image: Figure 1. Ubiquitous and tissue-specific DAF-2 degradation extends male lifespan. (A) Kaplan-Meier curves showing survival of C. elegans hermaphrodites and males following ubiquitous DAF-2 degradation. Purple lines denote hermaphrodites and green lines denote males. Dashed lines denote the negative controls (TIR1-only on auxin) and solid lines denote DAF-degradation with 1mM auxin treatment. Each line represents at least two biological replicates with total n = 183–235. (B) Kaplan-Meier curves showing survival of C. elegans males aged on either individual or group plates. The gray line denotes the negative controls treated with ethanol and the green line denotes ubiquitous DAF-degradation with 1mM auxin treatment. The dashed lines denote single males and the solid lines denote grouped males. Each line represents three biological replicates with total n = 69–200. (C, D) Kaplan-Meier curves showing survival of C. elegans males following DAF-2 degradation in the (C) intestine and (D) germline. Gray lines denote the negative controls treated with ethanol and green lines denote DAF-degradation with 1mM auxin treatment. Each line represents at least two biological replicates with total n = 137–218. The black dashed lines denote the age at which 50% of the population has died. The asterisks denote p-values from a Cox Proportional Hazards model where ****p<.0001, ***p<.001. For additional information and the output of the CPH model, see Supplementary Table 2.
Credit: Copyright: © 2026 Al-Saadi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“Our work shows that genetic interventions targeting the IIS pathway extend not only male lifespan, but also their reproductive healthspan.”
BUFFALO, NY — September 10, 2026 — A new research paper was published in Volume 18 of Aging on August 24, 2026, titled “Disruption of the insulin/IGF-1 signaling pathway in Caenorhabditis elegans dramatically increases male longevity and enhances reproductive health late in life.”
The research was conducted by Rose S. Al-Saadi, Hannah B. Lewack and Patrick C. Phillips. Al-Saadi and Lewack contributed equally to the study. Al-Saadi and Phillips are from the Institute of Ecology and Evolution at the University of Oregon, while Lewack is affiliated with both the Institute of Ecology and Evolution at the University of Oregon and the Department of Molecular Biology at the University of California, San Diego. Phillips is the corresponding author.
Insulin/IGF-1 signaling (IIS) is one of the best-established molecular pathways regulating longevity across animal species. In C. elegans, the gene daf-2 encodes an insulin/IGF-1 receptor, and reducing its activity can substantially extend lifespan. However, most previous aging studies in this model have focused on hermaphrodites, leaving considerably less known about how males respond to interventions targeting the same pathway.
To investigate these sex-specific effects, the researchers used an auxin-inducible degron system to selectively degrade the DAF-2 receptor throughout the body or within particular tissues. When DAF-2 was degraded throughout the body, the effect on male longevity was striking: median lifespan increased by 446%, compared with a 109% increase in hermaphrodites exposed to the same intervention. The age at which 10% of the population remained alive reached 106 days in treated males, compared with 15 days in controls. The authors describe this as one of the largest lifespan extensions reported in C. elegans—or any animal—from a single intervention.
The effects also depended strongly on which tissue was targeted. Degrading DAF-2 specifically in the male intestine increased median lifespan by 69.2%. In contrast, degradation in the male germline reduced median lifespan by 18.8%, the opposite of effects previously observed in hermaphrodites. Targeting DAF-2 in neurons or the hypodermis did not significantly alter male survival. These findings demonstrate that biological sex can influence not only the magnitude but also the direction of longevity responses to disruption of the same signaling pathway.
Importantly, the researchers examined whether longer lifespan was accompanied by better health later in life. They used male reproductive success as a measure of healthspan because mating in C. elegans is a complex behavior involving muscles, reproductive organs and much of the male-specific nervous system, and it normally declines rapidly with age.
Whole-body DAF-2 degradation preserved mating success in older males and substantially slowed its age-related decline. Treated males retained reproductive capacity at later ages, effectively doubling the maximum age of potential reproductive success. However, targeting DAF-2 in any single tissue tested was insufficient to reproduce this benefit, suggesting that maintaining reproductive health in later life depends on coordinated effects across multiple tissues and physiological systems.
The researchers also identified a previously undescribed age-related phenotype in male worms, termed an “uncoordinated tail.” Older males developed a stiff or immobile tail that interfered with the complex sequence of behaviors required for mating. Whole-body DAF-2 degradation reduced the incidence of this phenotype by 71.67% at day 7 and 63.64% at day 9, suggesting that preservation of tail function may contribute to the extended reproductive healthspan.
“Taken together, these results suggest that males represent a useful tool for future aging research, as they may be more susceptible to certain interventions—fairly early in life—and provide a complex behavioral context that can be used to assess the efficacy of interventions on reproductive healthspan.”
The findings also underscore an important distinction between lifespan and healthspan. Although intestine-specific DAF-2 degradation significantly prolonged male lifespan, it did not similarly preserve reproductive health. Whole-body degradation was required to produce the broader reproductive benefit, supporting the idea that extending life does not necessarily preserve all aspects of physiological function.
The study has important limitations for interpreting its broader implications. C. elegans is a powerful model for investigating conserved mechanisms of aging, but the dramatic lifespan extension observed here should not be interpreted as evidence that suppressing insulin or IGF-1 signaling would produce comparable effects in humans. The results instead demonstrate that responses to a well-established longevity pathway can differ substantially according to sex and tissue, highlighting the importance of incorporating sex-specific biology into aging research.
Overall, the study shows that disrupting DAF-2-mediated insulin/IGF-1 signaling can dramatically extend male C. elegans lifespan while also preserving reproductive function later in life. At the same time, the contrasting effects of tissue-specific DAF-2 degradation reveal that longevity and healthspan are regulated by complex, sex-dependent interactions across tissues. These findings provide a framework for further research into why males and females can respond differently to interventions targeting conserved pathways of aging.
Paper DOI: https://doi.org/10.18632/aging.206411
Corresponding author: Patrick C. Phillips – pphil@uoregon.edu
Abstract video: https://www.youtube.com/watch?v=zQ32BnBwEBI
Keywords: aging, Insulin/IGF-1 signaling, sex differences, Caenorhabditis elegans, reproductive health
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Journal
Aging-US
Method of Research
News article
Subject of Research
Animals
Article Title
Disruption of the insulin/IGF-1 signaling pathway in Caenorhabditis elegans dramatically increases male longevity and enhances reproductive health late in life
Article Publication Date
24-Aug-2026
COI Statement
The authors declare that they have no conflicts of interest.