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Published on: January 7, 2018
Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive
Dudley W Lamming1, Lan Ye, Clinton M Astle
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Abstract:
Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the life span of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats, and humans is associated with insulin resistance (J Am Soc Nephrol., 19, 2008, 1411; Diabetes, 00, 2010, 00; Science, 335, 2012, 1638). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum life span. We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. To gauge the overall consequences of rapamycin treatment on average blood glucose levels, we measured HBA1c. Dietary rapamycin increased HBA1c over the first 3 weeks of treatment in young animals, but the effect was lost by 3 months, and no effect was detected in older animals. Our results demonstrate that the extended life span of HET3 mice on a rapamycin diet occurs in the absence of major changes in insulin sensitivity and highlight the importance of strain background and delivery method in testing effects of longevity interventions.
Insights
Dietary rapamycin extends lifespan in HET3 mice but does not significantly impair insulin sensitivity. This study highlights the importance of mouse strain and rapamycin delivery method in longevity research.
Area of Science:
- Gerontology
- Metabolic Physiology
- Pharmacology
Background:
- Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) pathway, is known to extend lifespan across various species.
- Paradoxically, chronic rapamycin administration is often linked to insulin resistance, contrasting with the typical association between longevity interventions and improved insulin sensitivity.
Purpose of the Study:
- To investigate the impact of dietary rapamycin on glucose homeostasis and insulin resistance in HET3 mice, a strain exhibiting robust lifespan extension with this intervention.
- To determine if rapamycin-induced lifespan extension in HET3 mice is associated with altered insulin sensitivity, considering previous findings in other mouse strains and delivery methods.
Main Methods:
- HET3 mice of different ages were treated with dietary rapamycin.
- Glucose tolerance tests and insulin tolerance tests were performed to assess glucose homeostasis and insulin sensitivity.
- Hemoglobin A1c (HbA1c) levels were measured to evaluate average blood glucose over time.
Main Results:
- Rapamycin treatment induced glucose intolerance in both young and old HET3 mice.
- Unlike previous studies with injected rapamycin, dietary rapamycin did not impair insulin tolerance in HET3 mice.
- Dietary rapamycin transiently increased HbA1c in young mice but had no lasting effect, with no effect observed in older mice.
Conclusions:
- Lifespan extension in HET3 mice fed a rapamycin diet occurs without significant detrimental changes in insulin sensitivity.
- The findings underscore the critical influence of genetic background (mouse strain) and drug delivery method (dietary vs. injected) on the metabolic effects of rapamycin.
- This research provides crucial insights into the complex relationship between rapamycin, aging, and metabolic health, informing future longevity studies.
