2014 Articles
Seim I, Ma S, Zhou X, Gerashchenko MV, Lee SG, Suydam R, George JC, Bickham JW, Gladyshev VN. (2014) The transcriptome of the bowhead whale Balaena mysticetus reveals adaptations of the longest-lived mammal. Aging (Albany NY) 6, 879-899.
AbstractMammals vary dramatically in lifespan, by at least two-orders of magnitude, but the molecular basis for this difference remains largely unknown. The bowhead whaleBalaena mysticetus is the longest-lived mammal known, with an estimated maximal lifespan in excess of two hundred years. It is also one of the two largest animals and the most cold-adapted baleen whale species. Here, we report the first genome-wide gene expression analyses of the bowhead whale, based on the de novo assembly of its transcriptome. Bowhead whale or cetacean-specific changes in gene expression were identified in the liver, kidney and heart, and complemented with analyses of positively selected genes. Changes associated with altered insulin signaling and other gene expression patterns could help explain the remarkable longevity of bowhead whales as well as their adaptation to a lipid-rich diet. The data also reveal parallels in candidate longevity adaptations of the bowhead whale, naked mole rat and Brandt’s bat. The bowhead whale transcriptome is a valuable resource for the study of this remarkable animal, including the evolution of longevity and its important correlates such as resistance to cancer and other diseases. More Information
Fang X, Seim I, Huang Z, Gerashchenko MV, Xiong Z, Turanov AA, Zhu Y, Lobanov AV, Fan D, Yim SH, Yao X, Ma S, Yang L, Lee SG, Kim EB, Bronson RT, Sumbera R, Buffenstein R, Zhou X, Krogh A, Park TJ, Zhang G, Wang J, Gladyshev VN.(2014) Adaptations to a subterranean environment and longevity revealed by the analysis of mole rat genomes. Cell Rep. 8, 1354-1364.
AbstractSubterranean mammals spend their lives in dark, unventilated environments that are rich in carbon dioxide and ammonia and low in oxygen. Many of these animals are also long-lived and exhibit reduced aging-associated diseases, such as neurodegenerative disorders and cancer. We sequenced the genome of the Damaraland mole rat (DMR, Fukomys damarensis) and improved the genome assembly of the naked mole rat (NMR, Heterocephalus glaber). Comparative genome analyses, along with the transcriptomes of related subterranean rodents, revealed candidate molecular adaptations for subterranean life and longevity, including a divergent insulin peptide, expression of oxygen-carrying globins in the brain, prevention of high CO2-induced pain perception, and enhanced ammonia detoxification. Juxtaposition of the genomes of DMR and other more conventional animals with the genome of NMR revealed several truly exceptional NMR features: unusual thermogenesis, an aberrant melatonin system, pain insensitivity, and unique processing of 28S rRNA. Together, these genomes and transcriptomes extend our understanding of subterranean adaptations, stress resistance, and longevity. More Information
Kaya A, Lobanov AV, Gerashchenko MV, Koren A, Fomenko DE, Koc A, Gladyshev VN. (2014) Thiol Peroxidase Deficiency Leads to Increased Mutational Load and Decreased Fitness in Saccharomyces cerevisiae. Genetics 198, 905-917.
AbstractThiol peroxidases are critical enzymes in the redox control of cellular processes that function by reducing low levels of hydroperoxides and regulating redox signaling. These proteins were also shown to regulate genome stability, but how their dysfunction affects the actual mutations in the genome is not known. Saccharomyces cerevisiae has 8 thiol peroxidases of glutathione peroxidase and peroxiredoxin families, and the mutant lacking all these genes (∆8) is viable. In this study, we employed two independent ∆8 isolates to analyze the genome-wide mutation spectrum that results from deficiency in these enzymes. Deletion of these genes was accompanied by a dramatic increase in point mutations, many of which clustered in close proximity and scattered throughout the genome, suggesting strong mutational bias. We further subjected multiple lines of wild-type and ∆8 cells to long-term mutation accumulation, followed by genome sequencing and phenotypic characterization. ∆8 lines showed a significant increase in non-recurrent point mutations and indels. The original ∆8 cells exhibited reduced growth rate and decreased lifespan, which were further reduced in all ∆8 mutation accumulation lines. Although the mutation spectrum of the two independent isolates was different, similar patterns of gene expression were observed, suggesting the direct contribution of thiol peroxidases to the observed phenotypes. Expression of a single thiol peroxidase could partially restore the growth phenotype of ∆8 cells. This study shows how deficiency in non-essential, yet critical and conserved oxidoreductase function, leads to increased mutational load and decreased fitness. More Information
Gerashchenko MV, Gladyshev VN. (2014) Translation inhibitors cause abnormalities in ribosome profiling experiments. Nucleic Acids Res. 42, e134.
