bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒11‒28
28 papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01520-5. [Epub ahead of print]37(8): 110038
      Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
    Keywords:  DNA damage; LARP7; aging; atherosclerosis; senescence
  2. Int J Mol Sci. 2021 Nov 12. pii: 12232. [Epub ahead of print]22(22):
      Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.
    Keywords:  age-related diseases; angiopoietin-like 2; biomarker; programmed senescence; senescence
  3. Cells. 2021 Nov 03. pii: 3003. [Epub ahead of print]10(11):
      Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
    Keywords:  ROS; mitochondria; mitochondrial metabolic reprogramming; senescence amelioration
  4. Eur Cell Mater. 2021 Nov 25. 41 401-414
      Mesenchymal stem cells (MSCs) are promising cells for regenerative medicine therapies because they can differentiate towards multiple cell lineages. However, the occurrence of cellular senescence and the acquiring of the senescence-associated secretory phenotype (SASP) limit their clinical use. Since the transcription factor TWIST1 influences expansion of MSCs, its role in regulating cellular senescence was investigated. The present study demonstrated that silencing of TWIST1 in MSCs increased the occurrence of senescence, characterised by a SASP profile different from irradiation-induced senescent MSCs. Knowing that senescence alters cellular metabolism, cellular bioenergetics was monitored by using the Seahorse XF apparatus. Both TWIST1-silencing-induced and irradiation-induced senescent MSCs had a higher oxygen consumption rate compared to control MSCs, while TWIST1-silencing-induced senescent MSCs had a low extracellular acidification rate compared to irradiation-induced senescent MSCs. Overall, data indicated how TWIST1 regulation influenced senescence in MSCs and that TWIST1 silencing-induced senescence was characterised by a specific SASP profile and metabolic state.
  5. Curr Opin Clin Nutr Metab Care. 2021 Nov 22.
      PURPOSE OF REVIEW: Cell senescence is implicated in numerous age-related conditions. Antiageing therapies and nutritional approaches have been researched for purposes of removing senescent cells (senolytics) to treat or prevent age-related diseases, such as cognitive impairment and Alzheimer's disease. In this updated review, we examined the evidence from the last 18 months regarding nutrition senolytics, with a focus on cognitive ageing among older adults.RECENT FINDINGS: Overall, 19 systematic reviews and 17 intervention studies were included. Studies failed to provide evidence of nutritional senolytic agents or senescence-associated secretory phenotype (SASP) suppressors, for oral supplements providing beneficial effects on cognitive ageing among older adults. The protective role of food sources such as berries and nuts, and dietary patterns of Mediterranean diet and Mediterranean-DASH diet Intervention for Neurodegenerative Delay diet against cognitive decline or risk of dementia have been mostly supported by recent studies.
    SUMMARY: The present review gathered additional evidence for both oral supplements and foods/diets rich in nutritional senolytic agents or SASP suppressors on cognitive health among older adults. In pursuing antiageing strategies, the importance of whole foods and healthy diets should not be overlooked, future studies are warranted on long-term effects and cytotoxicity of nutritional senolytics.
  6. Int J Mol Sci. 2021 Nov 21. pii: 12539. [Epub ahead of print]22(22):
      Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.
    Keywords:  CMV; COVID-19; aging; cytokine storm; hyperinflammatory syndrome; immunosenescence; inflammaging; senescence-associated secretory phenotype (SASP)
  7. Commun Biol. 2021 Nov 24. 4(1): 1323
      Membrane contact sites emerged in the last decade as key players in the integration, regulation and transmission of many signals within cells, with critical impact in multiple pathophysiological contexts. Numerous studies accordingly point to a role for mitochondria-endoplasmic reticulum contacts (MERCs) in modulating aging. Nonetheless, the driving cellular mechanisms behind this role remain unclear. Recent evidence unravelled that MERCs regulate cellular senescence, a state of permanent proliferation arrest associated with a pro-inflammatory secretome, which could mediate MERC impact on aging. Here we discuss this idea in light of recent advances supporting an interplay between MERCs, cellular senescence and aging.
