Extending lifespan while shortening healthspan?

One of the central precepts of biogerontology is that meaningful lifespan extension will be concomitant with extension of the “healthspan”, i.e., the vigorous part of life — life that is, for lack of a better phrase, worth living.

This relationship is borne out both in nature (where longer-lived organisms also have longer healthspans) and in the laboratory, where genetic and pharmaceutical manipulations increase longevity also increase the duration of healthy life (q.v. Apfeld and Kenyon‘s study of the worm daf-2 mutant, which is still active and visually “young” at a time when most of its wildtype cohorts are moribund).

A related point is essentially the converse: We screen for longevity genes by looking for mutants that confer extended lifespan, rather than those that shorten it. It’s very easy to decrease longevity by making an animal sick. Genetic changes that derange or destroy vital functions are likely to hasten death but are unlikely to teach us anything about the fundamental mechanisms of aging.

In addition to being a unifying theme in academic biogerontology, this idea is also an important aspect of the way that those of us in the life extension movement answer an oft-encountered objection to longevity enhancement, which I will now state in the most charitable way I can: We’ve seen our parents and grandparents age and become frail, slowly stripped of their mental acuity and physical dignity. People aren’t so much living longer as “dying longer.” Why, then, would we want to add ten or twenty years to that painful process? (This line of thinking has been termed the Tithonus Error, after the Greek myth of the man whose immortal lover wished for him eternal life but forgot to add a clause for eternal youth; Tithonus ended up shrinking into a cricket, which the goddess kept in her pocket.)

The answer to this objection is that we don’t want to simply add years to life, but life to years — and, based on what we know from decades of biogerontological research, we expect lifespan extension to necessarily entail healthspan extension. In order for us to consider the Tithonus error to be an error, we must believe this is so. (There are those who would argue that conscious life at any cost is worthwhile, regardless of physical health, and I’m not sure they’re wrong, but that’s a subject for another time. The point here is that the “twenty more years in the ICU” objection is an important part of the larger public debate on the issue of longevity research, and it needs to be answered — and we feel like we have done so.)

Because of the importance of this assumption, we need to be on the lookout for counterexamples, such as the one provided by a recent study from Avanesian et al.. The authors show that lamotrigine, an anticonvulsant medication already shown to extend lifespan in the worm C. elegans, also has longevity benefits in the fly — but at an apparent cost to healthspan:

Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster

he discovery of life extension in Caenorhabditis elegans treated with anticonvulsant medications has raised the question whether these drugs are prospective anti-aging candidate compounds. The impact of these compounds on neural modulation suggests that they might influence the chronic diseases of aging as well. Lamotrigine is a commonly used anticonvulsant with a relatively good adverse-effects profile. In this study, we evaluated the interaction between the impacts of lamotrigine on mortality rate, lifespan, metabolic rate and locomotion. It has been proposed in a wide range of animal models that there is an inverse relationship between longevity, metabolic rate, and locomotion. We hypothesized that the survival benefits displayed by this compound would be associated with deleterious effects on health span, such as depression of locomotion. Using Drosophila as our model system, we found that lamotrigine decreased mortality and increased lifespan in parallel with a reduction in locomotor activity and a trend towards metabolic rate depression. Our findings underscore the view that assessing health span is critical in the pursuit of useful anti-aging compounds.

In short, lamotrigine extends life but decreases metabolism and locomotor activity. The conclusions are a bit confounded by the nature of the drug used. Lamotrigine is an anticonvulsant; it’s not surprising that long-term depression of neuromuscular activity would diminish locomotor activity. Still, the paper represents a clear counterexample to the positive association between healthspan and lifespan.

Let me be clear: I do not think that this study represents a serious blow against the idea that lifespan extension will entail healthspan extension — the idea is well supported in both nature and the laboratory. Rather, as the authors point out, the existence of exceptions to the general case underscores the importance of vetting each candidate longevity enhancement therapy for its effects on healthspan, before rushing into further development.

This raises a further question: We believe that lifespan is regulated, at least in part, by processes that have been conserved across evolution — this is the fundamental justification for studying aging in model organisms. When leads are generated in model organisms like worms and flies, however, should negative outcomes/side effects rule out further study and development in models that are evolutionarily closer to humans, such as mice? Or should any promising longevity enhancement therapy in the smaller metazoans be vetted in mice before conclusions are drawn?

Avanesian, A., Khodayari, B., Felgner, J., & Jafari, M. (2009). Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster Biogerontology DOI: 10.1007/s10522-009-9227-1