AbstractRibosome profiling and high-throughput sequencing provide unprecedented opportunities for the analysis of mRNA translation. Using this novel method, several studies have demonstrated the widespread role of short upstream reading frames in translational control as well as slower elongation at the beginning of open reading frames in response to stress. Based on the initial studies, the importance of adding or omitting translation inhibitors, such as cycloheximide, was noted as it markedly affected ribosome coverage profiles. For that reason, many recent studies omitted translation inhibitors in the culture medium. Here, we investigate the influence of ranging cycloheximide concentrations on ribosome profiles in Saccharomyces cerevisiae and demonstrate that increasing the drug concentration can overcome some of the artifacts. We subjected cells to various manipulations and show that neither oxidative stress nor heat shock nor amino acid starvation affect translation elongation. Instead, the observations in the initial studies are the result of cycloheximide-inflicted artifacts. Likewise, we find little support for short upstream reading frames to be involved in widespread protein synthesis regulation under stress conditions. Our study highlights the need for better standardization of ribosome profiling methods. More Information
Guo C, Chen X, Song H, Maynard MA, Zhou Y, Lobanov AV, Gladyshev VN, Ganis JJ, Wiley D, Jugo RH, Lee NY, Castroneves LA, Zon LI, Scanlan TS, Feldman HA, Huang SA. (2014) Intrinsic Expression of a Multiexon Type 3 Deiodinase Gene Controls Zebrafish Embryo Size. Endocrinology 155, 4069-4080.
AbstractThyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element. More Information
Labunskyy VM, Hatfield DL, Gladyshev VN. (2014) Selenoproteins: Molecular Pathways and Physiological Roles. Physiol Rev. 94, 739-777.
AbstractSelenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health. More Information
Gorbunova V, Seluanov A, Zhang Z, Gladyshev VN, Vijg J. (2014) Comparative genetics of longevity and cancer: insights from long-lived rodents. Nat Rev Genet. 15, 531-540.
AbstractMammals have evolved a remarkable diversity of ageing rates. Within the single order of Rodentia, maximum lifespans range from 4 years in mice to 32 years in naked mole rats. Cancer rates also differ substantially between cancer-prone mice and almost cancer-proof naked mole rats and blind mole rats. Recent progress in rodent comparative biology, together with the emergence of whole-genome sequence information, has opened opportunities for the discovery of genetic factors that control longevity and cancer susceptibility. More Information
Turanov AA, Shchedrina VA, Everley RA, Lobanov AV, Yim SH, Marino SM, Gygi SP, Hatfield DL, Gladyshev VN. (2014) Selenoprotein S is Involved in Maintenance and Transport of Multiprotein Complexes. Biochem J. 462, 555-565.
AbstractSelenoprotein S (SelS) is a selenocysteine-containing protein with roles in endoplasmic reticulum (ER) function and inflammation. It has been implicated in ER-associated protein degradation (ERAD), and clinical studies revealed an association of its promoter polymorphism with cytokine levels and human diseases. However, the pathways and interacting proteins that could shed light on pathogenesis of SelS-associated diseases have not been studied systematically. We performed a large-scale affinity isolation of human SelS and its mutant forms and analyzed proteins that interact with them. All previously known SelS targets and nearly two hundred additional proteins were identified, which were remarkably enriched for various multiprotein complexes. Subsequent chemical cross-linking experiments identified the specific interacting sites in SelS and its several targets. Most of these interactions involved coiled coil domains. The data suggest that SelS participates in intracellular membrane transport and maintenance of protein complexes by anchoring them to the ER membrane. More Information
Ables GP, Brown-Borg HM, Buffenstein R, Church CD, Elshorbagy AK, Gladyshev VN, Huang TH, Miller RA, Mitchell JR, Richie JP, Rogina B, Stipanuk MH, Orentreich DS, Orentreich N. (2014) The first international mini-symposium on methionine restriction and lifespan. Front Genet. 5, 122.
