Mutation of daf‐2 extends lifespan via tissue‐specific effectors that suppress distinct life‐limiting pathologies

Abstract

In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF‐1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf‐2 insulin/IGF‐1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf‐2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS‐regulated DAF‐16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF‐16 also promotes p Age in class 2 daf‐2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf‐2 interactions with the daf‐12 steroid receptor implies that previously described opposing effects of daf‐12 on daf‐2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF‐1 and steroid signaling. These findings support the view that wild‐type IIS acts through multiple distinct mechanisms which promote different life‐limiting pathologies, each of which contribute to late‐life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan.

The Replica Set Method is a Robust, Accurate, and High-Throughput Approach for Assessing and Comparing Lifespan in C. elegans Experiments

“…Even if the maximal probability of making such a mistake is just one in 50 animals, the shift in accuracy for TLM is nearly ten times that of RSM, at 19.4 days compared to 20.07 days, respectively ( Figure 6E , Supplementary Table S3 ). This difference is exacerbated further when assaying long-lived animals, as just a 2% mis-scoring rate increasing from mid-life reduced median survival results from TLM by approximately two days when populations were generated from a distribution based on daf-2(e1370) lifespan characteristics (median 42 days, maximum 60 days ( Kenyon et al, 1993 ; Bansal et al, 2015 ; Hahm et al, 2015 ; Podshivalova et al, 2017 ; Zhao et al, 2021 )) ( Supplementary Figure S3 ). When the possibility of mis-scoring increases to a maximum of 10%, the TLM estimate dips to 17.34 days ( Figure 6E ).…”

Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?

“…In this study [118], two types of deaths have been reported in adult C. elegans: an early death with a swollen, infected pharynx and a later death with pharyngeal atrophy [118]. Interestingly, additional work analyzing some of the well-known long-lived C. elegans mutants, such as glp-1, eat-2, ced-1, and daf-2 mutant lines, revealed that these interventions change the frequency and/or timing of either form of death, thereby leading to an increase in lifespan [118][119][120]. Again, these observations in C. elegans are also in line with the notion that the rescue of one specific life-limiting pathology may be sufficient to explain lifespan extension.…”

Molecular inhibition of RAS signalling to target ageing and age-related health

“…In worms, age-related death has a multitude of causes: early death is associated with a swollen, infected pharynx and death later in life with pharyngeal atrophy. Loss-of-function daf-2 mutations decrease death caused by pharyngeal defects ( Zhao et al, 2021 ) and increase the mutant worms' resistance to colonisation by dietary bacteria ( Podshivalova et al, 2017 ). Cardiac-specific overexpression of dFOXO in Drosophila protects against loss of cardiac function during ageing ( Wessells et al, 2009 ).…”