bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒04‒18
nineteen papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Cell Stem Cell. 2021 Apr 07. pii: S1934-5909(21)00123-5. [Epub ahead of print]
      Decline in hematopoietic stem cell (HSC) function with age underlies limited health span of our blood and immune systems. In order to preserve health into older age, it is necessary to understand the nature and timing of initiating events that cause HSC aging. By performing a cross-sectional study in mice, we discover that hallmarks of aging in HSCs and hematopoiesis begin to accumulate by middle age and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging. Using unbiased approaches, we find that decreased levels of the longevity-associated molecule IGF1 in the local middle-aged BM microenvironment are a factor causing HSC aging. Direct stimulation of middle-aged HSCs with IGF1 rescues molecular and functional hallmarks of aging, including restored mitochondrial activity. Thus, although decline in IGF1 supports longevity, our work indicates that this also compromises HSC function and limits hematopoietic health span.
    Keywords:  IGF1; aging; healthspan; hematopoiesis; hematopoietic stem cell; lineage bias; metabolism; microenvironment; middle age; niche
    DOI:  https://doi.org/10.1016/j.stem.2021.03.017
  2. Front Cell Dev Biol. 2021 ;9 645593
      Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
    Keywords:  DNA damage response (DDR); DREAM complex; cell cycle arrest; cellular senescence; senescence associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.3389/fcell.2021.645593
  3. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00018-X. [Epub ahead of print]150 335-363
      Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.
    Keywords:  Aging; Apoptosis; Autophagy; Lifespan; Metabolism; Senescence; Senolytics; mTOR
    DOI:  https://doi.org/10.1016/bs.acr.2021.02.002
  4. Front Cell Dev Biol. 2021 ;9 641315
      SIRT6 belongs to the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Its function is similar to the Silent Information Regulator 2 (SIR2), which prolongs lifespan and regulates genomic stability, telomere integrity, transcription, and DNA repair. It has been demonstrated that increasing the sirtuin level through genetic manipulation extends the lifespan of yeast, nematodes and flies. Deficiency of SIRT6 induces chronic inflammation, autophagy disorder and telomere instability. Also, these cellular processes can lead to the occurrence and progression of cardiovascular diseases (CVDs), such as atherosclerosis, hypertrophic cardiomyopathy and heart failure. Herein, we discuss the implications of SIRT6 regulates multiple cellular processes in cell senescence and aging-related CVDs, and we summarize clinical application of SIRT6 agonists and possible therapeutic interventions in aging-related CVDs.
    Keywords:  SIRT6; autophagy; cardiovascular diseases; oxidative stress; senescence
    DOI:  https://doi.org/10.3389/fcell.2021.641315
  5. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00007-5. [Epub ahead of print]150 113-145
      Both senescence and autophagy have been strongly linked to aging and also cancer development. Numerous molecular, cellular, and physiological changes are known to correlate with an increasing age, yet our understanding of what underlies these changes or how they combine to give rise to the various pathologies associated with aging is still unclear. Levels of autophagy activity are known to decrease with advancing age, in a variety of organisms including mammals. Whereas senescent cells are known to accumulate in our bodies with age. Herein we review evidence from some elegant genetic mouse models linking senescence and also autophagy to aging and cancer. It is especially interesting to note the convergence in the pathological phenotypes of these two processes, senescence and autophagy, in these mouse models.
    Keywords:  Aging; Autophagy; Cancer; Cellular senescence; Mouse models
    DOI:  https://doi.org/10.1016/bs.acr.2021.02.001
  6. Trends Endocrinol Metab. 2021 Apr 13. pii: S1043-2760(21)00071-0. [Epub ahead of print]
      Pathologic angiogenesis causes blindness in many eye diseases. Crespo-Garcia, Tsuruda, and Dejda et al. employed bioinformatics to characterize cell senescence as a primary factor in the common pathogenesis of retinopathies. They validated their findings using human and mouse retina with proliferative retinopathy. Clearance of senescent cells suppressed neovessel growth.
