Replicative senescence: a critical review

doi:10.1016/j.mad.2004.07.010

Mechanisms of Ageing and Development

Volume 125, Issues 10–11, October–November 2004, Pages 827-848

This critical review is dedicated to the memory of Arun Roy, scientist, scholar and friend.

https://doi.org/10.1016/j.mad.2004.07.010 Get rights and content

Abstract

Human cells in culture have a limited proliferative capacity. After a period of vigorous proliferation, the rate of cell division declines and a number of changes occur in the cells including increases in size, in secondary lysosomes and residual bodies, nuclear changes and a number of changes in gene expression which provide biomarkers for senescence. Although human cells in culture have been used for over 40 years as models for understanding the cellular basis of aging, the relationship of replicative senescence to aging of the organism is still not clear. In this review, we discuss replicative senescence in the light of current information on signal transduction and mitogenesis, cell stress, apoptosis, telomere changes and finally we discuss replicative senescence as a model of aging in vivo.

Section snippets

Introduction: the senescent phenotype

Cultures of diploid human fibroblasts can replicate only a finite number of times. During the proliferative lifespan of fibroblast cultures there is an initial phase of rapid proliferation followed by a period of declining replicative frequency; ultimately, cultures become senescent and are incapable of further proliferation. Replicative senescence is not specific to human fibroblasts; it has been described in cultures established from chickens as well as cell lines derived from numerous

Transduction of mitogenic signals at different stages of the replicative life history

Cellular responses to environmental cues are mediated via activation of complex signaling cascades that invariably induce changes in gene expression. For example, the first event in a cascade initiated by growth factors is the activation of their cognate receptors, followed by formation of multi-protein complexes, phospholipid turnover, calcium mobilization and activation of protein kinases, phosphatases and transcription factors. In response to mitogenic signals, the machinery of nuclear

Cellular stress and replicative senescence

With increasing replicative age, cells become more sensitive to environmental stressors, in part because of changes in gene expression. For example, the increased sensitivity of senescent fibroblasts to hyperthermic exposure can be attributed to their reduced expression of some heat shock proteins such as HSP 70, HSP 90 and HSP 28 (Luce and Cristofalo, 1992, Cristofalo et al., 1989a, Cristofalo et al., 1989b). Senescent fibroblasts also show a reduced response of the transcription factor NF-κB

Apoptosis and replicative senescence

Necrosis occurs when a cell loses control of its own ionic flow because of disruption in membrane integrity, loss of energy reserves, or others causes. Calcium then enters and precipitates the proteins, lactate accumulates and usually, because of osmotic changes, the cell lyses and releases its content to the extra-cellular environment (Trump and Berezesky, 1992).

Apoptosis, conversely, is a highly conserved process of programmed cell death which ensures that the entire content of a dying cell

Telomerase expression in normal and pathological conditions

Telomeres are nucleoprotein complexes at the ends of the chromosomes. In humans the telomeric DNA is composed of several kilo-bases of TTAGGG double-stranded repeats and of 5–400 bases of TTAGGG repeats in a 3′ single-stranded overhang (Hemann and Greider, 1999). When telomeric DNA is purified from its endogenously bound proteins, a fraction of the 3′ single-stranded overhang is found tucked back into the double-stranded telomeric tract forming a loop called the “T-loop” (Griffith et al., 1999,

Replicative senescence as a model of aging in vivo

The limited replicative lifespan of fibroblasts derived from various human tissues is commonly studied as a model of biological aging (Hayflick, 1965, Hayflick and Moorhead, 1961). There is little doubt that organismic failures in aging have a cellular basis. Replicative senescence in culture fits the description and definition of cell senescence; with subcultivation there is a gradual loss of proliferative capacity in the population until the culture can no longer be subcultivated. In vivo

