.

  Ageing and hyperhomocysteinemia (HHcy) are important risk factors for cardiovascular diseases (CVDs). HHcy affects the occurrence of vascular diseases in the elderly. So far, the mechanism of HHcy-induced vascular ageing remains largely unknown. Autophagy level is significantly reduced in the ageing process, and restoring impaired autophagy to a normal state may be one of the possible ways to extend the expected longevity and lifespan in the future. In this study, we established the HHcy rat model by feeding a 2.5% methionine diet. Small animal ultrasound and the tail-cuff method indicated that the vascular pulse wave velocity (PWV) and pulse pressure (PP) of HHcy rats were increased significantly compared with the control group. Vascular morphology and structure have been changed in HHcy rats, including lumen dilation, increased collagen fibre deposition and increased p53/p21/p16 expression. In vitro, under the stimulation of homocysteine (500 μmol/L, 24 hours), the rat vascular smooth muscle cells (VSMCs) presented senescence, which was characterized by the increased expression of ageing-related markers, such as p16, p21 and p53 as well as increased senescence-associated beta-galactosidase (SA-β-gal) activity. Meanwhile, the autophagy level was decreased both in vivo and in vitro, shown as the increased level of autophagy substrate p62 and the reduced level of autophagy marker LC3 II/I in the thoracic aorta of HHcy rats and in Hcy-treated VSMCs, respectively. The senescence phenotype of VSMCs was reversed by increased autophagy levels induced by rapamycin. Our findings indicate that decreased autophagy of VSMCs is involved in hyperhomocysteinemia-induced vascular ageing.

Keywords:  autophagy; hyperhomocysteinemia; vascular ageing; vascular smooth muscle cells

DOI:  https://doi.org/10.1111/1440-1681.13442
Aging Cell. 2021 Mar 15. e13343

Identification of SRY-box 30 as an age-related essential gatekeeper for male germ-cell meiosis and differentiation.

Fei Han, Li Yin, Xiao Jiang, Xi Zhang, Ning Zhang, Jun-Tang Yang, Wei-Ming Ouyang, Xiang-Lin Hao, Wen-Bin Liu, Yong-Sheng Huang, Hong-Qiang Chen, Fei Gao, Zhong-Tai Li, Qiao-Nan Guo, Jia Cao, Jin-Yi Liu.

  Although important factors governing the meiosis have been reported in the embryonic ovary, meiosis in postnatal testis remains poorly understood. Herein, we first report that SRY-box 30 (Sox30) is an age-related and essential regulator of meiosis in the postnatal testis. Sox30-null mice exhibited uniquely impaired testis, presenting the abnormal arrest of germ-cell differentiation and irregular Leydig cell proliferation. In aged Sox30-null mice, the observed testicular impairments were more severe. Furthermore, the germ-cell arrest occurred at the stage of meiotic zygotene spermatocytes, which is strongly associated with critical regulators of meiosis (such as Cyp26b1, Stra8 and Rec8) and sex differentiation (such as Rspo1, Foxl2, Sox9, Wnt4 and Ctnnb1). Mechanistically, Sox30 can activate Stra8 and Rec8, and inhibit Cyp26b1 and Ctnnb1 by direct binding to their promoters. A different Sox30 domain required for regulating the activity of these gene promoters, providing a "fail-safe" mechanism for Sox30 to facilitate germ-cell differentiation. Indeed, retinoic acid levels were reduced owing to increased degradation following the elevation of Cyp26b1 in Sox30-null testes. Re-expression of Sox30 in Sox30-null mice successfully restored germ-cell meiosis, differentiation and Leydig cell proliferation. Moreover, the restoration of actual fertility appeared to improve over time. Consistently, Rec8 and Stra8 were reactivated, and Cyp26b1 and Ctnnb1 were reinhibited in the restored testes. In summary, Sox30 is necessary, sufficient and age-associated for germ-cell meiosis and differentiation in testes by direct regulating critical regulators. This study advances our understanding of the regulation of germ-cell meiosis and differentiation in the postnatal testis.