    Keywords:  endothelial cells; metabolism; neovascularization; retinal angiogenesis; senescence
    DOI:  https://doi.org/10.1016/j.tem.2021.03.010
  7. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00001-4. [Epub ahead of print]150 285-334
      Senescence is a cellular state which can be viewed as a stress response phenotype implicated in various physiological and pathological processes, including cancer. Therefore, it is of fundamental importance to understand why and how a cell acquires and maintains a senescent phenotype. Direct evidence has pointed to the homeostasis of the endoplasmic reticulum whose control appears strikingly affected during senescence. The endoplasmic reticulum is one of the sensing organelles that transduce signals between different pathways in order to adapt a functional proteome upon intrinsic or extrinsic challenges. One of these signaling pathways is the Unfolded Protein Response (UPR), which has been shown to be activated during senescence. Its exact contribution to senescence onset, maintenance, and escape, however, is still poorly understood. In this article, we review the mechanisms through which the UPR contributes to the appearance and maintenance of characteristic senescent features. We also discuss whether the perturbation of the endoplasmic reticulum proteostasis or accumulation of misfolded proteins could be possible causes of senescence, and-as a consequence-to what extent the UPR components could be considered as therapeutic targets allowing for the elimination of senescent cells or altering their secretome to prevent neoplastic transformation.
    Keywords:  Aging; Endoplasmic reticulum; Homeostasis; Secretome; Senescence; Unfolded protein response
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.001
  8. Front Cardiovasc Med. 2021 ;8 658400
      The vascular endothelium occupies a catalog of functions that contribute to the homeostasis of the cardiovascular system. It is a physically active barrier between circulating blood and tissue, a regulator of the vascular tone, a biochemical processor and a modulator of coagulation, inflammation, and immunity. Given these essential roles, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related diseases of the heart and arteries, globally termed cardiovascular diseases (CVD). An example would be ischemic heart disease (IHD), which is the main cause of death from CVD. We have made phenomenal advances in treating CVD, but the aging endothelium, as it senesces, always seems to out-run the benefits of medical and surgical therapies. Remarkably, many epidemiological studies have detected a correlation between a flavonoid-rich diet and a lower incidence of mortality from CVD. Quercetin, a member of the flavonoid class, is a natural compound ubiquitously found in various food sources such as fruits, vegetables, seeds, nuts, and wine. It has been reported to have a wide range of health promoting effects and has gained significant attention over the years. A growing body of evidence suggests quercetin could lower the risk of IHD by mitigating endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis, accumulation of senescent endothelial cells, and endothelial-mesenchymal transition (EndoMT). In this review, we will explore these pathophysiological cascades and their interrelation with endothelial dysfunction. We will then present the scientific evidence to quercetin's anti-atherosclerotic, anti-hypertensive, senolytic, and anti-EndoMT effects. Finally, we will discuss the prospect for its clinical use in alleviating myocardial ischemic injuries in IHD.
    Keywords:  aging; atherosclerosis; endothelial (dys)function; flavonoids; hypertension; ischemia-reperfusion; quercetin; senescence
    DOI:  https://doi.org/10.3389/fcvm.2021.658400
  9. Stem Cells. 2021 Apr 13.
      Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.
    Keywords:  Cdc42; aging; hematopoietic stem cell; niche; osteopontin; rejuvenation
    DOI:  https://doi.org/10.1002/stem.3372
  10. FASEB J. 2021 May;35(5): e21558
      Aging is accompanied by chronic, low-grade systemic inflammation, termed inflammaging, a main driver of age-associated diseases. Such sterile inflammation is typically characterized by elevated levels of pro-inflammatory mediators, such as cytokines, chemokines and reactive oxygen species causing organ damage. Lipid mediators play important roles in the fine-tuning of both the promotion and the resolution of inflammation. Yet, it remains unclear how lipid mediators fit within the concept of inflammaging and how their biosynthesis and function is affected by aging. Here, we provide comprehensive signature profiles of inflammatory markers in organs afflicted with inflammation of young and old C57BL/6 mice. We reveal an organ-specific footprint of inflammation-related cytokines, chemokines and lipid mediators, which are distinctively affected by aging. While some organs are characterized by a pronounced pro-inflammatory microenvironment and impaired resolution during aging, others display elevated levels of pro-resolving mediators or an overall decrease in inflammatory signaling. Our results demonstrate that it proves difficult to establish a unifying concept for alterations of immunomodulatory mediators as consequence of aging and that organ specificity needs to be considered. Moreover, our data imply that inclusion of lipid mediators into the concept of inflammaging provides a comprehensive tool to characterize the inflammatory microenvironment during aging on a broader and yet, more detailed scope.