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A study on the anti-senescent effects of flavones derived from Prinsepia utilis Royle seed residue
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Prinsepia utilis Royle, also known as the Anas fruit, is a unique perennial woody oil plant from Yunnan Province, China. In the ancient texts of Dongba sutras and Yunnan Southern Materia Medica, it has been documented that the local Naxi, Tibetan, and Mosuo communities extensively utilize the root and leaf fruits of green thorns for various purposes. These include treating mild-to-moderate specific dermatitis, moisturising the skin, providing protection against UV damage, aiding childbirth in pregnant women, safeguarding stomach health, reducing the risk of arteriosclerosis, and delaying aging.
In this study, leftover residues from oil extraction were efficiently reused, and flavonoids were identified during subsequent extraction and separation processes. The anti-senescent effects of flavonoids in P. utilis Royle have not been systematically studied. Therefore, the objective of this study was to explore the anti-senescent properties of the flavonoids obtained from P. utilis Royle.
First, HPLC and other analytical techniques were used to identify the components of the P. utilis Royle flavonoid (PURF). Next, DPPH, hydroxyl radicals, superoxide anion O²⁻, collagenase, and elastase were initially detected using in vitro biochemical assays. To examine its antioxidant properties, a zebrafish model was used, and to confirm its anti-senescent effects, a d-galactose-induced mouse aging model was employed. The anti-senescent mechanism of PURF was examined using a natural senescence HFF model. Furthermore, the anti-senescent target was confirmed using a 3D full T-Skin™ model.
In vitro biochemical assays demonstrated that flavones exhibited potent antioxidant activity and anti-senescent potential by inhibiting DPPH, hydroxyl radicals, superoxide anion O²⁻, collagenase, and elastase. It significantly enhanced the antioxidant effect on zebrafish while suppressing ROS and inflammatory injury, up-regulating COL1A1, COL3A1, AMPK, and mTOR gene expression and down-regulating MMP-9, TGF-β, p21, and p16 gene expression suggesting its potential anti-senescent ability. Findings from the D-galactose-induced aging mouse model showed that PURF greatly increased SOD levels, while simultaneously decreasing HYP and MDA levels. In addition, when PURF was given to the HFF cell and 3D full T-Skin™ model, consistent trends were observed in gene and protein expression, with up-regulation of COL1A1, COL3A1, AMPK, and mTOR genes and down-regulation of TGF-β, MMP-1, MMP-9, p21, and p16 genes. Therefore, these preliminary findings indicate that flavones can modulate AMPK/mTOR/TGF-β signalling pathways to exert its influence.
The kernel residue of natural P. utilis Royle oil extracted from Yunnan province was previously considered agricultural waste, but we successfully extracted and isolated its flavonoid components. Our preliminary studies demonstrated its potential as an environmentally friendly anti-senescent raw material.
Short airway telomeres are associated with primary graft dysfunction and chronic lung allograft dysfunction
2023, Journal of Heart and Lung Transplantation
Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD.
In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 to 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age.
Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (p = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16-3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics.
PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.
Cellular Senescence
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The process of cell senescence was initially described in cell culture when it was shown that normal cells have a finite proliferative potential. Accumulated cell divisions trigger a stable growth arrest, and initially this was considered a reflection of the process of aging. Later, the same process was shown to occur in response to cellular stress, particularly after oncogene activation. Recent advances in this field now place cell senescence not only acting as a stress response to protect the cell from damage but also in physiological conditions, providing new ideas to understand the origin and the role of senescence.
Sargahydroquinoic acid (SHQA) suppresses cellular senescence through Akt/mTOR signaling pathway
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Citation Excerpt :
Consistently, we observed that upon exposure to low-dose H2O2, the protein expression levels of p53, p21, and p16 and the abundance of SA-β-Gal positive cells were elevated in HUVECs; meanwhile, the pretreatment of SHQA at 2.0 μM significantly suppressed their elevations, which suggested the ability of SHQA to repress the oxidative stress-induced senescence in HUVECs. Primary cells have a limited proliferative capacity and after finite times of division, cells become senescent and lose the capacity of proliferation (Cristofalo et al., 2004). In the present study, the long term supplementation of SHQA also notably delayed the growth arrest and lessened the raise of senescence biomarkers, including p53, p21, p16 and SA-β-Gal activity of HUVECs.
The effects of sargahydroquinoic acid (SHQA) on cellular senescence and the underlying mechanisms were investigated using human umbilical vascular endothelial cells (HUVECs).
SHQA or DMSO was supplemented into the medium. Low dose of H₂O₂ was used to induce premature senescence. Replicative senescence was achieved by continuously culturing cells until they reached a plateau phase. Senescence biomarkers, including p53, p21, and p16 proteins, and SA-β-Gal activity were measured.
Pretreatment of SHQA significantly suppressed the oxidative stress-induced protein expression of p53, p21, and p16, as well as the activity of SA-β-Gal. Additionally, SHQA also delayed the replicative senescence as indicated by an increased population doubling number, reduced protein expression of p53, p21, and p16, as well as a decreased SA-β-Gal activity. SHQA inhibited the phosphorylation of Akt, mTOR, and downstream targets of mTOR, such as p-S6K, which was elevated by premature senescence and replicative senescence. In the absence of senescence stimuli, SHQA also inhibited the Akt/mTOR signaling pathway and promoted autophagy.
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ReviewReplicative senescence: a critical review

Abstract

Section snippets

Introduction: the senescent phenotype

Transduction of mitogenic signals at different stages of the replicative life history

Cellular stress and replicative senescence

Apoptosis and replicative senescence

Telomerase expression in normal and pathological conditions

Replicative senescence as a model of aging in vivo

Exp. Cell Res.

Exp. Cell Res.

J. Biol. Chem.

Free Radic. Biol. Med.

Exp. Cell Res.

Cell

Exp. Cell Res.

Free Radic. Biol. Med.

Exp. Cell Res.

Cell

J. Ultrastruct. Res.

Exp. Gerontol.

Cell

Eur. J. Cancer

Exp. Gerontol.

Arch. Biochem. Biophys.

Exp. Gerontol.

Int. J. Biochem. Cell Biol.

Lancet

Cell

Mutat. Res.

Biochem. Biophys. Res. Commun.

Exp. Gerontol.

J. Biol. Chem.

FEBS Lett.

Mech. Ageing Dev.

Biochimie

Exp. Cell Res.

Exp. Gerontol.

Mech. Ageing Dev.

Exp. Cell Res.

J. Biol. Chem.

Exp. Gerontol.

Cell

Exp. Cell Res.

Exp. Cell Res.

Biochem. Pharmacol.

Exp. Cell Res.

Free. Radic. Biol. Med.

Exp. Cell Res.

J. Biol. Chem.

Free. Radic. Biol. Med.

Exp. Gerontol.

Hyperoxia inhibits proliferation of cultured rat tracheal smooth muscle cells

Am. J. Physiol.

Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts

Proc. Natl. Acad. Sci. U.S.A.

Oxidative stress and superoxide dismutase in development, aging and gene regulation

Age

Effects of oxygen on the antioxidant responses of normal and transformed cells

Exp. Cell Res.

Expression and regulation of SOD activity in human skin fibroblasts from donors of different ages

J. Cell. Physiol.

Telomere length predicts replicative capacity of human fibroblasts

Proc. Natl. Acad. Sci. U.S.A.

Effect of n-3 fatty acid supplementation on lipid peroxidation and protein aggregation in rat erythrocyte membranes

Lipids

Review
Replicative senescence: a critical review