Puzzles, promises and a cure for ageing

Vijg, Jan; Campisi, Judith

doi:10.1038/nature07216

Cited by 341 publications

(252 citation statements)

References 73 publications

(84 reference statements)

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“…Cellular senescence is an intricate and multifactorial phenomenon of growth arrest and distorted function (Vijg and Campisi 2008), which has been recognized as an important feature during tumor suppression and a contributor to aging . Various pathways have been proposed to explain senescence induction; the most studied is replicative senescence due to telomere shortening (Cristofalo et al 2004;Rodier et al 2009Rodier et al , 2010, along with other prematureinduced senescence provoked by diverse stimuli such as oxidative stress and radiation exposure (Toussaint et al 2000;López-Diazguerrero et al 2006;Lee et al 2011), autophagy impairment (Kang et al 2011;Fujii et al 2012), proteasome inhibition (Torres et al 2006;Bitto et al 2010), and oncogenic stress (Bartkova et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Maciel-Barón

Morales-Rosales

Aquino-Cruz

et al. 2016

AGE

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Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as an important feature during tumor suppression mechanisms and a contributor to aging. Senescent cells have an altered secretion pattern called Senescence-Associated Secretory Phenotype (SASP) that comprises a complex mix of factors including cytokines, growth factors, chemokines, and matrix metalloproteinases. SASP has been related with local inflammation that leads to cellular transformation and neurodegenerative diseases. Various pathways for senescence induction have been proposed; the most studied is replicative senescence due to telomere attrition called replicative senescence (RS). However, senescence can be prematurely achieved when cells are exposed to diverse stimuli such as oxidative stress (stressinduced premature senescence, SIPS) or proteasome inhibition (proteasome inhibition-induced premature senescence, PIIPS). SASP has been characterized in RS and SIPS but not in PIIPS. Hence, our aim was to determine SASP components in primary lung fibroblasts obtained from CD-1 mice induced to senescence by PIIPS and compare them to RS and SIPS. Our results showed important variations in the 62 cytokines analyzed, while SIPS and RS showed an increase in the secretion of most cytokines, and in PIIPS only 13 were incremented. Variations in glutathione-redox balance were also observed in SIPS and RS, and not in PIIPS. All senescence types SASP displayed a pro-inflammatory profile and increased proliferation in L929 mice fibroblasts exposed to SASP. However, the behavior observed was not exactly the same, suggesting that the senescence induction pathway might encompass dissimilar responses in adjacent cells and promote different outcomes.

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Section: Discussionmentioning

confidence: 99%

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Maciel-Barón

Morales-Rosales

Aquino-Cruz

et al. 2016

AGE

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“…The accumulation of damage by biological molecules has long been recognised as a potential contributing factor to functional decline in ageing organisms (Bailey 2001;Partridge and Gems 2002;Vijg and Campisi 2008). The low turnover of extracellular structural proteins in particular, as discussed in the previous section, exposes these macromolecular assemblies to degradation by enzymatic, chemical and biophysical mechanisms.…”

Section: Degradationmentioning

confidence: 99%

“…The accumulation of oxidative damage by biological macromolecules, including lipids, proteins and nucleic acids is thought to play an important role in the ageing process (Partridge and Gems 2002;Vijg and Campisi 2008). Reactive oxygen species (ROS) (Chakravarti and Chakravarti 2007), which are generated either as products of normal metabolism (Haenold et al 2005) or by interaction with environmental factors such as UV radiation (Yaar and Gilchrest 2007), are the primary agents of protein oxidation.…”

Section: Degradationmentioning

confidence: 99%

“…Perhaps the best hope, however, lies with preventing the damage from occurring; elastic fibres have a widespread tissue distribution, where they fulfil vital mechanical and biochemical roles and are uniquely long-lived and hence susceptible the accumulation of age-related damage. This combination of factors suggests that any preventative strategies which succeed in ameliorating the adverse effects of protein glycation and low grade inflammation (Vijg and Campisi 2008), for example, are likely to have profound effects on elastic fibre structure/ function in ageing tissues and hence on human morbidity and mortality.…”

