Quantitative identification of senescent cells in aging and disease

Biran, Anat; Zada, Lior; Karam, Paula Abou; Vadai, Ezra; Roitman, Lior; Ovadya, Yossi; Porat, Ziv; Krizhanovsky, Valery

doi:10.1111/acel.12592

Cited by 320 publications

(259 citation statements)

References 30 publications

(52 reference statements)

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“…Interestingly, the occurrence of apoptosis is diminished in syncytiotrophoblast cells after the 7 th week of human pregnancy, and an increase in BCL-2 expression is observed in these cells as the pregnancy advances (Ishihara et al, 2000). Another possible reason has to do with the morphology of senescent cells, which are characterized by an increase in cell size (Campisi, 2011;Biran et al, 2017). Such a structure would facilitate the expansion of the multinuclear syncytiotrophoblast tissue (estimated at 13-fold between 12 weeks and term), providing the fetus with an increased transfer area (Georgiades et al, 2002;Goldman-Wohl & Yagel, 2014;Cox & Redman, 2017).…”

Section: Discussionmentioning

confidence: 99%

Molecular pathways of senescence regulate placental structure and function

et al. 2019

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The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased. To elucidate the functions of pathways regulating senescence in syncytiotrophoblast, we used dynamic contrast‐enhanced MRI in mice with attenuated senescence programs. This approach revealed an altered dynamics in placentas of p53−/−, Cdkn2a−/−, and Cdkn2a−/−;p53−/− mice, accompanied by histopathological changes in placental labyrinths. Human primary syncytiotrophoblast upregulated senescence markers and molecular pathways associated with cell‐cycle inhibition and senescence‐associated secretory phenotype. The pathways and components of the secretory phenotype were compromised in mouse placentas with attenuated senescence and in human placentas from pregnancies with intrauterine growth restriction. We propose that molecular mediators of senescence regulate placental structure and function, through both cell‐autonomous and non‐autonomous mechanisms.

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Section: Discussionmentioning

confidence: 99%

Molecular pathways of senescence regulate placental structure and function

et al. 2019

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“…Although there is clear evidence that the burden of senescence increases with aging in human CD4 + lymphocytes, kidney epithelia, and skin, the quantification of senescence in vivo is complex because, in spite of the defined set of core features, heterogeneous forms of senescence develop according to different triggers and tissues (Koppelstaetter et al, ; Liu et al, ; Waaijer et al, ). Importantly, none of the characteristic biomarkers described above, including p53, p21, senescence‐associated β‐galactosidase, and SASP factors, are specific to senescence, and p16 Ink4a is not always present (Biran et al, ; Haferkamp et al, ; Laberge et al, ; Noren Hooten & Evans, ; Rodier & Campisi, ). Attempts to quantify senescent cell accumulation in humans from blood biomarkers assume that the SASP proteins dispersed in tissues spill over into circulation and may be detected there.…”

Section: Introductionmentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

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“…In particular, senescence may be initiated by stimuli such as repeated cell division, strong mitogenic signals, oxidative stress, inflammation, and DNA damage [10–19, 23]. Senescent cells have been shown to secrete cytokines, growth factors, extracellular matrix modifiers, and other biological compounds that promote chronic “sterile” inflammation and fibrosis through the so-called senescence-associated secretory phenotype (SASP) [13–19, 23]. Through these processes senescent cells can contribute to tissue injury [10–19, 23].…”

Section: Introductionmentioning

confidence: 99%

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

Chini

Hogan

Warner

et al. 2019

Biochemical and Biophysical Research Communications

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Tissue nicotinamide adenine dinucleotide (NAD+) decline has been implicated in aging. We have recently identified CD38 as a central regulator involved in tissue NAD+ decline during the aging process. CD38 is an ecto-enzyme highly expressed in endothelial and inflammatory cells. To date, the mechanisms that regulate CD38 expression in aging tissues characterized by the presence of senescent cells is not completely understood. Cellular senescence has been described as a hallmark of the aging process and these cells are known to secrete several factors including cytokines and chemokines through their senescent associated secretory phenotype (SASP). Here we investigated if the cellular senescence phenotype is involved in the regulation of CD38 expression and its NADase activity. We observed that senescent cells do not have high expression of CD38. However, the SASP factors secreted by senescent cells induced CD38 mRNA and protein expression and increased CD38-NADase activity in non-senescent cells such as endothelial cells or bone marrow derived macrophages. Our data suggest a link between cellular senescence and NAD+ decline in which SASP-mediated upregulation of CD38 can disrupt cellular NAD+ homeostasis.

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Quantitative identification of senescent cells in aging and disease

Cited by 320 publications

References 30 publications

Molecular pathways of senescence regulate placental structure and function

Molecular pathways of senescence regulate placental structure and function

Measuring biological aging in humans: A quest

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

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