Aubrey D.N.J. de Grey

Annotation of the Drosophila melanogaster euchromatic genome: a systematic review

BackgroundThe recent completion of the Drosophila melanogaster genomic sequence to high quality and the availability of a greatly expanded set of Drosophila cDNA sequences, aligning to 78% of the predicted euchromatic genes, afforded FlyBase the opportunity to significantly improve genomic annotations. We made the annotation process more rigorous by inspecting each gene visually, utilizing a comprehensive set of curation rules, requiring traceable evidence for each gene model, and comparing each predicted peptide to SWISS-PROT and TrEMBL sequences.ResultsAlthough the number of predicted protein-coding genes in Drosophila remains essentially unchanged, the revised annotation significantly improves gene models, resulting in structural changes to 85% of the transcripts and 45% of the predicted proteins. We annotated transposable elements and non-protein-coding RNAs as new features, and extended the annotation of untranslated (UTR) sequences and alternative transcripts to include more than 70% and 20% of genes, respectively. Finally, cDNA sequence provided evidence for dicistronic transcripts, neighboring genes with overlapping UTRs on the same DNA sequence strand, alternatively spliced genes that encode distinct, non-overlapping peptides, and numerous nested genes.ConclusionsIdentification of so many unusual gene models not only suggests that some mechanisms for gene regulation are more prevalent than previously believed, but also underscores the complex challenges of eukaryotic gene prediction. At present, experimental data and human curation remain essential to generate high-quality genome annotations.

HO2•: The Forgotten Radical

HO 2 , usually termed either hydroperoxyl radical or perhydroxyl radical, is the protonated form of superoxide; the protonation/deprotonation equilibrium exhibits a pKa of around 4.8. Consequently, about 0.3% of any superoxide present in the cytosol of a typical cell is in the protonated form. This ratio is rather accurately reflected by the published literature on the two species, as identified by a PubMed search; at the time of writing only 28 articles mention “HO2”, “hydroperoxyl” or “perhydroxyl” in their titles, as against 9228 mentioning superoxide. Here it is argued that this correlation is not justifiable: that HO 2 ’s biological and biomedical importance far exceeds the attention it has received. Several key observations of recent years are reviewed that can be explained much more economically when the participation of HO 2  is postulated. It is suggested that a more widespread appreciation of the possible role of HO 2  in biological systems would be of considerable benefit to biomedical research.

Time to Talk SENS: Critiquing the Immutability of Human Aging

Aging is a three‐stage process: metabolism, damage, and pathology. The biochemical processes that sustain life generate toxins as an intrinsic side effect. These toxins cause damage, of which a small proportion cannot be removed by any endogenous repair process and thus accumulates. This accumulating damage ultimately drives age‐related degeneration. Interventions can be designed at all three stages. However, intervention in metabolism can only modestly postpone pathology, because production of toxins is so intrinsic a property of metabolic processes that greatly reducing that production would entail fundamental redesign of those processes. Similarly, intervention in pathology is a “losing battle” if the damage that drives it is accumulating unabated. By contrast, intervention to remove the accumulating damage would sever the link between metabolism and pathology, and so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging—which we term “engineered negligible senescence”—may be within sight. Given the major demographic consequences if it came about, this possibility merits urgent debate.

Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging

Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of mutations in the mutator mice typically are more than an order of magnitude higher than typical levels in aged humans. Furthermore, most of the aging‐like features are not specific to the mtDNA mutator mice, but are shared with several other premature aging mouse models, where no mtDNA mutations are involved. We conclude that, although mtDNA mutator mouse is a very useful model for studies of phenotypes associated with mtDNA mutations, the aging‐like phenotypes of the mouse do not imply that mtDNA mutations are necessarily involved in natural mammalian aging. On the other hand, the fact that point mutations in aged human tissues are much less abundant than those causing premature aging in mutator mice does not mean that mtDNA mutations are not involved in human aging. Thus, mtDNA mutations may indeed be relevant to human aging, but they probably differ by origin, type, distribution, and spectra of affected tissues from those observed in mutator mice.

The Demographic and Biomedical Case for Late-Life Interventions in Aging

A global research agenda to slow or arrest the effects of biological aging has the potential to avert enormous economic, social, and human costs. The social and medical costs of the biological aging process are high and will rise rapidly in coming decades, creating an enormous challenge to societies worldwide. In recent decades, researchers have expanded their understanding of the underlying deleterious structural and physiological changes (aging damage) that underlie the progressive functional impairments, declining health, and rising mortality of aging humans and other organisms and have been able to intervene in the process in model organisms, even late in life. To preempt a global aging crisis, we advocate an ambitious global initiative to translate these findings into interventions for aging humans, using three complementary approaches to retard, arrest, and even reverse aging damage, extending and even restoring the period of youthful health and functionality of older people.

The foreseeability of real anti-aging medicine: focusing the debate.

There has recently been a sharp and very welcome increase in the rate of appearance of articles discussing the concept of medical interventions that would greatly increase the maximum healthy human lifespan. Much of this literature has emphasised the current non-existence of any such therapies, and has done so with laudable accuracy and authority. Regrettably, however, such articles have frequently extended their ambit to include the issues of how soon such interventions could be developed and of how advisable such an effort would be anyway, and have addressed these much more weakly, thereby diminishing the force of their main message. Here a survey is made of the more conspicuously flawed arguments suggesting tremendous difficulties or dangers in developing such interventions, with the aim thereby to tow those arguments firmly out into the ocean and give them the decent but unambiguous public burial that they so richly deserve. It is hoped that, by clearing the debate on future anti-aging advances of these obfuscations, the many aspects of this topic that have hitherto received much less attention than they warrant will be brought to the fore.

Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters Now

Should we be considering the social and economic ramifications of a society where life-span could be limitless?

The Unfortunate Influence of the Weather on the Rate of Ageing: Why Human Caloric Restriction or Its Emulation May Only Extend Life Expectancy by 2–3 Years

Much research interest, and recently even commercial interest, has been predicated on the assumption that reasonably closely-related species – humans and mice, for example – should, in principle, respMuch research interest, and recently even commercial interest, has been predicated on the assumption that reasonably closely-related species – humans and mice, for example – should, in principle, respond to ageing-retarding interventions with an increase in maximum lifespan roughly proportional to their control lifespan (that without the intervention). Here, it is argued that the best-studied life-extending manipulations of mice are examples of a category that is highly unlikely to follow this rule, and more likely to exhibit only a similar absolute increase in maximum lifespan from one species to the next, independent of the species’ control lifespan. That category – reduction in dietary calories or in the organism’s ability to metabolize or sense them – is widely recognized to extend lifespan as an evolutionary adaptation to transient starvation in the wild, a situation which alters the organism’s optimal partitioning of resources between maintenance and reproduction. What has been generally overlooked is that the extent of the evolutionary pressure to maintain adaptability to a given duration of starvation varies with the frequency of that duration, something which is – certainly for terrestrial animals and less directly for others – determined principally by the weather. The pattern of starvation that the weather imposes is suggested here to be of a sort that will tend to cause all terrestrial animals, even those as far apart phylogenetically as nematodes and mice, to possess the ability to live a similar maximum absolute (rather than proportional) amount longer when food is short than when it is plentiful. This generalization is strikingly in line with available data, leading (given the increasing implausibility of further extending human mean but not maximum lifespan in the industrialized world) to the biomedically and commercially sobering conclusion that interventions which manipulate caloric intake or its sensing are unlikely ever to confer more than 2 or 3 years’ increase in human mean or maximum lifespan at the most.

Resistance to debate on how to postpone ageing is delaying progress and costing lives

Open discussions in the biogerontology community would attract public interest and influence funding policyAperennial complaint in biogerontology, and one whose legitimacy I would be the last to dispute, is that public funding for ageing research is far lower than it should be. Such funding has roughly kept pace with biomedical research spending as a whole, but much more is warranted because postponement of ageing would have a far greater impact on public health and healthcare spending than postponement of any or all of the major age-related diseases. Here, I discuss whether our obstinately modest funding is due, as most of my biogerontologist colleagues evidently feel, to a failure on our part to communicate the scientific and biomedical realities to our political paymasters, and is therefore best rectified by continuing to repeat the arguments we have used for decades until they sink in. I argue that it is instead because those arguments are genuinely weak. I then discuss whether our neglect of more effective justifications for greater investment in biogerontology research is because we overlook key components of the trade-offs that determine funding policy, or whether the problem is the failure of most biogerontologists to maintain an open mind concerning the scientific options. I conclude that it is for both those reasons. Thus, our field is passing up the opportunity to elevate itself to its rightful level of public appreciation and investment, with the result that much longer healthy lives are being denied those who will die before ‘real anti-ageing medicine’ arrives unless we start working harder towards it now. This essay covers controversial and sensitive issues, so I start with the safest one. Most biogerontologists believe, or at least claim, that a legitimate and plausible longterm goal of their research is to extend the healthy human lifespan by intervening in the ageing process. Even that seemingly anodyne description of what biogerontologists seek is replete with land mines, so I prepare the ground by clarifying what biogerontologists, by and large, do and do not mean by it.

Annotation of the Drosophila melanogastereuchromatic genome: a systematic review

BackgroundThe recent completion of the Drosophila melanogaster genomic sequence to high quality and the availability of a greatly expanded set of Drosophila cDNA sequences, aligning to 78% of the predicted euchromatic genes, afforded FlyBase the opportunity to significantly improve genomic annotations. We made the annotation process more rigorous by inspecting each gene visually, utilizing a comprehensive set of curation rules, requiring traceable evidence for each gene model, and comparing each predicted peptide to SWISS-PROT and TrEMBL sequences.ResultsAlthough the number of predicted protein-coding genes in Drosophila remains essentially unchanged, the revised annotation significantly improves gene models, resulting in structural changes to 85% of the transcripts and 45% of the predicted proteins. We annotated transposable elements and non-protein-coding RNAs as new features, and extended the annotation of untranslated (UTR) sequences and alternative transcripts to include more than 70% and 20% of genes, respectively. Finally, cDNA sequence provided evidence for dicistronic transcripts, neighboring genes with overlapping UTRs on the same DNA sequence strand, alternatively spliced genes that encode distinct, non-overlapping peptides, and numerous nested genes.ConclusionsIdentification of so many unusual gene models not only suggests that some mechanisms for gene regulation are more prevalent than previously believed, but also underscores the complex challenges of eukaryotic gene prediction. At present, experimental data and human curation remain essential to generate high-quality genome annotations.