Section: Conclusion: Repairing and Preventing Elastic Fibre Degradationmentioning

confidence: 99%

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Tissue elasticity and the ageing elastic fibre

Sherratt

2009

AGE

259

186

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The ability of elastic tissues to deform under physiological forces and to subsequently release stored energy to drive passive recoil is vital to the function of many dynamic tissues. Within vertebrates, elastic fibres allow arteries and lungs to expand and contract, thus controlling variations in blood pressure and returning the pulmonary system to a resting state. Elastic fibres are composite structures composed of a cross-linked elastin core and an outer layer of fibrillin microfibrils. These two components perform distinct roles; elastin stores energy and drives passive recoil, whilst fibrillin microfibrils direct elastogenesis, mediate cell signalling, maintain tissue homeostasis via TGFβ sequestration and potentially act to reinforce the elastic fibre. In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality. This review considers how the unique molecular structure, tissue distribution and longevity of elastic fibres pre-disposes these abundant extracellular matrix structures to the accumulation of damage in ageing dermal, pulmonary and vascular tissues. As compromised elasticity is a common feature of ageing dynamic tissues, the development of strategies to prevent, limit or reverse this loss of function will play a key role in reducing age-related morbidity and mortality.

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“…Increased autophagy in Zmpste24-deficient mice is caused by a reduced activity of mTOR, which, in turn, is linked to activation of LKB1-AMPK signalling, transcriptional changes in key genes for lipid and glucose metabolism regulation, hypoglycemia and other alterations in serum factors such as leptin, insulin and adiponectin . These signalling alterations and their associated metabolic changes have been related to situations prolonging lifespan, such as calorie restriction (Vijg and Campisi 2008), and could be part of a response triggered by the nuclear abnormalities present in Zmpste24-deficient animals. However, the chronic activation of this pro-survival strategy can result in a pro-ageing effect that contributes to the progeroid phenotype of these mice .…”

Section: Zmpste24-deficient Mice As a Model Of Accelerated Ageingmentioning

confidence: 99%

Accelerated ageing: from mechanism to therapy through animal models

et al. 2008

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Ageing research benefits from the study of accelerated ageing syndromes such as HutchinsonGilford progeria syndrome (HGPS), characterized by the early appearance of symptoms normally associated with advanced age. Most HGPS cases are caused by a mutation in the gene LMNA, which leads to the synthesis of a truncated precursor of lamin A known as progerin that lacks the target sequence for the metallopotease FACE-1/ZMPSTE24 and remains constitutively farnesylated. The use of Face-1/Zmpste24-deficient mice allowed us to demonstrate that accumulation of farnesylated prelamin A causes severe abnormalities of the nuclear envelope, hyper-activation of p53 signalling, cellular senescence, stem cell dysfunction and the development of a progeroid phenotype. The reduction of prenylated prelamin A levels in genetically modified mice leads to a complete reversal of the progeroid phenotype, suggesting that inhibition of protein farnesylation could represent a therapeutic option for the treatment of progeria. However, we found that both prelamin A and its truncated form progerin can undergo either farnesylation or geranylgeranylation, revealing the need of targeting both activities for an efficient treatment of HGPS. Using Face-1/Zmpste24-deficient mice as model, we found that a combination of statins and aminobisphosphonates inhibits both types of modifications of prelamin A and progerin, improves the ageing-like symptoms of these mice and extends substantially their longevity, opening a new therapeutic possibility for human progeroid syndromes associated with nuclear-envelope defects. We discuss here the use of this and other animal models to investigate the molecular mechanisms underlying accelerated ageing and to test strategies for its treatment.

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Puzzles, promises and a cure for ageing

Cited by 341 publications

References 73 publications

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Tissue elasticity and the ageing elastic fibre

Accelerated ageing: from mechanism to therapy through animal models

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