AbstractIt has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt’s bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3). More Information
Avanesov AS, Ma S, Pierce KA, Yim SH, Lee BC, Clish CB, Gladyshev VN. (2014) Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation. eLife 3, e02077.
AbstractAging is thought to be associated with increased molecular damage, but representative markers vary across conditions and organisms, making it difficult to assess properties of cumulative damage throughout lifespan. We used nontargeted metabolite profiling to follow age-associated trajectories of >15,000 metabolites in Drosophila subjected to control and lifespan-extending diets. We find that aging is associated with increased metabolite diversity and low-abundance molecules, suggesting they include cumulative damage. Remarkably, the number of detected compounds leveled-off in late-life, and this pattern associated with survivorship. Fourteen percent of metabolites showed age-associated changes, which decelerated in late-life and long-lived flies. In contrast, known metabolites changed in abundance similarly to nontargeted metabolites and transcripts, but did not increase in diversity. Targeted profiling also revealed slower metabolism and accumulation of lifespan-limiting molecules. Thus, aging is characterized by gradual metabolome remodeling, and condition- and advanced age-associated deceleration of this remodeling is linked to mortality and molecular damage. More Information
Otero L, Romanelli-Cedrez L, Turanov AA, Gladyshev VN, Miranda-Vizuete A, Salinas G. (2014) Adjustments, extinction, and remains of selenocysteine incorporation machinery in the nematode lineage. RNA 20, 1023-1034.
AbstractSelenocysteine (Sec) is encoded by an UGA codon with the help of a SECIS element present in selenoprotein mRNAs. SECIS-binding protein (SBP2/SCBP-2) mediates Sec insertion, but the roles of its domains and the impact of its deficiency on Sec insertion are not fully understood. We used Caenorhabditis elegans to examine SBP2 function since it possesses a single selenoprotein, thioredoxin reductase-1 (TRXR-1). All SBP2 described so far have an RNA-binding domain (RBD) and a Sec-incorporation domain (SID). Surprisingly, C. elegans SBP2 lacks SID and consists only of an RBD. An sbp2 deletion mutant strain ablated Sec incorporation demonstrating SBP2 essentiality for Sec incorporation. Further in silico analyses of nematode genomes revealed conservation of SBP2 lacking SID and maintenance of Sec incorporation linked to TRXR-1. Remarkably, parasitic plant nematodes lost the ability to incorporate Sec, but retained SecP43, a gene associated with Sec incorporation. Interestingly, both selenophosphate synthetase (SPS) genes are absent in plant parasitic nematodes, while only Cys-containing SPS2 is present in Sec-incorporating nematodes. Our results indicate that C. elegans and the nematode lineage provide key insights into Sec incorporation and the evolution of Sec utilization trait, selenoproteomes, selenoproteins, and Sec residues. Finally, our study provides evidence of noncanonical translation initiation in C. elegans, not previously known for this well-established animal model. More Information
Labunskyy VM, Suzuki Y, Hanly TJ, Murao A, Roth FP, Gladyshev VN. (2014) The Insertion Green Monster (iGM) Method for Expression of Multiple Exogenous Genes in Yeast. G3 (Bethesda) 4, 183-191.
AbstractBeing a simple eukaryotic organism, Saccharomyces cerevisiae provides numerous advantages for expression and functional characterization of proteins from higher eukaryotes, including humans. However, studies of complex exogenous pathways using yeast as a host have been hampered by the lack of tools to engineer strains overexpressing a large number of genetic components. In addition to inserting multiple genes, it is often desirable to knock out or replace multiple endogenous genes that might interfere with the processes studied. Here, we describe the ‘insertion Green Monster’ (iGM) set of expression vectors that enable precise insertion of many heterologous genes into the yeast genome in a rapid and reproducible manner and permit simultaneous replacement of selected yeast genes. As a proof-of-principle, we have used the iGM method to replace components of the yeast pathway for methionine sulfoxide reduction with genes encoding the human selenoprotein biosynthesis machinery, and generated a single yeast strain carrying 11 exogenous components of the selenoprotein biosynthetic pathway in precisely engineered loci.
KEYWORDS: Saccharomyces cerevisiae, flow cytometry, green fluorescent protein, multi-gene insertions, synthetic biology More Information
KEYWORDS: Saccharomyces cerevisiae, flow cytometry, green fluorescent protein, multi-gene insertions, synthetic biology More Information
Han SJ, Lee BC, Yim SH, Gladyshev VN, Lee SR. (2014) Characterization of Mammalian selenoprotein o: a redox-active mitochondrial protein. PLoS One 9, e95518.
