Cellular senescence and tumor promotion: Is aging the key?

Loaiza, Natalia; Demaria, Marco

doi:10.1016/j.bbcan.2016.01.007

Cited by 72 publications

(88 citation statements)

References 134 publications

(221 reference statements)

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“…Within the senescence-associated signature of fibroblasts, multiple genes related to transcription and RNA synthesis were downregulated, while genes involved in vesicle transport were upregulated (Figure 1B). Among the main gene ontology (GO) pathways [19, 20] showing altered in senescent cells, “chromatin organization,” “DNA repair,” “membrane trafficking,” and “activation of NF-kappaB” were notable for their known links to senescence and aging (Figure 1C) (Figure 1C) [1, 10, 21, 22]. …”

Section: Resultsmentioning

confidence: 99%

“… SUMMARY Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9].…”

mentioning

confidence: 99%

“…Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A ( CDKN2A ) and p21CIP1 ( CDKN1A ), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 ( LMNB1 ) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10].…”

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confidence: 99%

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Unmasking Transcriptional Heterogeneity in Senescent Cells

et al. 2017

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SUMMARY Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Unmasking Transcriptional Heterogeneity in Senescent Cells

et al. 2017

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“…They described this phenomenon as “cellular senescence” and postulated its importance during aging (Hayflick & Moorhead, 1961). Subsequent studies demonstrated that senescent cells gradually accumulate with increasing age in various organisms (Loaiza & Demaria, 2016). During aging, senescent cells impair cellular turnover and tissue regeneration due to their inability to proliferate, and stimulate a pro‐disease environment by the chronic secretion of various pro‐inflammatory and tissue‐remodeling factors, a phenotype called Senescence‐Associated Secretory Phenotype (SASP; Loaiza & Demaria, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Senescent cells are visible during aging and at sites of age‐related pathologies in both human and mice (Loaiza & Demaria, 2016; Childs et al., 2017). The use of genetic models showed that elimination of senescent cells can reduce age‐related pathologies and improve health span and lifespan (Demaria et al., 2017; Jeon et al., 2017; Baker et al., 2016).…”

Section: Introductionmentioning

confidence: 99%

The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon

et al. 2018

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SummaryCalorie restriction (CR) is an effective strategy to delay the onset and progression of aging phenotypes in a variety of organisms. Several molecular players are involved in the anti‐aging effects of CR, but mechanisms of regulation are poorly understood. Cellular senescence—a cellular state of irreversible growth arrest—is considered a basic mechanism of aging. Senescent cells accumulate with age and promote a number of age‐related pathologies. Whether environmental conditions such as diet affect the accumulation of cellular senescence with age is still unclear. Here, we show that a number of classical transcriptomic markers of senescent cells are reduced in adult but relatively young mice under CR. Moreover, we demonstrate that such senescence markers are not induced in the colon of middle‐age human volunteers under CR in comparison with age‐matched volunteers consuming normal Western diets. Our data support the idea that the improvement in health span observed in different organisms under CR might be partly due to a reduction in the number of senescent cells.

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Repurposing drugs to fight aging: The difficult path from bench to bedside

Vaiserman

Koliada

Lushchak

et al. 2020

Medicinal Research Reviews

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The steady rise in life expectancy occurred across all developed countries during the last century. This demographic trend is, however, not accompanied by the same healthspan extension. This is since aging is the main risk factor for all age‐associated pathological conditions. Therefore, slowing the rate of aging is suggested to be more efficient in preventing or delaying age‐related diseases than treat them one by one, which is the common approach in a current pharmacological disease‐oriented paradigm. To date, a variety of medications designed to treat particular pathological conditions have been shown to exhibit pro‐longevity effects in different experimental models. Among them, there are many commonly used prescription and over‐the‐counter pharmaceuticals such as metformin, rapamycin, aspirin, statins, melatonin, vitamin antioxidants, etc. All of them are being increasingly investigated in preclinical and clinical trials with the aim of determine whether they have potential for extension of human healthspan. The results from these trials are frequently inconclusive and fall short of initial expectations, suggesting that innovative research ideas and additional translational steps are required to overcome obstacles for implementation of such approaches in clinical practice. In this review, recent advances and challenges in the field of repurposing widely used conventional pharmaceuticals to target the aging process are summarized and discussed.

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Cellular senescence and tumor promotion: Is aging the key?

Cited by 72 publications

References 134 publications

Unmasking Transcriptional Heterogeneity in Senescent Cells

Unmasking Transcriptional Heterogeneity in Senescent Cells

The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon

Repurposing drugs to fight aging: The difficult path from bench to bedside

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