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Diminished mTOR signaling: a common mode of action for endocrine longevity factors.

Lamming DW - Springerplus (2014)

Bottom Line: The mechanism by which CR and these other interventions extend lifespan is the subject of significant debate and research.These findings can be reconciled if longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling.This review presents a unifying hypothesis that explains the lifespan-extending effects of a variety of genetic mutations and pharmaceutical interventions and points towards new molecular pathways which may also be leveraged to promote healthy aging.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin USA ; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin USA.

ABSTRACT
Since the initial observation that a calorie-restricted (CR) diet can extend rodent lifespan, many genetic and pharmaceutical interventions that also extend lifespan in mammals have been discovered. The mechanism by which CR and these other interventions extend lifespan is the subject of significant debate and research. One proposed mechanism is that CR promotes longevity by increasing insulin sensitivity, but recent findings that dissociate longevity and insulin sensitivity cast doubt on this hypothesis. These findings can be reconciled if longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling. This review presents a unifying hypothesis that explains the lifespan-extending effects of a variety of genetic mutations and pharmaceutical interventions and points towards new molecular pathways which may also be leveraged to promote healthy aging.

No MeSH data available.


Related in: MedlinePlus

The sexually dimorphic effect of rapamycin treatment. Rapamycin consistently has a stronger effect on average and maximum female lifespan than on male lifespan in both HET3 and C57BL/6 mice. Data taken from (Zhang et al. 2014; Miller et al. 2014; Harrison et al. 2009; Fok et al. 2014b); median lifespan not available for HET3 mice initiated on 14ppm rapamycin at 20 months of age, mean is shown instead.
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Fig3: The sexually dimorphic effect of rapamycin treatment. Rapamycin consistently has a stronger effect on average and maximum female lifespan than on male lifespan in both HET3 and C57BL/6 mice. Data taken from (Zhang et al. 2014; Miller et al. 2014; Harrison et al. 2009; Fok et al. 2014b); median lifespan not available for HET3 mice initiated on 14ppm rapamycin at 20 months of age, mean is shown instead.

Mentions: Finally, we have discussed that the context in which PI3K/Akt/mTOR signaling is regulated may be critical to understanding the effect on longevity. One of the most significant contexts is sex, and both genetic and pharmaceutical interventions in the insulin/IGF-1/mTOR signaling pathway consistently show greater benefits in females than males. This sexual disparity in lifespan extension is observed in mice for either Irs1 or S6K1 (Selman et al. 2009, 2011), mice heterozygous for both mTOR and mLST8 (Lamming et al. 2012), and consistently and across a range of doses in mice treated with rapamycin (Figure 3) (Miller et al. 2014). While the mechanistic and physiologic basis for this effect is unknown, 17β-estradiol plays a protective role against the development of rapamycin-induced diabetes, suggesting a possible contribution of sex hormones (Schindler et al. 2014). A deeper understanding the role of sex hormones and other endocrine factors in the PI3K/Akt/mTOR-dependent regulation of longevity will provide a platform for the development of interventions that can extend lifespan across the sexes and in a wide range of physiological contexts.Figure 3


Diminished mTOR signaling: a common mode of action for endocrine longevity factors.

Lamming DW - Springerplus (2014)

The sexually dimorphic effect of rapamycin treatment. Rapamycin consistently has a stronger effect on average and maximum female lifespan than on male lifespan in both HET3 and C57BL/6 mice. Data taken from (Zhang et al. 2014; Miller et al. 2014; Harrison et al. 2009; Fok et al. 2014b); median lifespan not available for HET3 mice initiated on 14ppm rapamycin at 20 months of age, mean is shown instead.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4320218&req=5

Fig3: The sexually dimorphic effect of rapamycin treatment. Rapamycin consistently has a stronger effect on average and maximum female lifespan than on male lifespan in both HET3 and C57BL/6 mice. Data taken from (Zhang et al. 2014; Miller et al. 2014; Harrison et al. 2009; Fok et al. 2014b); median lifespan not available for HET3 mice initiated on 14ppm rapamycin at 20 months of age, mean is shown instead.
Mentions: Finally, we have discussed that the context in which PI3K/Akt/mTOR signaling is regulated may be critical to understanding the effect on longevity. One of the most significant contexts is sex, and both genetic and pharmaceutical interventions in the insulin/IGF-1/mTOR signaling pathway consistently show greater benefits in females than males. This sexual disparity in lifespan extension is observed in mice for either Irs1 or S6K1 (Selman et al. 2009, 2011), mice heterozygous for both mTOR and mLST8 (Lamming et al. 2012), and consistently and across a range of doses in mice treated with rapamycin (Figure 3) (Miller et al. 2014). While the mechanistic and physiologic basis for this effect is unknown, 17β-estradiol plays a protective role against the development of rapamycin-induced diabetes, suggesting a possible contribution of sex hormones (Schindler et al. 2014). A deeper understanding the role of sex hormones and other endocrine factors in the PI3K/Akt/mTOR-dependent regulation of longevity will provide a platform for the development of interventions that can extend lifespan across the sexes and in a wide range of physiological contexts.Figure 3

Bottom Line: The mechanism by which CR and these other interventions extend lifespan is the subject of significant debate and research.These findings can be reconciled if longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling.This review presents a unifying hypothesis that explains the lifespan-extending effects of a variety of genetic mutations and pharmaceutical interventions and points towards new molecular pathways which may also be leveraged to promote healthy aging.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin USA ; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin USA.

ABSTRACT
Since the initial observation that a calorie-restricted (CR) diet can extend rodent lifespan, many genetic and pharmaceutical interventions that also extend lifespan in mammals have been discovered. The mechanism by which CR and these other interventions extend lifespan is the subject of significant debate and research. One proposed mechanism is that CR promotes longevity by increasing insulin sensitivity, but recent findings that dissociate longevity and insulin sensitivity cast doubt on this hypothesis. These findings can be reconciled if longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling. This review presents a unifying hypothesis that explains the lifespan-extending effects of a variety of genetic mutations and pharmaceutical interventions and points towards new molecular pathways which may also be leveraged to promote healthy aging.

No MeSH data available.


Related in: MedlinePlus