AbstractSelenoproteins exhibit diverse biological functions, most of which are associated with redox control. However, the functions of approximately half of mammalian selenoproteins are not known. One such protein is Selenoprotein O (SelO), the largest mammalian selenoprotein with orthologs found in a wide range of organisms, including bacteria and yeast. Here, we report characterization of mammalian SelO. Expression of this protein could be verified in HEK 293T cells by metabolic labeling of cells with 75Se, and it was abolished when selenocysteine was replaced with serine. A CxxU motif was identified in the C-terminal region of SelO. This protein was reversibly oxidized in a time- and concentration-dependent manner in HEK 293T cells when cells were treated with hydrogen peroxide. This treatment led to the formation of a transient 88 kDa SelO-containing complex. The formation of this complex was enhanced by replacing the CxxU motif with SxxC, but abolished when it was replaced with SxxS, suggesting a redox interaction of SelO with another protein through its Sec residue. SelO was localized to mitochondria and expressed across mouse tissues. Its expression was little affected by selenium deficiency, suggesting it has a high priority for selenium supply. Taken together, these results show that SelO is a redox-active mitochondrial selenoprotein. More Information
Barroso M, Florindo C, Kalwa H, Silva Z, Turanov AA, Carlson BA, Tavares de Almeida I, Blom HJ, Gladyshev VN, Hatfield DL, Michel T, Castro R, Loscalzo J, Handy DE. (2014) Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase-1 Expression. J Biol Chem. 289, 15350-15362.
AbstractS-adenosylhomocysteine (SAH) is a negative regulator of most methyltransferases and the precursor for the cardiovascular risk factor homocysteine. We have previously identified a link between the homocysteine-induced suppression of the selenoprotein glutathione peroxidase-1 (GPx-1) and endothelial dysfunction. Here, we demonstrate a specific mechanism by which hypomethylation, promoted by the accumulation of the homocysteine precursor SAH, suppresses GPx-1 expression and leads to inflammatory activation of endothelial cells. The expression of GPx-1 and a subset of other selenoproteins is dependent on the methylation of the tRNASec to the Um34 form; the formation of methylated tRNASec facilitates translational incorporation of selenocysteine at a UGA codon. Our findings demonstrate that SAH accumulation in endothelial cells suppresses the expression of GPx-1 to promote oxidative stress. Hypomethylation stress, caused by SAH accumulation, inhibits the formation of the methylated isoform of the tRNASec and reduces GPx-1 expression. In contrast, under these conditions, the expression and activity of thioredoxin reductase-1, another selenoprotein, is increased. Furthermore, SAH-induced oxidative stress creates a pro-inflammatory activation of endothelial cells characterized by upregulation of adhesion molecules and an augmented capacity to bind leukocytes. Taken together, these data suggest that SAH accumulation in endothelial cells can induce tRNASec hypomethylation which alters the expression of selenoproteins, such as GPx-1, to contribute to a pro-atherogenic endothelial phenotype. More Information
Lee BC, Kaya A, Ma S, Kim G, Gerashchenko MV, Yim SH, Hu Z, Harshman LG, Gladyshev VN. (2014) Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status. Nat Commun. 5, 3592.
AbstractReduced methionine (Met) intake can extend lifespan of rodents; however, whether this regimen represents a general strategy for regulating aging has been controversial. Here we report that Met restriction extends lifespan in both fruit flies and yeast, and that this effect requires low amino-acid status. Met restriction in Drosophila mimicks the effect of dietary restriction and is associated with decreased reproduction. However, under conditions of high amino-acid status, Met restriction is ineffective and the trade-off between longevity and reproduction is not observed. Overexpression of InRDN or Tsc2 inhibits lifespan extension by Met restriction, suggesting the role of TOR signalling in the Met control of longevity. Overall, this study defines the specific roles of Met and amino-acid imbalance in aging and suggests that Met restiction is a general strategy for lifespan extension. More Information
Malinouski M, Hasan NM, Zhang Y, Seravalli J, Lin J, Avanesov A, Lutsenko S, Gladyshev VN. (2014) Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism. Nat Commun. 5, 3301.