  8. Front Immunol. 2021 ;12 692321
      Neuropsychiatric manifestations targeting the central, peripheral, and autonomic nervous system are common in systemic lupus erythematosus (SLE); collectively, these symptoms are termed neuropsychiatric SLE (NPSLE). Among a wide variety of neuropsychiatric symptoms, depression is observed in about 24-39% of SLE patients. Several cytokines and chemokines have been identified as biomarkers or therapeutic targets of NPSLE; in particular, the levels of type 1 interferons, TNFs, and IL-6 are elevated in SLE patient's cerebrospinal fluid (CSF), and these factors contribute to the pathology of depression. Here, we show that senescent neural cells accumulate in the hippocampal cornu ammonis 3 (CA3) region in MRL/lpr SLE model mice with depressive behavior. Furthermore, oral administration of fisetin, a senolytic drug, reduced the number of senescent neural cells and reduced depressive behavior in the MRL/lpr mice. In addition, transcription of several senescence and senescence-associated secretory phenotype (SASP) factors in the hippocampal region also decreased after fisetin treatment in the MRL/lpr mice. These results indicate that the accumulation of senescent neural cells in the hippocampus plays a role in NPSLE pathogenesis, and therapies targeting senescent cells may represent a candidate approach to treat NPSLE.
    Keywords:  SASP (senescence-associated secretory phenotype); depression; inflammation; senescence; systemic lupus erythematosus
  9. Geroscience. 2021 Nov 24.
      Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.
    Keywords:  Aging; NOP; Senescence; Senolytic
  10. Cells. 2021 Nov 01. pii: 2974. [Epub ahead of print]10(11):
      Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism's health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system's activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging.
    Keywords:  aging; biological age; immune cells; inflammatory stress; oxidative stress
  11. Int J Mol Sci. 2021 Nov 17. pii: 12415. [Epub ahead of print]22(22):
      Various stresses latently induce cellular senescence that occasionally deteriorates the functioning of surrounding tissues. Nevertheless, little is known about the appearance and function of senescent cells, caused by the implantation of beta-tricalcium phosphate (β-TCP)-used widely in dentistry and orthopedics for treating bone diseases. In this study, two varying sizes of β-TCP granules (<300 μm and 300-500 μm) were implanted, and using histological and immunofluorescent staining, appearances of senescent-like cells in critical-sized bone defects in the calvaria of Sprague Dawley rats were evaluated. Parallelly, bone formation in defects was investigated with or without the oral administration of senolytics (a cocktail of dasatinib and quercetin). A week after the implantation, the number of senescence-associated beta-galactosidase, p21-, p19-, and tartrate-resistant acid phosphatase-positive cells increased and then decreased upon administrating senolytics. This administration of senolytics also attenuated 4-hydroxy-2-nonenal staining, representing reactive oxygen species. Combining senolytic administration with β-TCP implantation significantly enhanced the bone formation in defects as revealed by micro-computed tomography analysis and hematoxylin-eosin staining. This study demonstrates that β-TCP granules latently induce senescent-like cells, and senolytic administration may improve the bone-forming ability of β-TCP by inhibiting senescence-associated mechanisms.
    Keywords:  beta-tricalcium phosphate; bone formation; cellular senescence; senolytics
  12. J Clin Med. 2021 Nov 16. pii: 5331. [Epub ahead of print]10(22):
      Osteoarthritis (OA) is recognized as being a cellular senescence-linked disease. Intra-articular injections of glucocorticoids (GC) are frequently used in knee OA to treat synovial effusion but face controversies about toxicity. We investigated the influence of GC on cellular senescence hallmarks and senescence induction in fibroblast-like synoviocytes (FLS) from OA patients and mesenchymal stem cells (MSC).METHODS: Cellular senescence was assessed via the proliferation rate, β-galactosidase staining, DNA damage and CKI expression (p21, p16INK4A). Experimental senescence was induced by irradiation.
