Biology subjects

Maeyens, L. T.

Publications and source records attributed to Maeyens, L. T..

3 recordsLinked to original sources

bioRxiv2026

Beneficial early, harmful later: age-dependent effects of testicular factors on male mortality

Men live shorter lives than women across nearly all human populations, a disadvantage that extends across most biological causes of death and that cannot be fully explained by behavioral or environmental differences. This suggests that fundamental biological mechanisms contribute to elevated male mortality. Our previous work implicated testicular factors as a major contributor, showing that prepubertal castration extends male lifespan to that of females in UM-HET3 mice, a genetically heterogeneous stock. However, it remains unknown when testicular factors begin to exert their detrimental effects on mortality. Here, we castrated UM-HET3 males before puberty (20 days), after puberty (60 days), or immediately before the typical rise in male mortality (240 days). Castration at all three ages prevented the early male mortality and increased median lifespan by 19.3%, 25.8%, and 32.9%, respectively. The comparable survival benefits of prepubertal and postpubertal castration indicate that exposure to the pubertal surge in testicular factors, including male sex hormones, is not responsible for establishing the male longevity disadvantage. Remarkably, castration at 240 days not only preserved the survival benefit of earlier castration but produced significantly greater survival than earlier castration, suggesting that testicular exposure before 240 days is actually beneficial. The immediate prevention of excess male mortality following castration at 240 days also indicates that the responsible testicular factors act rapidly and that their continued presence is necessary to sustain elevated male mortality. Longitudinal body-composition measurements further revealed that castration shifted males toward a female-like phenotype, characterized by reduced lean mass and continued fat accumulation into later life. Our findings reveal opposing age-dependent effects of testicular factors on survival and narrow the potential therapeutic window to later adulthood.

physiology↗

bioRxiv2026

A prediction-interval framework for identifying outlier control cohorts in lifespan studies

Control cohorts anchor the interpretation of lifespan-extending interventions, yet their lifespans vary even under identical experimental conditions. Without quantifying this expected variation, it is difficult to distinguish unusually short- or long-lived cohorts arising by chance from those reflecting potential experimental anomalies, with important consequences for interpreting treatment effects. The National Institute on Aging Interventions Testing Program (ITP), which tests interventions in mice across three independent sites using standardized protocols, provides a unique opportunity to address this problem. Previously, unusually short-lived males at the University of Texas in 2017 and unusually long-lived females at The Jackson Laboratory in 2022 were identified as potentially anomalous, but no standardized framework existed to determine whether such deviations exceeded expected variation. Here, we analyzed 10,757 control mice spanning 18 years of the ITP to quantify historical variation within and between sites and develop a prediction-interval framework for prospectively identifying unusual cohorts. We found that year-to-year variation, particularly in males, contributed substantially more to variation among cohort means than expected from random sampling alone. Accounting for this variation, our predictive framework flagged the 2022 Jackson Laboratory females but not 2017 University of Texas males, while flagging a previously unrecognized male cohort. Excluding this newly flagged cohort from the original lifespan analysis changed the statistical significance of two rapamycin regimens. These findings highlight the importance of a standardized framework for outlier detection and demonstrate the importance of accounting for natural variability in aging studies.

bioinformatics↗

bioRxiv2026

Non-enzymatic ABHD6 interacts with Akt-FoxO1 axis to regulate selective hepatic insulin resistance

The enzymatic function of ABHD6 on insulin secretion and insulin resistance is well documented. However, its non-enzymatic function, especially its effects on selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) is completely unexplored. ABHD6 is elevated under conditions of diet-induced obesity and aging. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver specific overexpression of native and enzymatic inactive mutant ABHD6 mouse models. We demonstrated that ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD and liver fibrosis. Furthermore, we found that non-enzymatic ABHD6, rather than its enzymatic form, contributes to this regulation. Mechanistically, we found that ABHD6 translocated into the nucleus and interacted with Akt/FoxO1 axis to regulate its function. In addition, knockdown of FoxO1 in primary hepatocytes or overexpression of constitutively active mutant FoxO1 by AAV approach could completely abolish the effects of ABHD6 on glucose tolerance and gluconeogenesis. Our study reveals an entirely different mechanism underlying selective hepatic insulin resistance that involves a previously unknown non-enzymatic function of ABHD6. This study opens an avenue for the development of a novel class of ABHD6 inhibitors to treat MASLD and liver fibrosis. HighlightsO_LIABHD6 expression in the liver is increased with obesity and aging. C_LIO_LIABHD6 manipulation affects selective hepatic insulin resistance, MASLD and liver fibrosis. C_LIO_LINon-enzymatic ABHD6 interacts with Akt/FoxO1 axis to regulate FoxO1 transcriptional activity. C_LIO_LIThe effects of ABHD6 on glucose tolerance and hepatic gluconeogenesis are completely dependent on FoxO1 activity. C_LI

physiology↗