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Cited by 111Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

The DOI matches its Crossref record; 123 of the 123 references it cites were found in a registry or an index.

The right time for senescence

Open access
Paramos-de-Carvalho, Diogo, Jacinto, Antonio, Saúde, Leonor·2021·eLife
DOI 10.7554/elife.72449PMC PMC8580479
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Abstract

Cellular senescence is a highly complex and programmed cellular state with diverse and, at times, conflicting physiological and pathological roles across the lifespan of an organism. Initially considered a cell culture artifact, senescence evolved from an age-related circumstance to an intricate cellular defense mechanism in response to stress, implicated in a wide spectrum of biological processes like tissue remodelling, injury and cancer. The development of new tools to study senescence in vivo paved the way to uncover its functional roles in various frameworks, which are sometimes hard to reconcile. Here, we review the functional impact of senescent cells on different organismal contexts. We provide updated insights on the role of senescent cells in tissue repair and regeneration, in which they essentially modulate the levels of fibrosis and inflammation, discussing how "time" seems to be the key maestro of their effects. Finally, we overview the current clinical research landscape to target senescent cells and contemplate its repercussions on this fast-evolving field.

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Figure 1. The hallmark features of cellular senescence. Cells may be induced to senesce by different stimuli, including telomere erosion, oncogene activation (oncogene-induced senescence [OIS]), DNA damage, oxidative stress, irradiation, chemotherapy, induced pluripotent stem cell (iPSC) reprogramming, developmental cues, and tissue damage. These stresses trigger the upregulation of key cell cycle inhibitors, namely p16INK4a, p21CIP1, p53, p15INK4b, p14ARF, and p27KIP1, leading to a permanent cell cycle arrest (either in G1 or G2 phase). BCL-2 and PI3K/AKT anti-apoptotic pathways also become upregulated, bestowing senescent cells (SCs) with resistance to apoptotic cues. Other phenotypic alterations include an enlarged cell size (up to 2.5 times the normal counterpart) and metabolic changes such as mitochondrial and lysosomal expansion, which increase the production of reactive oxygen species (ROS) as well as the activity of lysosomal senescence-associated β-galactosidase (SA-β-gal, detected at pH 6.0). ROS accumulation induces protein aggregates which crosslink with sugars and lipids and form insoluble lipofuscin aggresomes. Autophagy rate is increased during the early senescence programme but is highly compromised in later stages. SCs are characterized by a complex senescence-associated secretory phenotype (SASP) that comprises a plethora of different growth factors, cytokines, chemokines, proteases, and matrix components. Primary transcriptional activators of the SASP include nuclear factor kappa B (NF-κB), CCAAT/enhancer binding protein β (c/EBPβ), and mammalian target of rapamycin (mTOR). SASP factors, such as IL-6, IL-8, Gro-α, IGFBP-7, and PAI-1, reinforce the senescence programme in an autocrine manner, while others, like ROS, IFN-γ, TGF-β, IL-1α, VEGF, CCL2, and CCL20, induce paracrine senescence in neighbouring cells. Upon the initiation of the senescence programme, the chromatin suffers deep modifications towards the repression of proliferation-related genes and the stimulation of SASP-related genes. This results in the appearance of DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) as well as senescence-associated heterochromatic foci (SAHF). Chromatin alterations are accompanied by a downregulation of lamin B1, a major component of the nuclear lamina, compromising its integrity and leading to the extravasation of chromatin fragments into the cytosol. Cytosolic chromatin fragments (CCFs) are recognized by cyclic GMP-AMP synthase (cGAS) which, in turn, triggers the activation of stimulator of interferon genes (STING). The cGAS-STING pathway stimulates pro-inflammatory SASP responses through upregulation of NF-κB. Recent studies suggest that urokinase-type plasminogen activator receptor (uPAR), a cell-surface protein, is also broadly expressed during senescence. The biomarkers in bold represent the most common hallmark features of cellular senescence. None of these hallmarks is exclusively specific and their manifestation can diverge according to the nature of the senescence trigger, the cell/tissue type and time of the senescence programme.
Figure 1. The hallmark features of cellular senescence. Cells may be induced to senesce by different stimuli, including telomere erosion, oncogene activation (oncogene-induced senescence [OIS]), DNA damage, oxidative stress, irradiation, chemotherapy, induced pluripotent stem cell (iPSC) reprogramming, developmental cues, and tissue damage. These stresses trigger the upregulation of key cell cycle inhibitors, namely p16INK4a, p21CIP1, p53, p15INK4b, p14ARF, and p27KIP1, leading to a permanent cell cycle arrest (either in G1 or G2 phase). BCL-2 and PI3K/AKT anti-apoptotic pathways also become upregulated, bestowing senescent cells (SCs) with resistance to apoptotic cues. Other phenotypic alterations include an enlarged cell size (up to 2.5 times the normal counterpart) and metabolic changes such as mitochondrial and lysosomal expansion, which increase the production of reactive oxygen species (ROS) as well as the activity of lysosomal senescence-associated β-galactosidase (SA-β-gal, detected at pH 6.0). ROS accumulation induces protein aggregates which crosslink with sugars and lipids and form insoluble lipofuscin aggresomes. Autophagy rate is increased during the early senescence programme but is highly compromised in later stages. SCs are characterized by a complex senescence-associated secretory phenotype (SASP) that comprises a plethora of different growth factors, cytokines, chemokines, proteases, and matrix components. Primary