Keywords:  SRY-box 30; induced recovery; meiosis arrest; postnatal testis; retinoic acid signalling; zygotene spermatocyte

DOI:  https://doi.org/10.1111/acel.13343
Nanomedicine. 2021 Mar 10. pii: S1549-9634(21)00022-8. [Epub ahead of print] 102379

Fluorescent nanocarriers targeting VCAM-1 for early detection of senescent endothelial cells.

Eugenia Belcastro, Asad Ur Rehman, Lamia Remila, Sin-Hee Park, Dal Seong Gong, Nicolas Anton, Cyril Auger, Olivier Lefebvre, Jacky G Goetz, Mayeul Collot, Andrey S Klymchenko, Thierry F Vandamme, Valérie B Schini-Kerth.

  Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang II-induced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPA:DHA 6:1) were more effective than native EPA:DHA 6:1 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-β- galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.

Keywords:  Endothelial senescence and dysfunction; Nanocarriers; Omega 3 polyunsaturated fatty acid; VCAM-1

DOI:  https://doi.org/10.1016/j.nano.2021.102379
J Neuroinflammation. 2021 Mar 18. 18(1): 75

Senescent accelerated prone 8 (SAMP8) mice as a model of age dependent neuroinflammation.

Andrés Fernández, Elena Quintana, Patricia Velasco, Belén Moreno-Jimenez, Belén de Andrés, Maria Luisa Gaspar, Isabel Liste, Marçal Vilar, Helena Mira, Eva Cano.

   BACKGROUND: Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process.
METHODS: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1+ clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation.
RESULTS: Aged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1+ clusters, but not an increase in the number of Iba1+ cells. We have further observed an increase of main inflammatory mediator IL-1β, and an augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45+ cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1β) transcription is enhanced in CD45+BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1β expression is further augmented in aged SAMP8 compared to control SAMR1.
CONCLUSION: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

Keywords:  Aging; Brain myeloid cells; IL-1β; Inflammation; Microglia; SAMP8

DOI:  https://doi.org/10.1186/s12974-021-02104-3
Trends Cell Biol. 2021 Mar 11. pii: S0962-8924(21)00034-9. [Epub ahead of print]

Elimination of Senescent Endothelial Cells: Good or Bad Idea?

Nadine Martin, Anda Huna, David Bernard.

  Cellular senescence has a critical role in many physiopathological contexts. Recent studies highlight the beneficial and adverse effects that eliminating senescent endothelial cells can have on health span, questioning the current development of drugs that induce the death of senescent cells, named senolytics, as a therapeutic strategy.

Keywords:  cellular senescence; endothelial cells; health span; senolytics

DOI:  https://doi.org/10.1016/j.tcb.2021.02.009
Aging Cell. 2021 Mar 15. e13336

PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.

Julia Adelöf, John Wiseman, Madeleine Zetterberg, Malin Hernebring.

  With age, protein damage accumulates and increases the risk of age-related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti-aggregation effect was maintained in young adult (7 months) to middle-aged (15 months) and old (22 months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior-a behavioral hallmark of aging-but were as explorative as young mice. PA28αOE lowered PA28-dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28-dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth-like exploration at old age. The cognitive effects of PA28αβ combined with its anti-aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.

Keywords:  F2 hybrid transgenic mice; PA28αβ; aging; exploratory behavior; healthy aging; learning and memory; proteasome activator; protein aggregation

DOI:  https://doi.org/10.1111/acel.13336
Life Sci. 2021 Mar 11. pii: S0024-3205(21)00328-3. [Epub ahead of print]274 119343

Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke.

Sejal Sharma, Saeideh Nozohouri, Bhuvaneshwar Vaidya, Thomas Abbruscato.

