Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance

Ye, Lan; Widlund, Anne L.; Sims, Carrie A.; Lamming, Dudley W.; Guan, Yuxia; Davis, James G.; Sabatini, David M.; Harrison, David G.; Vang, Ole; Baur, Joseph A.

doi:10.18632/aging.100576

Cited by 46 publications

(23 citation statements)

References 52 publications

(84 reference statements)

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“…Our findings support previous studies indicating that inhibition of the mTORC1 signaling pathway by rapamycin leads to autophagy activation in HGPS cells [26, 57], and we also provide evidence that progerin is degraded via the autophagy pathway [26, 37, 56, 58]. Indeed, temsirolimus treatment reduces progerin nuclear accumulation and improves the growth rate and lifespan of HGPS cells in vitro , as previously reported for rapamycin [26].…”

Section: Discussionsupporting

confidence: 92%

Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

2016

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Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.

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Section: Discussionsupporting

confidence: 92%

Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

2016

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“…However, the doses of rapamycin that can prolong mice lifespan did not induce manifest mitochondrial dysfunction in mouse skeletal muscle (441). In this scenario, recent evidence in mice is consistent with the concept that the increase of lifespan brought about by rapamycin depends on the energy-saving reductions of protein synthesis and cell proliferation, which might assign the resulting surplus energy to the preservation of mitochondrial proteins, among other pivotal proteins (116).…”

Section: Mtor Sirtuins and Klotho: The Most Consistently Altered Tasupporting

confidence: 64%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…Importantly, they also illustrate the importance of using the assessment of synthetic rates as a mechanistic outcome. The inhibition of mTOR has been the focus of much research, because of its potential to slow the aging process (Flynn et al, 2013; Wilkinson et al, 2012; Wu et al, 2013; Ye et al, 2013). However, our findings in CL indicate that lifespan extension can happen independently of a decrease in mTOR activity (Drake et al, 2014).…”

Section: 2 Discussionmentioning

confidence: 99%

The measurement of protein synthesis for assessing proteostasis in studies of slowed aging

Miller

Drake

Naylor

et al. 2014

Ageing Research Reviews

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Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or proteostasis) is important for slowing the aging process. Since proteostasis is a dynamic process, monitoring it is not a simple task and requires use of appropriate methods. This review will introduce methods to assess protein and DNA synthesis using deuterium oxide (D2O), and how protein and DNA synthesis outcomes provide insight into proteostatic mechanisms. Finally, we provide a discussion on how these assessments of protein and DNA synthesis are “mechanistic” investigations and provide an appropriate framework for the further development of slowed aging treatments.

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Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance

Cited by 46 publications

References 52 publications

Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

The measurement of protein synthesis for assessing proteostasis in studies of slowed aging

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