    RESULTS: The GC prednisolone did not induce an apparent senescence phenotype in FLS, with even higher proliferation, no accumulation of β-galactosidase-positive cells nor DNA damage and reduction in p21mRNA, only showing the enhancement of p16INK4A. Prednisolone did not modify experimental senescence induction in FLS, with no modulation of any senescence parameters. Moreover, prednisolone did not induce a senescence phenotype in MSC: despite high β-galactosidase-positive cells, no reduction in proliferation, no DNA damage and no CKI enhancement was observed.
    CONCLUSIONS: We provide reassuring in vitro data about the use of GC regarding cellular senescence involvement in OA: the GC prednisolone did not induce a senescent phenotype in OA FLS (the proliferation ratio was even higher) and in MSC and did not worsen cellular senescence establishment.
    Keywords:  clinical studies; osteoarthritis; synovial membrane
  13. Aging Cell. 2021 Nov 22. e13523
      The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro-longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the livers of old male mice. This down-regulation of Cisd2 may result in the aging liver exhibiting non-alcoholic fatty liver disease (NAFLD) phenotype. Here, we use Cisd2 transgenic mice to investigate whether maintaining Cisd2 protein at a persistently high level is able to slow down liver aging. Our study identifies four major discoveries. Firstly, that Cisd2 expression attenuates age-related dysregulation of lipid metabolism and other pathological abnormalities. Secondly, revealed by RNA sequencing analysis, the livers of old male mice undergo extensive transcriptomic alterations, and these are associated with steatosis, hepatitis, fibrosis, and xenobiotic detoxification. Intriguingly, a youthful transcriptomic profile, like that of young 3-month-old mice, was found in old Cisd2 transgenic male mice at 26 months old. Thirdly, Cisd2 suppresses the age-associated dysregulation of various transcription regulators (Nrf2, IL-6, and Hnf4a), which keeps the transcriptional network in a normal pattern. Finally, a high level of Cisd2 protein protects the liver from oxidative stress, and this is associated with a reduction in mitochondrial DNA deletions. These findings demonstrate that Cisd2 is a promising target for the development of therapeutic agents that, by bringing about an effective enhancement of Cisd2 expression, will slow down liver aging.
    Keywords:  Cisd2; RNA sequencing; fibrosis; liver aging; non-alcoholic fatty liver disease; oxidative stress; transcriptomics
  14. Front Cell Dev Biol. 2021 ;9 733831
      Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin β3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-β, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.
    Keywords:  ITGB3; TGF-β1; cell senescence; isoliquiritigenin; renal fibrosis
  15. Cells. 2021 Oct 22. pii: 2839. [Epub ahead of print]10(11):
      Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed.
    Keywords:  TGF-β; acetyltransferase p300; cellular senescence; diabetes; heart disease; hypertension; small molecule inhibitors; vascular calcification
  16. Aging Cell. 2021 Nov 23. e13505
      Somatopause refers to the gradual declines in growth hormone (GH) and insulin-like growth factor-1 throughout aging. To define how induced somatopause affects skeletal integrity, we used an inducible GH receptor knockout (iGHRKO) mouse model. Somatopause, induced globally at 6 months of age, resulted in significantly more slender bones in both male and female iGHRKO mice. In males, induced somatopause was associated with progressive expansion of the marrow cavity leading to significant thinning of the cortices, which compromised bone strength. We report progressive declines in osteocyte lacunar number, and increases in lacunar volume, in iGHRKO males, and reductions in lacunar number accompanied by ~20% loss of overall canalicular connectivity in iGHRKO females by 30 months of age. Induced somatopause did not affect mineral/matrix ratio assessed by Raman microspectroscopy. We f ound significant increases in bone marrow adiposity and high levels of sclerostin, a negative regulator of bone formation in iGHRKO mice. Surprisingly, however, despite compromised bone morphology, osteocyte senescence was reduced in the iGHRKO mice. In this study, we avoided the confounded effects of constitutive deficiency in the GH/IGF-1 axis on the skeleton during growth, and specifically dissected its effects on the aging skeleton. We show here, for the first time, that induced somatopause compromises bone morphology and the bone marrow environment.