  Aging is a risk factor for major central nervous system (CNS) disorders. More specifically, aging can be inked to neurodegenerative diseases (NDs) because of its deteriorating impact on neurovascular unit (NVU). Metformin, a first line FDA-approved anti-diabetic drug, has gained increasing interest among researchers for its role in improving aging-related neurodegenerative disorders. Additionally, numerous studies have illustrated metformin's role in ischemic stroke, a cerebrovascular disorder in which the NVU becomes dysfunctional which can lead to permanent life-threatening disabilities. Considering metformin's beneficial preclinical actions on various disorders, and the drug's role in alleviating severity of these conditions through involvement in commonly characterized cellular pathways, we discuss the potential of metformin as a suitable drug candidate for repurposing in CNS disorders.

Keywords:  Anti- aging; Diabetes; Electronic cigarette vaping; Ischemic stroke; Metformin; Neurodegenerative diseases; Tobacco smoking

DOI:  https://doi.org/10.1016/j.lfs.2021.119343
Front Cell Dev Biol. 2021 ;9 628463

Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction.

Hao Zhang, Chengling Zhao, Guojun Jiang, Bei Hu, Huifeng Zheng, Yimei Hong, Zhen Cui, Linli Shi, Xin Li, Fang Lin, Yue Ding, Lu Wei, Mimi Li, Xiaoting Liang, Yuelin Zhang.

  The protective effects of mesenchymal stem cell (MSC)-based therapy for myocardial infarction (MI) are largely hampered as they age. Apelin is an endogenous ligand of its receptor APJ and plays an essential role in regulating multiple biological activities including MSC proliferation and survival. In this study, we investigated whether Apelin regulates MSC senescence and whether its overexpression could rejuvenate aged MSCs (AMSCs) to improve cardiac protection following infarction in mice. MSC senescence was evaluated by senescence-associated β-galactosidase assays. Apelin level was examined by western blotting. Autophagy was determined by transmission electron microscopy. The cardioprotective effect of AMSCs with Apelin overexpression (Apelin-AMSCs) was assessed in a mouse MI model. Apelin expression was dramatically reduced in AMSCs. Interestingly, knockdown of Apelin induced young MSCs (YMSC) senescence, whereas overexpression rescued AMSC senescence. Apelin overexpression also increased AMSC angiogenic capacity. Mechanistically, Apelin overexpression upregulated the autophagy level of AMSCs by activating AMP-activated protein kinase (AMPK) signaling, thereby rejuvenating AMSCs. Compared with AMSCs, transplantation of Apelin-AMSCs achieved better therapeutic efficacy for MI by enhancing cell survival and angiogenesis. In conclusion, our results reveal that Apelin activates AMPK to rejuvenate AMSCs by increasing autophagy and promotes cardioprotection following infarction in mice. This study identified a novel target to rejuvenate AMSCs and enhance their therapeutic efficacy.

Keywords:  apelin; mesenchymal stem cells; myocardial infarction; rejuvenation; senescence

DOI:  https://doi.org/10.3389/fcell.2021.628463
Aging (Albany NY). 2021 Mar 10. 13

PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury.

Longhui Yuan, Yujia Yuan, Fei Liu, Lan Li, Jingping Liu, Younan Chen, Jingqiu Cheng, Yanrong Lu.

  Because of the key role of impaired mitochondria in the progression of acute kidney injury (AKI), it is striking that peroxisome proliferator γ coactivator 1-α (PGC-1α), a transcriptional coactivator of genes involved in mitochondrial biogenesis and autophagy, protects from kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. In vivo, along with the severe kidney damage, the expression of PGC-1α was decreased in cisplatin-induced AKI mice. Conversely, PGC-1α activator (ZLN005) administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or ZLN005 treatment inhibited cell apoptosis and mitochondrial dysfunction induced by cisplatin. Moreover, ZLN005 treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria, suggesting that the mitophagy was activated. Furthermore, PGC-1α-mediated the activation of mitophagy was reliant on the increased expression of TFEB, and the protective effects were abrogated in TFEB-knockdown cells. These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy.