    Keywords:  aging; cytokines; inflammation; lipid mediators; resolution
    DOI:  https://doi.org/10.1096/fj.202002684R
  11. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00004-X. [Epub ahead of print]150 209-247
      Autophagy is an evolutionarily conserved process necessary to maintain cell homeostasis in response to various forms of stress such as nutrient deprivation and hypoxia as well as functioning to remove damaged molecules and organelles. The role of autophagy in cancer varies depending on the stage of cancer. Cancer therapeutics can also simultaneously evoke cancer cell senescence and ploidy increase. Both cancer cell senescence and polyploidization are reversible by depolyploidization giving rise to the progeny. Autophagy activation may be indispensable for cancer cell escape from senescence/polyploidy. As cancer cell polyploidy is proposed to be involved in cancer origin, the role of autophagy in polyploidization/depolyploidization of senescent cancer cells seems to be crucial. Accordingly, this review is an attempt to understand the complicated interrelationships between reversible cell senescence/polyploidy and autophagy.
    Keywords:  Autophagy; Cancer life cycle; Cancer origin; Polyploidization/depolyploidization; Therapy-induced senescence; mTOR
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.004
  12. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00006-3. [Epub ahead of print]150 249-284
      The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA approval of inhibitors of DNA repair, and targeting innate immunity to enhance the efficacy of DNA-damaging agents have gained much attention. Yet, inherent or acquired resistance against DNA-damaging therapies persists as a fundamental drawback. While cancer eradication by causing cancer cell death through induction of apoptosis is the ultimate goal of anti-cancer treatments, autophagy and senescence are two major cellular responses induced by clinically tolerable doses of DNA-damaging therapies. Unlike apoptosis, autophagy and senescence can act as both pro-tumorigenic as well as tumor suppressive mechanisms. DNA damage-induced senescence is associated with a pro-inflammatory secretory phenotype, which contributes to reshaping the tumor- immune microenvironment. Moreover, PTEN (phosphatase and tensin homolog) is a tumor supressor deleted in many tumors, and has been implicated in both senescence and autophagy. This review presents an overview of the literature on the regulation and consequences of DNA damage- induced senescence in cancer cells, with a specific focus on autophagy and PTEN. Both autophagy and senescence occur concurrently in the same cells in response to DNA damaging agents. However, a deterministic relationship between these fundamental processes has been controversial. We present experimental evidence obtained with tumor cells, with a prime focus on two models of cancer, prostate and lung. A better understanding of mechanisms associated with DNA damage-induced cellular senescence is central to fully exploit the potential of DNA-damaging agents against cancer.
    Keywords:  Autophagy; DNA damage response; DNA repair; Lung cancer; PTEN; Prostate cancer; Radiotherapy; Senescence; TMPRSS2-ERG fusion gene; USP14
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.006
  13. Elife. 2021 04 13. pii: e62293. [Epub ahead of print]10
      Aging is associated with complex molecular and cellular processes that are poorly understood. Here we leveraged the Tabula Muris Senis single-cell RNA-seq data set to systematically characterize gene expression changes during aging across diverse cell types in the mouse. We identified aging-dependent genes in 76 tissue-cell types from 23 tissues and characterized both shared and tissue-cell-specific aging behaviors. We found that the aging-related genes shared by multiple tissue-cell types also change their expression congruently in the same direction during aging in most tissue-cell types, suggesting a coordinated global aging behavior at the organismal level. Scoring cells based on these shared aging genes allowed us to contrast the aging status of different tissues and cell types from a transcriptomic perspective. In addition, we identified genes that exhibit age-related expression changes specific to each functional category of tissue-cell types. Altogether, our analyses provide one of the most comprehensive and systematic characterizations of the molecular signatures of aging across diverse tissue-cell types in a mammalian system.
    Keywords:  aging; computation; computational biology; mouse; single cell; systems biology
    DOI:  https://doi.org/10.7554/eLife.62293
  14. Adv Cancer Res. 2021 ;pii: S0065-230X(21)00002-6. [Epub ahead of print]150 1-74
      Tumor cells can undergo diverse responses to cancer therapy. While apoptosis represents the most desirable outcome, tumor cells can alternatively undergo autophagy and senescence. Both autophagy and senescence have the potential to make complex contributions to tumor cell survival via both cell autonomous and cell non-autonomous pathways. The induction of autophagy and senescence in tumor cells, preclinically and clinically, either individually or concomitantly, has generated interest in the utilization of autophagy modulating and senolytic therapies to target autophagy and senescence, respectively. This chapter summarizes the current evidence for the promotion of autophagy and senescence as fundamental responses to cancer therapy and discusses the complexity of their functional contributions to cell survival and disease outcomes. We also highlight current modalities designed to exploit autophagy and senescence in efforts to improve the efficacy of cancer therapy.
