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Editorials
to promote longevity to the extent that it benefits the passage of genetic material to subsequent generations.13 Different animals have evolved different strategies for somatic maintenance that maximize reproductive suc- cess, and the extension of youth through additional investment in tissue maintenance would be disfavored if the costs (often manifested through reduced investment in reproduction) outweigh benefits. As concisely noted by George Williams,14 “natural selection may be said to be biased in favor of youth over old age whenever a conflict of interests arises.” For a small vulnerable animal like a field mouse that faces high extrinsic hazards (such as pre- dation), natural selection has favored a “fast” life history – a breed early, breed often strategy with little investment in longevity. For larger animals like humans, elephants and whales, or for animals like tortoises, moles, bats and birds that have evolved other strategies to greatly reduce extrinsic hazards, natural selection has favored a “slow” life history, with greater and/or prolonged tissue mainte- nance leading to longer potential lifespans. While we understand how natural selection has shaped the path- ways that control longevity, we know less about what these pathways actually are. Studies from model organ- isms have clearly demonstrated that modulation of the insulin-like growth factor-1 (IGF-1) pathway, which posi- tively regulates the mTOR pathway and negatively regu- lates autophagy, can significantly impact longevity.1,15 Decreases in IGF-1 and mTOR, or increases in autophagy,
Figure 1. A small region on chromo- some 11 determines hematopoiet- ic stem and progenitor cells (HSPC) traits and lifespan. A simplified schema showing the K and A line BXD congenic mice that demon- strate that HSPC sensitivity to hydroxyurea (HU), lifespan and the expression levels of PTTG1 all map to a 18.6 Mb region on chromo- some 11. Chromosomal regions of C57Bl/6 origin are shown in dark gray, and regions from DBA/2 are shown in blue. See Figure 1D of Brown et al.4 for a more accurate depiction of the congenic regions, as there are small contributions from the other strain on other regions of chromosome 11, with the 18.6 Mb region encompassing the shared overlap between the K and A congenic lines.
have been shown to prolong lifespans in organisms rang- ing from yeast to mammals. Additional studies have shown how inflammation can contribute to aging-associ- ated phenotypes, and polymorphisms in genes control- ling the IGF-1 pathway and inflammation are enriched in human centenarians,16 but the extent to which these poly- morphisms and their impact on inflammation are con- tributing to differences in longevity has not been estab- lished.
While genetic screens in model organisms have revealed key pathways that regulate lifespan, the mecha- nisms employed by natural selection in the evolution of lifespans largely remain a mystery. Although one could argue that the selective breeding to generate different mouse strains over the last couple of centuries may not qualify as “natural” selection, the studies of Brown et al. reveal at least one potential (and novel) mediator of lifes- pan control. Key questions remain: Do variations in PTTG1 expression or activity contribute to lifespan dif- ferences across species, and perhaps within a species (including variability in the human population)? Would modulation of PTTG1 expression or activity promote the extension of healthspan or lifespan? How do activities known to modulate lifespan, such as dietary restriction and exercise, influence PTTG1 activity? Are there links between known aging pathways such as via IGF-1 and PTTG1? Good science generates good questions, leading to new insights (and sometimes even solutions). As a sen-
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