Keywords:  PGC-1α; TFEB; acute kidney injury; autophagy; mitochondrial dysfunction

DOI:  https://doi.org/10.18632/aging.202653
Aging Cell. 2021 Mar 17. e13325

Proteomics in aging research: A roadmap to clinical, translational research.

Ruin Moaddel, Ceereena Ubaida-Mohien, Toshiko Tanaka, Alexey Lyashkov, Nathan Basisty, Birgit Schilling, Richard D Semba, Claudio Franceschi, Myriam Gorospe, Luigi Ferrucci.

  The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational "omics" since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)-based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O-Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age-associated across studies. Enrichment analysis of the 232 age-associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin-like growth factor (IGF) signaling, mitogen-activated protein kinases (MAPK), hypoxia-inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age-relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy.

Keywords:  aging; geroscience; human; proteomics

DOI:  https://doi.org/10.1111/acel.13325
Nat Aging. 2021 Feb;1(2): 165-178

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress.

Terytty Yang Li, Maroun Bou Sleiman, Hao Li, Arwen W Gao, Adrienne Mottis, Alexis Maximilien Bachmann, Gaby El Alam, Xiaoxu Li, Ludger J E Goeminne, Kristina Schoonjans, Johan Auwerx.

Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

DOI: https://doi.org/10.1038/s43587-020-00025-z
Mol Ther Nucleic Acids. 2021 Mar 05. 23 1323-1333

SIRT1-induced deacetylation of Akt expedites platelet phagocytosis and delays HEMEC aging.

Yong Lan, Min Dong, Yongjun Li, Yongpeng Diao, Zuoguang Chen, Yangfang Li.

  Maintaining the health of the endothelium is of critical importance to prevention against cell aging. The current study was performed to clarify the role of sirtuin1 (SIRT1) in platelet phagocytosis in cell aging and identified its downstream molecular mechanism. Platelet phagocytosis by human endometrial microvascular endothelial cells (HEMECs) was characterized by transmission electron and fluorescence microscopy. Functional experiments were conducted to examine platelet phagocytosis and cell aging using the overexpression or knockdown plasmids of SIRT1 and G alpha-interacting, vesicle-associated protein (GIRDIN) as well as Akt inhibitor and activator. It was found that SIRT1 facilitated platelet phagocytosis by HEMECs, contributing to inhibition of cell aging. Akt activation facilitated platelet phagocytosis and repressed cell aging. GIRDIN overexpression accelerated platelet phagocytosis by HEMECs, leading to a delay in cell aging. GIRDIN phosphorylation at Ser1417 was induced by Akt activation, while activation of Akt was induced by SIRT1-mediated deacetylation, consequently augmenting platelet phagocytosis and delaying cell aging. Taken together, SIRT1 delayed aging of HEMECs by deacetylating Akt, phosphorylating GIRDIN, and inducing platelet phagocytosis. The study highlights a possible target for the prevention of HEMEC aging.

Keywords:  Akt; GIRDIN; SIRT1; cell aging; human endometrial microvascular endothelial cells; platelet phagocytosis

DOI:  https://doi.org/10.1016/j.omtn.2021.01.023
Adv Exp Med Biol. 2021 ;1286 145-161

Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.

Oleh Lushchak, Veronika Piskovatska, Olha Strilbytska, Iryna Kindrat, Nadya Stefanyshyn, Alexander Koliada, Volodymyr Bubalo, Kenneth B Storey, Alexander Vaiserman.