    Keywords:  Apoptosis; Autophagy; Cancer; Chemotherapy; Cytoprotective; Dormancy; Durable growth arrest; Radiation; SASP; Senescence; Senolytics
    DOI:  https://doi.org/10.1016/bs.acr.2021.01.002
  15. Biochem Pharmacol. 2021 Apr 12. pii: S0006-2952(21)00159-3. [Epub ahead of print] 114563
      Aging is a multifactorial process likely stemming from damage accumulation and/or a decline in maintenance and repair mechanisms in the organisms that eventually determine their lifespan. In our review, we focus on the morphological and functional alterations that the aging brain undergoes affecting sleep and the circadian clock in both human and rodent models. Although both species share mammalian features, differences have been identified on several experimental levels, which we outline in this review. Additionally, we delineate some challenges on the preferred analysis and we suggest that a uniform route is followed so that findings can be smoothly compared. We conclude by discussing potential interventions and highlight the influence of physical exercise as a beneficial lifestyle intervention, and its effect on healthy aging and longevity. We emphasize that even moderate age-matched exercise is able to ameliorate several aging characteristics as far as sleep and circadian rhythms are concerned, independent of the species studied.
    Keywords:  Aging; Circadian clock; Physical exercise; Rodent models; Sleep
    DOI:  https://doi.org/10.1016/j.bcp.2021.114563
  16. Ageing Res Rev. 2021 Apr 13. pii: S1568-1637(21)00090-8. [Epub ahead of print] 101343
      The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns or residing at high altitudes, may impart favorable effects on aging and mortality. Moreover, controlled hypoxia exposure may represent a treatment strategy for age-related neurological disorders. This review discusses evidence of hypoxia's beneficial vs. detrimental impacts on the aging brain and the molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search on the effects of hypoxia/altitude on brain aging, and detailed analysis of all identified studies directly comparing brain responses to hypoxia in young vs. aged humans or rodents. Special attention is directed toward the risks vs. benefits of hypoxia exposure to the elderly, and potential therapeutic applications of hypoxia for neurodegenerative diseases. Finally, important questions for future research are discussed.
    Keywords:  HIF; aging; dementia; hippocampus; intermittent hypoxia; mitochondria
    DOI:  https://doi.org/10.1016/j.arr.2021.101343
  17. Cell Signal. 2021 Apr 13. pii: S0898-6568(21)00095-4. [Epub ahead of print]84 110007
      Chemotherapy-induced senescent cancer cells secrete several factors in their microenvironment called SASP. Accumulated evidence states that SASP is responsible for some of the harmful effects of chemotherapy such as drug resistance and the induction of cancer cell proliferation, migration, and invasion. Therefore, to develop senolytic and/or senomorphic drugs, targeting the senescent cells gains importance as a new strategy for preventing the damage that senescent cancer cells cause. In the current work, we evaluated whether Rho/Rho kinase pathway has the potential to be used as a target pathway for the development of senolytic and/or senomorphic drugs in doxorubicin-induced senescent cancer cell lines. We have determined that inhibition of Rho/Rho kinase pathway with CT04 and Y27632 reduced the secretory activity of senescent cancer cells and changed the composition of SASP. Our results indicate that ROCK 2 isoform was responsible for these observed effects on the SASP. In addition, non-senescent cancer cell proliferation and migration accelerated by senescent cells were set back to the pre-induction levels after ROCK inhibition. Moreover, contrary to the previous observations, another important finding of the current work is that senescent HeLa and A549 cells did not engulf the non-senescent HeLa, A549 cells, and non-cancer HUVEC. These results indicate that ROCK inhibitors, in particular ROCK 2 specific inhibitors, have the potential to be developed as novel senomorphic drugs. In addition, we found that all senescent cancer cells do not share the same engulfment ability, and this process should not be generalized.
    Keywords:  Chemotherapy-induced senescence; Rho/ROCK pathway; Senescence-associated secretory phenotype; Senescent cell secretome; Senotherapeutic
    DOI:  https://doi.org/10.1016/j.cellsig.2021.110007
  18. Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00299-0. [Epub ahead of print]35(2): 108985
      Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
    Keywords:  Pink1; aging; autophagy; cognitive function; dietary spermidine; memory; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2021.108985