Mutant mammals with normal lifespan: an underappreciated resourse





A.D.N.J. de Grey

Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK



Biogerontology proceeds largely by designing interventions to alter the life expectancy, or sometimes the maximum lifespan, of an experimental population. Interventions designed to extend an organism's lifespan are often claimed to be far more informative than ones designed to shorten it, because shortening lifespan can be done in innumerable ways that do not necessarily have anything to do with what limited the controls' lifespan, whereas to extend lifespan one must modulate all the organism's life-limiting processes. I suggest that this overlooks a critical point. Our goal is to test hypotheses concerning which mechanisms do and do not greatly influence lifespan. An intervention that extends lifespan does not generally do this, because putative markers of lifespan-limiting processes (PMLPs) that are postponed may be causal in determining lifespan or may be mere bystanders, while ones that are not postponed may be unimportant for lifespan or may be important but better tolerated because of the intervention. Moreover, interventions designed to extend lifespan but which fail to do so also tell us nothing, because PMLPs that they postpone are not shown to be irrelevant (only to be not the only ones that are relevant), while ones that are not postponed are again neither supported nor challenged (they could either matter or not for lifespan). When the intervention is designed to shorten lifespan, on the other hand, information can be gained that truly falsifies hypotheses. True, when lifespan is indeed shortened we learn little, since the organism may have been killed by something irrelevant to controls: thus, no PMLPs are falsified. But if lifespan is unaffected by the intervention, the situation is totally different: any PMLP that is accelerated is unambiguously eliminated as being relevant to the determination of lifespan in that organism. I will discuss the many mammalian examples of this "failed shortening of lifespan" that are now available and a number of tests of prominent hypotheses that they make possible.




Key words: mammals, lifespan, interventions, falsification







Problems or questions regarding this site should be directed to webmaster@americanaging.org