  Aging is a biological process with effects at the molecular, cellular, tissue, organ, system, and organismal levels and is characterized by decline in physical function and higher risks of age-related diseases. The use of anti-aging drugs for disease prevention has become a high priority for science and is a new biomedicine trend. Geroprotectors are compounds which slow aging and increase lifespan of the organism in question. The common painkiller aspirin, a member of the non-steroidal anti-inflammatory drug (NSAID) family, is one of the potential geroprotective agents. Aspirin is often used in treatment of mild to moderate pain. It has anti-inflammatory and anti-pyretic properties and acts as an inhibitor of cyclooxygenase which results in inhibition of prostaglandin. Acetylsalicylic acid as an active compound of aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Aspirin has shown life-extending effects in numerous model organisms. This chapter reviews the evidence for clinical efficacy of aspirin including cardiovascular disease prevention, anti-cancer effects, and improvement of cognitive function. However, there are some limitations of these therapies, including the risk of excessive bleeding. We have also summarized numerous experimental and analytical data that support health and longevity benefits of aspirin treatment by affecting pro-longevity pathways.

Keywords:  Age-related diseases; Aging; Aspirin; Geroprotector; Geroscience; NSAID

DOI:  https://doi.org/10.1007/978-3-030-55035-6_11
Aging (Albany NY). 2021 Mar 18. 13

A ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice.

Zeyu Zhou, Kevork Hagopian, José A López-Domínguez, Kyoungmi Kim, Mittal Jasoliya, Megan N Roberts, Gino A Cortopassi, Megan R Showalter, Bryan S Roberts, José A González-Reyes, Keith Baar, Jennifer Rutkowsky, Jon J Ramsey.

  Declines in mitochondrial mass are thought to be a hallmark of mammalian aging, and a ketogenic diet (KD) may prevent the age-related decreases in mitochondrial content. The objective of this study was to investigate the impact of a KD on markers of mitochondrial mass. Mice were fed an isocaloric control diet (CD) or KD from 12 months of age. Tissues were collected after 1 month and 14 months of intervention, and a panel of commonly used markers of mitochondrial mass (mitochondrial enzyme activities and levels, mitochondrial to nuclear DNA ratio, and cardiolipin content) were measured. Our results showed that a KD stimulated activities of marker mitochondrial enzymes including citrate synthase, Complex I, and Complex IV in hindlimb muscle in aged mice. KD also increased the activity of citrate synthase and prevented an age-related decrease in Complex IV activity in aged brain. No other markers were increased in these tissues. Furthermore, the impacts of a KD on liver and kidney were mixed with no pattern indicative of a change in mitochondrial mass. In conclusion, results of the present study suggest that a KD induces tissue-specific changes in mitochondrial enzyme activities, or structure, rather than global changes in mitochondrial mass across tissues.

Keywords:  brain; diet; kidney; liver; skeletal muscle

DOI:  https://doi.org/10.18632/aging.202834
Semin Cell Dev Biol. 2021 Mar 16. pii: S1084-9521(21)00030-6. [Epub ahead of print]

Aging: All roads lead to mitochondria.

Jyung Mean Son, Changhan Lee.

  Mitochondria were described as early as 1890 as ubiquitous intracellular structures by Ernster and Schatz (1981) [1]. Since then, the accretion of knowledge in the past century has revealed much of the molecular details of mitochondria, ranging from mitochondrial origin, structure, metabolism, genetics, and signaling, and their implications in health and disease. We now know that mitochondria are remarkably multifunctional and deeply intertwined with many vital cellular processes. They are quasi-self organelles that still possess remnants of its bacterial ancestry, including an independent genome. The mitochondrial free radical theory of aging (MFRTA), which postulated that aging is a product of oxidative damage to mitochondrial DNA, provided a conceptual framework that put mitochondria on the map of aging research. However, several studies have more recently challenged the general validity of the theory, favoring novel ideas based on emerging evidence to understand how mitochondria contribute to aging and age-related diseases. One prominent topic of investigation lies on the fact that mitochondria are not only production sites for bioenergetics and macromolecules, but also regulatory hubs that communicate and coordinate many vital physiological processes at the cellular and organismal level. The bi-directional communication and coordination between the co-evolved mitochondrial and nuclear genomes is especially interesting in terms of cellular regulation. Mitochondria are dynamic and adaptive, rendering their function sensitive to cellular context. Tissues with high energy demands, such as the brain, seem to be uniquely affected by age-dependent mitochondrial dysfunction, providing a foundation for the development of novel mitochondrial-based therapeutics and diagnostics.