transcriptional activators of the SASP include nuclear factor kappa B (NF-κB), CCAAT/enhancer binding protein β (c/EBPβ), and mammalian target of rapamycin (mTOR). SASP factors, such as IL-6, IL-8, Gro-α, IGFBP-7, and PAI-1, reinforce the senescence programme in an autocrine manner, while others, like ROS, IFN-γ, TGF-β, IL-1α, VEGF, CCL2, and CCL20, induce paracrine senescence in neighbouring cells. Upon the initiation of the senescence programme, the chromatin suffers deep modifications towards the repression of proliferation-related genes and the stimulation of SASP-related genes. This results in the appearance of DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) as well as senescence-associated heterochromatic foci (SAHF). Chromatin alterations are accompanied by a downregulation of lamin B1, a major component of the nuclear lamina, compromising its integrity and leading to the extravasation of chromatin fragments into the cytosol. Cytosolic chromatin fragments (CCFs) are recognized by cyclic GMP-AMP synthase (cGAS) which, in turn, triggers the activation of stimulator of interferon genes (STING). The cGAS-STING pathway stimulates pro-inflammatory SASP responses through upregulation of NF-κB. Recent studies suggest that urokinase-type plasminogen activator receptor (uPAR), a cell-surface protein, is also broadly expressed during senescence. The biomarkers in bold represent the most common hallmark features of cellular senescence. None of these hallmarks is exclusively specific and their manifestation can diverge according to the nature of the senescence trigger, the cell/tissue type and time of the senescence programme.CC BY · PubMed Central
Figure 2. A time-gated model for the senescence-associated secretory phenotype (SASP)-mediated biological activities of cellular senescence. The SASP can have a wide range of effects in the surrounding microenvironment, including matrix remodelling, mitogenic signalling, clearance regulation, inflammation, immune modulation, cell proliferation, migration, differentiation and plasticity, as well as vascularization. Depending on the time duration of the senescence programme and the associated SASP response, effects can be beneficial or detrimental. Anti-fibrotic and anti-inflammatory effects are normally correlated to a transient SASP and favour tissue repair and regeneration. A short-term SASP also favours immune-mediated clearance of SCs in order to avoid their accumulation and persistence. Likewise, a transient senescence profile is fundamental for tissue patterning during development. In contrast, long-lasting SASP responses have detrimental pro-fibrotic and pro-inflammatory effects on the microenvironment. Therefore, the persistent accumulation of SCs leads to tissue dysfunction and is associated with chronic inflammation and a broad spectrum of aging-related diseases. Persistent senescence responses can also deplete stem cell progenitor pools, impairing the repair/regenerative capability of affected tissues. In turn, the role of the SASP in cancer is more ambiguous than the rest, as SCs can both promote tumour suppression and tumour progression/invasiveness. However, current knowledge suggests that the SASP suppresses tumour growth in early stages, while supplying pro-tumourigenic chronic inflammatory environments in later stages.
Figure 2. A time-gated model for the senescence-associated secretory phenotype (SASP)-mediated biological activities of cellular senescence. The SASP can have a wide range of effects in the surrounding microenvironment, including matrix remodelling, mitogenic signalling, clearance regulation, inflammation, immune modulation, cell proliferation, migration, differentiation and plasticity, as well as vascularization. Depending on the time duration of the senescence programme and the associated SASP response, effects can be beneficial or detrimental. Anti-fibrotic and anti-inflammatory effects are normally correlated to a transient SASP and favour tissue repair and regeneration. A short-term SASP also favours immune-mediated clearance of SCs in order to avoid their accumulation and persistence. Likewise, a transient senescence profile is fundamental for tissue patterning during development. In contrast, long-lasting SASP responses have detrimental pro-fibrotic and pro-inflammatory effects on the microenvironment. Therefore, the persistent accumulation of SCs leads to tissue dysfunction and is associated with chronic inflammation and a broad spectrum of aging-related diseases. Persistent senescence responses can also deplete stem cell progenitor pools, impairing the repair/regenerative capability of affected tissues. In turn, the role of the SASP in cancer is more ambiguous than the rest, as SCs can both promote tumour suppression and tumour progression/invasiveness. However, current knowledge suggests that the SASP suppresses tumour growth in early stages, while supplying pro-tumourigenic chronic inflammatory environments in later stages.CC BY · PubMed Central

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Metadata

Authors
Paramos-de-Carvalho, D., Jacinto, A., & Saúde, L.
Affiliations
  • University of Lisbon (PT)
  • CEDOC, NOVA Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa
Corresponding author
  • Paramos-de-Carvalho, Diogo
  • Saúde, Leonor
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-11-10
Volume
10
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.72449
PMC
PMC8580479
OpenAlex
W3211748729
Cited by
111
References
123
Citations by year
2026: 8 · 2025: 24 · 2024: 30 · 2023: 34 · 2022: 14
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fundação para a Ciência e a Tecnologia (PD/BD/105770/2014, PTDC/MED-NEU/30428/2017, HR18-00187)
  • "la Caixa" Banking Foundation (HR18-00187)
  • Santa Casa da Misericórdia de Lisboa (MC36-2020 (Melo e Castro Award))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, senolytics, tissue repair, tissue regeneration, fibrosis, inflammation, aging, stress response, cancer
MeSH terms
Aging, Animals, Fibrosis, Humans, Inflammation, Regeneration, Cellular Senescence

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