Biomedical subjects

Simon Melov

Publications and source records attributed to Simon Melov.

8 recordsLinked to original sources

PubMed2026

Senotypes define the diverse landscape of senescent cells.

Cellular senescence was initially defined in vitro as a stable cell-cycle arrest that occurs after repeated replication, but it is now recognized as a heterogeneous state shaped by cell type, species, senescence-inducing stress, tissue microenvironment and time. To organize this complexity, we propose the term 'senotype' to classify senescent cells by their inputs, molecular features and functional effects. We outline a practical framework incorporating: (1) cell identity and context; (2) inducing mechanism; (3) temporal stage; (4) multimodal molecular and structural features; and (5) physiological or pathological functions. Experimentally defined senotypes can serve as references for interpreting tissue-derived senotypes, where parameters may be incomplete. Senotypes should be anchored in combinations of core hallmarks (that is, durable cell-cycle arrest, altered secretory profiles, macromolecular or organelle damage, disrupted homeostasis) rather than single markers. Advances in single-cell, spatial, proteomic and computational methods enable rigorous senotype characterization, improving consistency and accelerating development of targeted senotherapeutics.

Cellular Senescence↗

PubMed2003

Microarray workshop on aging.

The advent of microarrays in studying gene expression in aging has created tremendous excitement due to its potential for uncovering molecular mechanisms of aging and age-related disease. However, the appropriate implementation of this technology in the science of aging requires serious attention to methodological detail and statistical rigor. This report highlights discussions from the microarray workshop on aging held at the First Conference on Functional Genomics of Aging in Seville, Spain. The topics discussed by the participants included technical issues relating to the printing of arrays, RNA isolation, cDNA labeling and hybridization, optimal design of microarray experiments, and statistical analysis of these data. Microarray analysis of complex tissues through the use of laser capture microdissection was also discussed.

Aging↗

PubMed2003

Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts.

Most mammalian cells do not divide indefinitely, owing to a process termed replicative senescence. In human cells, replicative senescence is caused by telomere shortening, but murine cells senesce despite having long stable telomeres. Here, we show that the phenotypes of senescent human fibroblasts and mouse embryonic fibroblasts (MEFs) differ under standard culture conditions, which include 20% oxygen. MEFs did not senesce in physiological (3%) oxygen levels, but underwent a spontaneous event that allowed indefinite proliferation in 20% oxygen. The proliferation and cytogenetic profiles of DNA repair-deficient MEFs suggested that DNA damage limits MEF proliferation in 20% oxygen. Indeed, MEFs accumulated more DNA damage in 20% oxygen than 3% oxygen, and more damage than human fibroblasts in 20% oxygen. Our results identify oxygen sensitivity as a critical difference between mouse and human cells, explaining their proliferative differences in culture, and possibly their different rates of cancer and ageing.

Animals↗

PubMed2002

Applied proteomics: mitochondrial proteins and effect on function.

The identification of a majority of the polypeptides in mitochondria would be invaluable because they play crucial and diverse roles in many cellular processes and diseases. The endogenous production of reactive oxygen species (ROS) is a major limiter of life as illustrated by studies in which the transgenic overexpression in invertebrates of catalytic antioxidant enzymes results in increased lifespans. Mitochondria have received considerable attention as a principal source---and target---of ROS. Mitochondrial oxidative stress has been implicated in heart disease including myocardial preconditioning, ischemia/reperfusion, and other pathologies. In addition, oxidative stress in the mitochondria is associated with the pathogenesis of Alzheimer's disease, Parkinson's disease, prion diseases, and amyotrophic lateral sclerosis (ALS) as well as aging itself. The rapidly emerging field of proteomics can provide powerful strategies for the characterization of mitochondrial proteins. Current approaches to mitochondrial proteomics include the creation of detailed catalogues of the protein components in a single sample or the identification of differentially expressed proteins in diseased or physiologically altered samples versus a reference control. It is clear that for any proteomics approach prefractionation of complex protein mixtures is essential to facilitate the identification of low-abundance proteins because the dynamic range of protein abundance within cells has been estimated to be as high as 10(7). The opportunities for identification of proteins directly involved in diseases associated with or caused by mitochondrial dysfunction are compelling. Future efforts will focus on linking genomic array information to actual protein levels in mitochondria.

Animals↗

PubMed2002

'...and C is for Clioquinol' - the AbetaCs of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder that has been intensively studied over the last several years. In vitro and in vivo studies have led to an understanding of some of the physico-chemical properties of amyloid, a well-characterized hallmark of AD. Clioquinol is a drug that acts on amyloid by perturbing amyloid's metallo-chemistry, and Clioquinol treatment has been shown to be beneficial in a mouse model of AD. This short review examines the recent studies relating to Clioquinol and AD, and anticipates the imminent results of a Phase II trial of Clioquinol in AD, due in March 2002.

Alzheimer Disease↗

PubMed2002

Animal models of oxidative stress, aging, and therapeutic antioxidant interventions.

Oxidative stress is a ubiquitous phenomena in all cell types, and it is primarily produced in mitochondria which are essential for multicellular life. Oxidative stress targets can be wide ranging and include nucleic acids and a variety of macromolecules. This review discusses the role of oxidative stress in the context of animal models, focusing in particular on animal models of aging, as well as the development of a new class of therapeutic small molecular weight antioxidants that have proven effective in extending the lifespan of a simple invertebrate nematode.

Aging↗

PubMed2002

Oxidative stress and aging: beyond correlation.

The oxidative stress theory of aging has become increasingly accepted as playing a role in the aging process, based primarily on a substantial accumulation of circumstantial evidence. In recent years, the hypothesis that mitochondrially generated reactive oxygen species play a role in organismal aging has been directly tested in both invertebrate and mammalian model systems. Initial results imply that oxidative damage, specifically the level of superoxide, does play a role in limiting the lifespans of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. In mammalian model systems, the effect of oxidative stress on lifespan is less clear, but there is evidence that antioxidant treatment protects against age-related dysfunction, including cognitive decline.

Aging↗

PubMed2002

Therapeutics against mitochondrial oxidative stress in animal models of aging.

During the course of normal metabolism, reactive oxygen species (ROS) are produced from within the respiratory chain of the mitochondria. These ROS have the capacity to oxidize and damage a variety of cellular constituents including lipids, DNA, and proteins. We have taken a genetic and pharmacological approach in delineating the range of molecular targets that can be oxidatively damaged by mitochondrial ROS. Specifically, we use mice that are lacking the mitochondrial form of superoxide dismutase (sod 2(-/-) mice) to better understand the possible phenotypes that can arise from mitochondrial oxidative stress. sod 2(-/-) mice can be used to test the efficacy of antioxidants, and more generally the efficacy of antioxidants against mitochondrial oxidative stress. We have evaluated superoxide dismutase/catalase mimetics in this mammalian model of mitochondrial oxidative stress, and have shown a high degree of efficacy in protecting against ROS produced within the mitochondria. Similarly, we have employed the nematode Caenorhabditis elegans to test the hypothesis that effective antioxidant therapy can prolong the life span of an invertebrate.

Aging↗