Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

Fok, Wilson C.; Zhang, Yiqiang; Salmon, Adam B.; Bhattacharya, Alok; Gunda, Rakesh; Jones, Dean P.; Ward, Walter F.; Fisher, Kathleen; Richardson, Arlan; Pérez, Viviana

doi:10.1093/gerona/gls127

Cited by 55 publications

(58 citation statements)

References 55 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observation that protein RRs (i.e., proteolytic clearance rates) are reduced in the three models evaluated is perhaps counterintuitive in light of reports of reduced mTORC1 signaling and enhanced autophagy in these models (Hsieh & Papaconstantinou, 2004; Wang & Miller, 2012; Fok et al ., 2013). Autophagy is a lysosomal pathway that degrades various cellular components, including proteins and organelles, and is suppressed by mTORC1 signaling and upregulated in response to certain forms of stress, such as nutrient deprivation (Klionsky & Emr, 2000).…”

Section: Discussionmentioning

confidence: 99%

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

et al. 2015

View full text Add to dashboard Cite

SummaryCombating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age‐related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie‐restricted (CR), and rapamycin (Rapa)‐treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half‐lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa‐treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S‐transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

show abstract

Section: Discussionmentioning

confidence: 99%

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Recent work showed that 40% CR for 6 mo upregulates mouse liver mRNA levels of all seven sirtuins (138).…”

Section: Calorie Restriction and Agingmentioning

confidence: 99%

“…A study aimed at testing this notion in mice (138) showed that both CR and rapamycin reduce mTOR signaling (as assessed by ribosomal protein S6 phosphorylation) and correspondingly increase autophagy; however, only CR decreased the fat mass, and increased insulin sensitivity, SIRT1-7 gene expression, and the reduced-to-oxidized glutathione ratio. In addition, rapamycin-mediated lifespan extension in genetically heterogeneous mice was not accompanied by some metabolic and endocrine changes that are present in mice subjected to CR, and the hepatic expression of xenobiotic metabolism genes was different for each of these interventions (282).…”

Section: Calorie Restriction and Agingmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

“…Although rapamycin and caloric restriction both increase the life span of mice, they probably do not occur through similar mechanisms. Dietary restricted mice (40% food restriction) and rapamycin-treated mice both exhibited increased levels of autophagy [29]. The fat mass was similar between control and rapamycin-treated mice, but lower for the caloric restricted mice.…”

Section: Agingmentioning

confidence: 93%

Altering Autophagy: Mouse Models of Human Disease

Hale¹,

Ledbetter²,

Gawriluk³

2013

Autophagy - A Double-Edged Sword - Cell Survival or Death?

View full text Add to dashboard Cite

Short-Term Treatment With Rapamycin and Dietary Restriction Have Overlapping and Distinctive Effects in Young Mice

Cited by 55 publications

References 55 publications

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

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

Altering Autophagy: Mouse Models of Human Disease

Contact Info

Product

Resources

About