How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude

Abstract

Summary The goal of aging research is to extend healthy, active life. For decades, C. elegans daf-2 insulin/IGF-1 receptor mutants have served as a model for extended lifespan and youthfulness. However, a recent report suggested that their longevity is associated with an undesirable phenotype: a disproportionately long period of decrepitude at the end of life. In a human population, such an outcome would be a burden to society, bringing into question the relevance of daf-2 mutants as a model for life extension. However, here we report that, following an extended period of movement, daf-2 mutants survive longer in a decrepit state because of a beneficial trait: they are resistant to colonization of the digestive tract by dietary bacteria, a condition that leads to premature death in wild type and prevents their manifestation of decrepitude. If bacterial colonization is prevented, daf-2 mutants lead chronologically and proportionately healthier lives relative to wild type.

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway

“…(2015) and Hahm et al. (2015) did not include intermediate movement phenotypes, but other recent studies observed that an extended intermediate movement behavior was characteristic of both long‐lived mutants as well as long‐lived worms in wild‐type background (Churgin et al., 2017; Podshivalova et al., 2017; Zhang et al., 2016). Zhang et al.…”

“…Podshivalova et al. (2017) show that an extended period of reduced movement in daf‐2 mutants is due to enhanced resistance to bacterial colonization that leads to premature death in wild‐type animals. The observations for other long‐lived mutants may be explained by a similar survivor benefit, a trade‐off between fitness and longevity, or inappropriate activation of the dauer pathway (Arantes‐Oliveira, Berman, & Kenyon, 2003).…”

“…Further, the time in Class A was not predictive of time in Class B or C. Consistent with this, Podshivalova et al. (2017) report early‐life vigor for daf‐2 mutants, including movement behavior, that was not correlated with the duration of later‐life decrepitude. In summary, the data show that early‐life movement (Class A) is not a good indicator of later‐life movement (Class B or C), thereby reducing the quality of its usage as a healthspan biomarker.…”

“…(2017) utilized both metrics of movement velocity and distance travelled in two daf‐2 alleles. They show that daf‐2(e1370) and daf‐2(e1368) maintained movement longer than wild‐type, although the daf‐2(e1370) mutant had slower velocity and dauer‐like movement behaviors.…”

“…They found that some longevity mutants (e.g., clk‐1) extend frailty, but others (e.g., daf‐2) do not. Corroborating these findings, Podshivalova, Kerr, and Kenyon (2017) found that two daf‐2 mutants have extended movement ability and that the daf‐2(e1370) , but not the daf‐2(e1368) allele, has reduced movement velocity. Taken together, the comodulation of lifespan and healthspan remains murky.…”