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• W1839954080 abstract "A young boy from New York was visiting a school in the Midwest, and participating in a field trip to the woods. ‘Hey, look at dose boids’, he said, to which the teacher replied, ‘Those are not boids, they are birds.’‘Cheez, dey look just like boids’, the boy said. Professor Austad is a thoughtful, articulate scholar, and I agree with most of the points he has made in his commentary, ‘Is aging programmed?’ Let us start with his analogy of the Kia, the Lexus and aging: if someone were to find a bolt that could be loosened, or a piston or shaft that could be removed, from the Kia, so that it would suddenly last longer than the Lexus – indeed, twice as long – and, further, that a combination of loosenings and removals would increase the Kia's ‘lifespan’ six-fold (and potentially even more), while apparently allowing normal driving performance, then this information would be worth billions to the drivers and manufacturers of the Kia (and, under such circumstances, it is to be hoped that a significant fraction of the newly realized income would be designated for research on aging). If Austad is aware of such a bolt or piece, then his analogy is certainly apt. Let us take the analogy one step further: imagine that, instead of having to loosen bolts and remove various manifolds or joints, there was a hierarchical system set up so that a single switch could be thrown, which in turn would loosen or remove (reversibly) all of the same car parts, so that the ‘lifespan’ of the car would increase several fold by the simple throwing of that switch. Now, the car salesperson would explain to you that the auto had been ‘preprogrammed so that a single switch can be thrown to increase the life of the car by an amazing 500%!’ What a selling point! That is the crux of the issue – we know of nothing that is actively inhibiting the ‘longevity’ of an automobile, no switch that can be thrown to effect a combination of changes leading to a multiple-fold increase in the lifespan of the car. But there is for an aging organism. Let us consider another of the analogies offered in the commentary: ‘Decay and design are fundamentally different unless the nature and rate of decay are part of the design, which is very rarely the case. Fruit ripen by a genetic program, they rot for other reasons.’ If one found a single gene whose deletion retarded the fruit's rotting, it may have any of many functions – for example, it might simply make the fruit less interesting, for any of a number of reasons, to the relevant micro-organisms. However, if a hierarchical biochemical pathway (i.e. program) controlled the rate of fruit rotting over an order of magnitude, then one would be forced to reconsider the assumption that rotting is completely without programmatic aspects. Similar assumptions were of course made about cell death until work by various groups demonstrated the morphological uniformity, transcriptional dependence and molecular underpinnings of cell death programs – just as is now occurring for the programmatic aspects of lifespan determination. This morphological uniformity – or relative lack of uniformity – is another point addressed by Austad in his commentary. Interestingly, he begins with a description of an organism that, he agrees, does indeed undergo programmed organismal death – the Pacific salmon of the genus Onchrhynchus. So, apparently, we are in complete agreement for at least one organism; how about the rest? ‘Mice, even those that are genetically identical and are raised in identical circumstances, exhibit a wide variety of phenotypes as they age.’ But, are the similarities of the aging phenotype not striking? Indeed, the sideshow barker who guesses the ages of all comers within two years or so depends on this phenomenon; we all can readily tell the difference between a 25-year-old and a 75-year-old; age-related histological changes in various organs are easily identified by any board-certified pathologist; and, most importantly, microarray studies are beginning to reveal common transcriptional events in the aging process (e.g. Lu et al., 2004). Returning to the comparison with PCD (programmed cell death), there is a finite number of different, morphologically and biochemically distinguishable programs by which cells commit suicide; it is not likely that POD (programmed organismal death) will be any simpler. These comments notwithstanding, neither the well-recognized morphological similarities nor the emerging gene expression and proteome similarities, in the aging phenotype, prove by any means a programmatic aspect to the aging process; they simply highlight the fact that the claim of differences in the aging phenotype as proof of a lack of program in aging is a weak argument indeed. Austad and I are also in agreement about whether it ‘matter[s] whether we think aging is programmed or not’, although for somewhat different reasons: he points out that the appreciation that development, but not senescence, is programmed, ‘… helps researchers focus on possible early life side-effects of treatments that retard decay.’ I would argue that it matters for at least two additional reasons: first, because the assumption that aging is without a programmatic component delayed both the initiation and the early acceptance of genetic studies of aging in invertebrates; and secondly, because studies of the longevistat, and a putative organismal death program, may help define targets with potential therapeutic value. Austad and I also agree on the importance of determining whether or not long-lived mutants must sacrifice fitness in one way or another. He writes, ‘With more natural fluctuations in food availability, the age-1 mutant was shown to be at a severe competitive advantage [sic, at least in the copy sent to me] relative to wild-type worms. It is this sort of subtle effect that an emphasis on performance is likely to uncover.’ Setting aside for the moment the Freudian slip, and assuming that Austad meant to write ‘competitive disadvantage’, I agree with his point – increasing lifespan may turn out to require fitness losses that, as he points out, may be extremely subtle; however, from a practical point of view, would not a vanishingly subtle loss of performance be acceptable if one could enhance longevity and delay aging-associated diseases? Furthermore, the worm experiment that Austad quotes illuminates the importance of the organism's environment: given the relatively rapid and severe change in humans’ living practices, during an interval of time when, by the evolutionary clock, little has changed at the genome level, it is extremely unlikely that we as humans are optimized for our current environment and lifestyle, and thus there is the possibility of performance enhancements– not just performance compromises – accompanying therapeutics and other manipulations that increase longevity. Recognition of at least the possibility of a programmatic aspect, or aspects, to the determination of longevity and the process of aging should optimize our chances to identify appropriate therapeutic targets both for longevity enhancement and disease prevention." @default.
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• W1839954080 date "2004-09-02" @default.
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• W1839954080 title "Rebuttal to Austad: ‘Is aging programmed?" @default.
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• W1839954080 doi "https://doi.org/10.1111/j.1474-9728.2004.00120.x" @default.
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