    Keywords:  Raman microspectroscopy; bone; growth hormone; micro-CT; sexual dimorphism
  17. J Pers Med. 2021 Oct 20. pii: 1050. [Epub ahead of print]11(11):
      This review summarizes the current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the senescence of all somatic cells and stem cells in particular. Basic mechanisms of regulation for circadian genes CLOCK-BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by the finely tuned regulation of transcription and rely on various epigenetic mechanisms including the activation of enhancers/suppressors, acetylation/deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Additionally included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for cell aging, and oncogenesis. Eliminating some of them (for example, Sirt1) accelerates the aging process, while the overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, the main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock and stem cells rejuvenation as part of antiaging therapy are discussed.
    Keywords:  CpG-islands; DNA methylation; aging; circadian clock; epigenetic clock; induced pluripotent stem cells; methylome; reprogramming; senescence
  18. Proc Natl Acad Sci U S A. 2021 Nov 30. pii: e2103585118. [Epub ahead of print]118(48):
      Mitotic errors can activate cyclic GMP-AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2'3'-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.
    Keywords:  cGAS; cancer; chemotherapy; interferon; mitosis
  19. Cells. 2021 Oct 26. pii: 2898. [Epub ahead of print]10(11):
      Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.
    Keywords:  STING; TLR9; extracellular cf-mtDNA; inflammasome; mitochondria; mtDNA
  20. Stem Cell Rev Rep. 2021 Nov 23.
      Biology of aging is an active and rapidly expanding area of biomedical research. Over the years, focus of work in this field has been gradually shifting from studying the effects and symptoms of aging to searching for mechanisms of the aging process. Progress of this work led to an additional shift from looking for "the mechanism" of aging and formulating the corresponding "theories of aging" to appreciation that aging represents a net result of multiple physiological changes and their intricate interactions. It was also shown that mechanisms of aging include nutrient-dependent signaling pathways which have been remarkably conserved in the course of the evolution. Another important development in this field is increased emphasis on searching for pharmacological and environmental interventions that can extend healthspan or influence other aspects of aging. Progress in understanding the key role of aging as a risk factor for chronic disease provides impetus for these studies. Data from the recent pandemic provided additional evidence for the impact of age on resilience. Progress of work in this area also was influenced by major analytical and technological advances, including greatly improved methods for the study of gene expression, protein, lipids, and metabolites profiles, enhanced ability to produce various genetic modifications and novel approaches to assessment of biological age. Progress in research on the biology of aging provides reasons for optimism about the chances that safe and widely applicable anti-aging interventions with significant benefits for both individual and public health will be developed in the not too distant future.
    Keywords:  Aging; Geroscience; Healthspan; Interventions; Lifespan
  21. Cell Metab. 2021 Nov 19. pii: S1550-4131(21)00530-1. [Epub ahead of print]
      Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.
    Keywords:  Cellular senescence; NF-κB; diabetes; fat transplantation; senolytics; xenograft
  22. Aging Cell. 2021 Nov 22. e13522
      The cell-to-cell transfer of α-synuclein (α-Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α-Syn pathology. During this process, extracellular α-Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α-Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α-Syn inhibited the autophagy initiation, as indicated by LC3-II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia-enriched population isolated from α-Syn-overexpressing mice induced by adeno-associated virus (AAV2/9)-encoded wildtype human α-Syn injection into the substantia nigra (SN). Mechanistically, α-Syn led to microglial autophagic impairment through activating toll-like receptor 4 (Tlr4) and its downstream p38 and Akt-mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α-Syn-induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α-Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2cre )-mediated depletion of autophagy-related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α-Syn-overexpressing mice. Taken together, the results suggest that extracellular α-Syn, via Tlr4-dependent p38 and Akt-mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development.
    Keywords:  Parkinson's disease; autophagy; microglia; neuroinflammation; α-synuclein
  23. Aging Cell. 2021 Nov 27. e13488
      Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.