Keywords:  Aging; Communication; Genomic instability; Immunity; Inflammation; Longevity; Mitochondria; Mitochondrial-derived peptides; Mitonuclear; Oxidative stress

DOI:  https://doi.org/10.1016/j.semcdb.2021.02.006
Nature. 2021 Mar 17.

DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation.

L Robert Hollingsworth, Humayun Sharif, Andrew R Griswold, Pietro Fontana, Julian Mintseris, Kevin B Dagbay, Joao A Paulo, Steven P Gygi, Daniel A Bachovchin, Hao Wu.

Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis1-4. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin4-6. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains7-9, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT)10,11. Cytosolic dipeptidyl peptidases 8 and 9 (hereafter, DPP8/DPP9) both interact with NLRP1, and small-molecule inhibitors of DPP8/DPP9 activate NLRP1 by mechanisms that are currently unclear10,12-14. Here we report cryo-electron microscopy structures of the human NLRP1-DPP9 complex alone and with Val-boroPro (VbP), an inhibitor of DPP8/DPP9. The structures reveal a ternary complex that comprises DPP9, full-length NLRP1 and the NLRPT CT. The binding of the NLRP1 CT to DPP9 requires full-length NLRP1, which suggests that NLRP1 activation is regulated by the ratio of NLRP1 CT to full-length NLRP1. Activation of the inflammasome by ectopic expression of the NLRP1 CT is consistently rescued by co-expression of autoproteolysis-deficient full-length NLRP1. The N terminus of the NLRP1 CT inserts into the DPP9 active site, and VbP disrupts this interaction. Thus, VbP weakens the NLRP1-DPP9 interaction and accelerates degradation of the N-terminal fragment10 to induce inflammasome activation. Overall, these data demonstrate that DPP9 quenches low levels of NLRP1 CT and thus serves as a checkpoint for activation of the NLRP1 inflammasome.

DOI: https://doi.org/10.1038/s41586-021-03350-4
Nat Commun. 2021 Mar 19. 12(1): 1789

The decrease of intraflagellar transport impairs sensory perception and metabolism in ageing.

Yincong Zhang, Xiaona Zhang, Yumin Dai, Mengjiao Song, Yifei Zhou, Jun Zhou, Xiumin Yan, Yidong Shen.

Sensory perception and metabolic homeostasis are known to deteriorate with ageing, impairing the health of aged animals, while mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. We find that the reduced IFT in sensory cilia thus impairs sensory perception with ageing. Moreover, we demonstrate that whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. We show that upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our study determines an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing.

DOI: https://doi.org/10.1038/s41467-021-22065-8
J Immunol. 2021 Mar 17. pii: ji2001016. [Epub ahead of print]

Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis.

Sylvia Torres-Odio, Yuanjiu Lei, Suzana Gispert, Antonia Maletzko, Jana Key, Saeed S Menissy, Ilka Wittig, Georg Auburger, A Phillip West.

Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease that degrades damaged or misfolded mitochondrial proteins. CLPP-null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome, but also display immune system alterations. However, the molecular mechanisms and signaling pathways underlying immunological changes in CLPP-null mice remain unclear. In this study, we report the steady-state activation of type I IFN signaling and antiviral gene expression in CLPP-deficient cells and tissues, resulting in marked resistance to RNA and DNA virus infection. Depletion of the cyclic GMP-AMP (cGAS)-stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotype of CLPP-null cells. Moreover, we report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Pharmacological and genetic approaches to deplete mtDNA or inhibit cytosolic release markedly reduce antiviral gene expression, implicating mtDNA stress as the driver of IFN-I signaling in CLPP-null mice. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding Perrault syndrome and other human diseases involving CLPP dysregulation.

DOI: https://doi.org/10.4049/jimmunol.2001016