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1.  Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts 
Age  2011;33(4):555-564.
Resveratrol, trans-3,5,4′-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalised reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 μm or less. However, concentrations above 25 μm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 μm.
PMCID: PMC3220406  PMID: 21318333
Resveratrol; Cellular senescence; Ageing; MRC5; HCA2; Ek1.Br; p38 MAP kinase
2.  Characterization of cellular senescence mechanisms in human corneal endothelial cells 
Aging Cell  2012;11(2):234-240.
The human cornea is a tri-laminar structure composed of several cell types with substantial mitotic potential. Age-related changes in the cornea are associated with declining visual acuity and the onset of overt age-related corneal diseases. Corneal transplantation is commonly used to restore vision in patients with damaged or diseased corneas. However, the supply of donor tissue is limited, and thus there is considerable interest in the development of tissue-engineered alternatives. A major obstacle to these approaches is the short replicative lifespan of primary human corneal endothelial cells (HCEC). Accordingly, a comprehensive investigation of the signalling pathways and mechanisms underpinning proliferative lifespan and senescence in HCEC was undertaken. The effects of exogenous human telomerase reverse transcriptase expression, p53 knockdown, disruption of the pRb pathway by over-expression of CDK4 and reduced oxygen concentration on the lifespan of primary HCEC were evaluated. We provide proof-of-principle that forced expression of telomerase, when combined with either p53 knockdown or CDK4 over-expression, is sufficient to produce immortalized HCEC lines. The resultant cell lines express an HCEC-specific transcriptional fingerprint, and retain expression of the corneal endothelial temperature-sensitive potassium channel, suggesting that significant dedifferentiation does not occur as a result of these modes of immortalization. Exploiting these insights into proliferative lifespan barriers in HCEC will underpin the development of novel strategies for cell-based therapies in the human cornea.
PMCID: PMC3440103  PMID: 22128747
senescence; telomeres; telomerase; p53; oxidative stress; CDK4; replicative senescence
3.  Back to the future? Transatlantic collaboration on ageing research 
Age  2010;31(4):257-259.
PMCID: PMC2813044  PMID: 21119825
4.  Chemical changes in aging Drosophila melanogaster 
Age  2009;31(4):343-351.
The “Green Theory” of aging proposes that organismal lifespan is limited by the failure to repair molecular damage generated by a broad range of metabolic processes. Two specific predictions arise from this: (1) that these processes will produce a wide variety of stable but dysfunctional compounds that increase in concentration with age, and (2) that organisms maintained under conditions that extend lifespan will display a reduced rate of accumulation of such “molecular rubbish”. To test these predictions, novel analytical techniques were developed to investigate the accumulation of damaged compounds in Drosophila melanogaster. Simple preparative techniques were developed to produce digests of whole D. melanogaster for use in three-dimensional (3D) fluorimetry and 1H NMR spectrometry. Cohorts of Drosophila maintained under normal conditions showed an age-related increase in signals consistent with damage whereas those maintained under conditions of low temperature and dietary restriction did not. 1H NMR revealed distinct age-associated spectral changes that will facilitate the identification of novel compounds that both increase and decrease during aging in this species. These findings are consistent with the predictions of the “Green Theory”.
PMCID: PMC2813051  PMID: 19585275
Drosophila melanogaster; Aging; Green theory; Oxidative damage; Glycation; Spectroscopy

Results 1-4 (4)