AbstractTrace elements are essential for human metabolism and dysregulation of their homoeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and post-translational modifications; and the iron levels are influenced by iron import and expression of the iron/haeme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated data set opens new directions for studies of human trace element metabolism. More Information
Hatfield DL, Tsuji PA, Carlson BA, Gladyshev VN. (2014) Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci. 39, 112-120.
AbstractThe many biological and biomedical effects of selenium are relatively unknown outside the selenium field. This fascinating element, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid-1990s selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results. However, basic research on selenium continued to move at a rapid pace, elucidating its many roles in health, development, and in cancer prevention and promotion. Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions. More Information
Labunskyy VM, Gerashchenko MV, Delaney JR, Kaya A, Kennedy BK, Kaeberlein M, Gladyshev VN. (2014) Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response. PLoS Genet. 10, e1004019.
AbstractCells respond to accumulation of misfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR) signaling pathway. The UPR restores ER homeostasis by degrading misfolded proteins, inhibiting translation, and increasing expression of chaperones that enhance ER protein folding capacity. Although ER stress and protein aggregation have been implicated in aging, the role of UPR signaling in regulating lifespan remains unknown. Here we show that deletion of several UPR target genes significantly increases replicative lifespan in yeast. This extended lifespan depends on a functional ER stress sensor protein, Ire1p, and is associated with constitutive activation of upstream UPR signaling. We applied ribosome profiling coupled with next generation sequencing to quantitatively examine translational changes associated with increased UPR activity and identified a set of stress response factors up-regulated in the long-lived mutants. Besides known UPR targets, we uncovered up-regulation of components of the cell wall and genes involved in cell wall biogenesis that confer resistance to multiple stresses. These findings demonstrate that the UPR is an important determinant of lifespan that governs ER stress and identify a signaling network that couples stress resistance to longevity. More Information
Romagné F, Santesmasses D, White L, Sarangi GK, Mariotti M, Hübler R, Weihmann A, Parra G, Gladyshev VN, Guigó R, Castellano S. (2014) SelenoDB 2.0: annotation of selenoprotein genes in animals and their genetic diversity in humans. Nucleic Acids Res. 42, D437-D443.
AbstractSelenoDB (http://www.selenodb.org) aims to provide high-quality annotations of selenoprotein genes, proteins and SECIS elements. Selenoproteins are proteins that contain the amino acid selenocysteine (Sec) and the first release of the database included annotations for eight species. Since the release of SelenoDB 1.0 many new animal genomes have been sequenced. The annotations of selenoproteins in new genomes usually contain many errors in major databases. For this reason, we have now fully annotated selenoprotein genes in 58 animal genomes. We provide manually curated annotations for human selenoproteins, whereas we use an automatic annotation pipeline to annotate selenoprotein genes in other animal genomes. In addition, we annotate the homologous genes containing cysteine (Cys) instead of Sec. Finally, we have surveyed genetic variation in the annotated genes in humans. We use exon capture and resequencing approaches to identify single-nucleotide polymorphisms in more than 50 human populations around the world. We thus present a detailed view of the genetic divergence of Sec- and Cys-containing genes in animals and their diversity in humans. The addition of these datasets into the second release of the database provides a valuable resource for addressing medical and evolutionary questions in selenium biology. More Information
Gladyshev VN. (2014) The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 20, 727-731.
AbstractThe free radical theory of aging posits that aging is caused by accumulation of damage inflicted by reactive oxygen species (ROS). Although this concept has been very useful in defining the contribution of oxidative damage to the aging process, an increasing number of studies contradict it. The idea that oxidative damage represents only one of many causes of aging also has limitations, as it does not explain causal relationships and inevitability of damage accumulation. Here, it is discussed that infidelity, heterogeneity and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms. Although ROS are prototypical by-products, their contribution to aging is governed by the metabolic organization of the cell, its protective systems, and genotype. These factors are controlled by natural selection and, like dietary and genetic interventions that extend lifespan, change the composition of cumulative damage and the rates of accumulation of its various forms. Oxidative damage, like other specific damage types viewed in isolation or in combination, does not represent the cause of aging. Instead, biological imperfectness, which leads to inevitable accumulation of damage in the form of mildly deleterious molecular species, may help define the true root of aging. Free radical and other specialized damage theories served their purpose in the understanding of the aging process, but in the current form they limit further progress in this area. More Information