    Keywords:  anti-diabetes drug; biguanide; genetic diversity; healthspan; longevity
  24. Aging Cell. 2021 Nov 24. e13515
      Alzheimer's disease (AD) is characterized by the progressive accumulation of β-amyloid (Aβ)-containing amyloid plaques, and microglia play a critical role in mediating Aβ clearance. Mounting evidence has confirmed that the ability of microglia in clearing Aβ decreased with aging and AD progress, but the underlying mechanisms are unclear. Previously, we have demonstrated that Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with myelin, can decrease adhesion and migration of microglia to fibrils Aβ with aging. However, whether NgR expressed on microglia affect microglia phagocytosis of fibrils Aβ with aging remains unclear. Here, we found that aged but not young microglia showed increased NgR expression and decreased Aβ phagocytosis in APP/PS1 transgenic mice. NgR knockdown APP/PS1 mice showed simultaneous reduced amyloid burden and improved spatial learning and memory, which were associated with increased Aβ clearance. Importantly, Nogo-P4, an agonist of NgR, enhanced the protein level of p-Smad2/3, leading to a significant transcriptional inhibition of CD36 gene expression, which in turn decreased the microglial phagocytosis of Aβ. Moreover, ROCK accounted for Nogo-P4-induced activation of Smad2/3 signaling. Finally, the decreasing effect of NgR on microglial Aβ uptake was confirmed in a mouse model of intra-hippocampal fAβ injection. Our findings suggest that NgR may play an important role in the regulation of Aβ homeostasis, and has potential as a therapeutic target for AD.
    Keywords:  Aβ; NgR; alzheimer's disease; microglia; phagocytosis
  25. Ageing Res Rev. 2021 Nov 21. pii: S1568-1637(21)00275-0. [Epub ahead of print] 101528
      Adult stem cells sustain tissue homeostasis and regeneration; their functional decline is often linked to aging, which is characterized by the progressive loss of physiological functions across multiple tissues and organs. The resident stem cells in skeletal muscle, termed satellite cells, are normally quiescent but activate upon injury to reconstitute the damaged tissue. In this review, we discuss the current understanding of the molecular processes that contribute to the functional failure of satellite cells during aging. This failure is due not only to intrinsic changes but also to extrinsic factors, most of which are still undefined but originate from the muscle tissue microenvironment of the satellite cells (the niche), or from the systemic environment. We also highlight the emerging applications of the powerful single-cell sequencing technologies in the study of skeletal muscle aging, particularly in the heterogeneity of the satellite cell population and the molecular interaction of satellite cells and other cell types in the niche. An improved understanding of how satellite cells communicate with their environment, and how this communication is perturbed with aging, will be helpful for defining countermeasures against loss of muscle regenerative capacity in sarcopenia.
    Keywords:  Aging; niche; rejuvenation; satellite cell; single-cell omics; skeletal muscle regeneration; stem cell
  26. Int J Mol Sci. 2021 Nov 13. pii: 12280. [Epub ahead of print]22(22):
      Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer's disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer's disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.
    Keywords:  DNA; epigenetics; hippocampus; histone; memory; neurodegeneration
  27. Nat Rev Immunol. 2021 Nov 23.
      Ageing leads to profound alterations in the immune system and increases susceptibility to some chronic, infectious and autoimmune diseases. In recent years, widespread application of single-cell techniques has enabled substantial progress in our understanding of the ageing immune system. These comprehensive approaches have expanded and detailed the current views of ageing and immunity. Here we review a body of recent studies that explored how the immune system ages using unbiased profiling techniques at single-cell resolution. Specifically, we discuss an emergent understanding of age-related alterations in innate and adaptive immune cell populations, antigen receptor repertoires and immune cell-supporting microenvironments of the peripheral tissues. Focusing on the results obtained in mice and humans, we describe the multidimensional data that align with established concepts of immune ageing as well as novel insights emerging from these studies. We further discuss outstanding questions in the field and highlight techniques that will advance our understanding of immune ageing in the future.