The primary goal of longevity science is to extend healthy life span. A secondary, less important goal is to reduce the time spent in ill health and declining function at the end of life. That secondary goal receives more attention for largely political reasons, however; it is what researchers talk about when they want to avoid talking about extension of life span. It is unfortunate that this is still a subject that is avoided by many in the research community. People should be more open when it comes to the fact the goal of treating aging as a medical condition is ultimately to extend healthy life indefinitely, to greatly extend the present all too short human life span. Trying to hide that away just makes everything harder.
The merits of a potential approach to treating aging should be judged primarily by the degree to which it can extend healthy life span. It is quite reasonable to expect some classes of treatment to also extend the period of decline in late life. Aging is caused by an accumulation of metabolic waste and molecular damage. A method that slows the pace of damage accumulation should both extend health and extend frailty. A method that periodically repairs damage should extend health and may or may not extend frailty, depending on the details. A method that improves resistance to damage or some of its consequences might fail to extend health while extending the period of frailty. All of these are possible outcomes, and the research community should aim for the most desirable of them, taking into account the size of the effect. A large extension to health span followed by a large extension to the period of frailty is a good deal better than a small gain in health span that does not extend the period of frailty.
Caenorhabditis elegans has been an invaluable experimental organism for the discovery and characterization of conserved pathways that extend lifespan. In particular, reduced signaling through the stress and nutrient-sensing insulin/insulin-like growth factor 1 (IGF-1) pathway was first shown to double the lifespan of C. elegans and was later found to increase the longevity of other species, including mammals. C. elegans with partial loss-of-function mutations in daf-2, the C. elegans insulin/IGF-1-receptor gene, not only live longer but also maintain more youthful characteristics, such as active movement, neuronal function, and memory, indicating an extension of healthspan as well as lifespan. However, a recent study followed the functional ability of daf-2 mutants and found that the daf-2 healthspan, although chronologically longer than that of the wild-type, did not scale with lifespan, resulting in a disproportionately extended period of age-related decrepitude. This report was disconcerting because such an outcome would be undesirable in a human society, where population aging has already increased healthcare costs substantially. It also brought into question the validity of C. elegans as a model organism to study healthy life extension.
In this study, we set out to accomplish three goals: to undertake a quantitative large-scale analysis to corroborate the reported disproportionately extended end-of-life decrepitude in a daf-2 mutant, to determine whether this phenotype could be due to behavioral particularities of the specific daf-2 allele that was examined, and, if not, to elucidate the cause of this apparently undesirable phenotype. We found that two very different daf-2 mutants both remain active longer and age more slowly than the wild-type, at least through mid-life, but then go on to stay alive but decrepit for a long time. We wanted to understand what might cause this extended decrepitude. Theoretically, eliminating a cause of death that kills relatively young individuals would result in a population's growing older and frailer.
We wondered whether resistance to bacterial toxicity might play a role. We measured bacterial colonization of a daf-2 mutant. Colonization of the upper digestive tract was delayed and never reached the same maximum as in the wild-type. This finding is consistent with the idea that resistance to colonization allows daf-2 mutants to survive into old age. Why bacterial colonization occurs in old C. elegans and how exactly it causes death remains unknown. Decreased immune function with age could contribute to bacterial accumulation and proliferation, and daf-2 mutants have higher expression of some antimicrobial genes that curtail the rate of bacterial proliferation in the intestine. If reduced risk of death due to bacterial colonization allows daf-2 mutants to live long enough to become decrepit, then eliminating bacterial colonization as a cause of "premature" death should allow wild-type worms, too, to live long enough to enter a state of end-of-life decrepitude. To test this hypothesis, we fed wild-type animals bacteria killed by gentamicin from the time of hatching. Using killed bacteria as a food source extended the wild-type lifespan by 40%. Eliminating bacterial colonization as a cause of death in wild-type worms copied the extended period of decrepitude seen in daf-2 mutants.
In summary, we find that the level of bacterial colonization predicts wild-type lifespan. The extent of colonization is significantly greater in the wild-type than in daf-2 mutants, and eliminating colonization in wild-type animals allows them to avoid an early death; instead, they remain alive for a longer time in a decrepit, aged state, just like daf-2 mutants. Therefore, we conclude that a beneficial trait (resistance to bacterial colonization) can explain the extended end-of-life frailty of daf-2 mutants. Surviving the hazard from bacterial colonization allows these mutants to grow biologically older and more decrepit than end-of-life wild-type animals. Together, these findings support the argument that C. elegans daf-2 mutants are valuable for studying healthy lifespan extension. daf-2 mutants live longer because of a two-part mechanism: a slower rate of aging (leading to extension of healthspan) and an increased ability to resist death due to bacterial colonization (leading to extension of decrepitude). More generally, the results presented here show how the healthspan of an organism can be affected in opposite ways at different times of life by an intervention that both decreases the rate of aging and also mitigates a disease that kills old individuals. This is important to keep in mind when seeking to develop interventions that act by different demographic mechanisms to increase human lifespan.