SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass - PubMed (original) (raw)

doi: 10.1111/acel.12220. Epub 2014 Jun 16.

Sarah J Mitchell, Alejandro Martin-Montalvo, Robin K Minor, Maria Almeida, Ana P Gomes, Morten Scheibye-Knudsen, Hector H Palacios, Jordan J Licata, Yongqing Zhang, Kevin G Becker, Husam Khraiwesh, José A González-Reyes, José M Villalba, Joseph A Baur, Peter Elliott, Christoph Westphal, George P Vlasuk, James L Ellis, David A Sinclair, Michel Bernier, Rafael de Cabo

Affiliations

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass

Evi M Mercken et al. Aging Cell. 2014 Oct.

Abstract

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.

Keywords: healthspan; inflammation; lifespan; muscle wasting; osteoporosis; sirtuins.

Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

PubMed Disclaimer

Figures

Figure 1

Figure 1

SRT2104 treatment improves whole-body physiology and extends lifespan in mice fed a standard diet. (A) Kaplan–Meier survival curves of mice fed a standard diet (SD) or a SD supplemented with SRT2104. The arrow at 28 weeks indicates the age at which SRT2104 treatment was started. (B–M) The following parameters were analyzed in SD-fed mice without and with SRT2104 supplementation: (B) bodyweights; (C) percentage fat mass; (D) average caloric intake; (E) spontaneous locomotor activity; (F) treadmill performance; (G) time to fall from an accelerating rotarod; (H) trabecular bone volume; (I) trabecular connectivity; (J) trabecular bone mineral density (BMD); (K) circulating glucose and (L) insulin levels were measured after 16 h of fasting; (M) homeostatic measure of insulin resistance (HOMA-IR) index. Data are shown as mean ± SEM. *P < 0.05 compared with SD-fed animals. BV, bone volume; TV, total volume; Tb, trabecular.

Figure 2

Figure 2

SRT2104 changes the gene expression profile differently in liver and muscle. (A) Principal component analysis (PCA) was performed on liver and muscles tissues of mice fed a SD or SD supplemented with SRT2104. (B) Parametric analysis of gene-set enrichment (PAGE) analysis was performed on microarray data from mice fed a SD or subjected to SRT2104. Columns show pathways significantly upregulated (red) or downregulated (blue) by SRT2104 treatment. See also Tables S5–S7. (C) Effect of SRT2104 on inflammatory and mitochondrial-related pathways from the PAGE analysis for liver and skeletal muscle. (D) Venn diagrams of overlapping gene sets significantly modified by SRT2104 vs. calorie restriction (CR). Upregulated gene sets are depicted in red and the downregulated gene sets in blue. (E) Effect of SRT2104 and CR on select gene sets from mouse liver and muscle. The list of the significantly modified gene sets can be found in Tables S6 and S7. SD, standard diet.

Figure 3

Figure 3

SRT2104 treatment increases mitochondrial content and suppresses the inflammatory response. (A) Representative transmission electron micrographs of liver and muscle, and the respective mitochondrial quantification. (B) Citrate synthase activity. (C) Representative immunoblots from inflammatory markers in liver and muscle tissues. (D) mRNA levels of COMMD genes assessed by quantitative real-time PCR. Relative expression values were normalized to SD-fed mice. (E) Representative immunoblots from oxidative stress markers in liver and muscles. Data are shown as mean ± SEM. *P < 0.05 compared with SD-fed mice.

Figure 4

Figure 4

Short-term SRT2104 treatment preserves muscle and bone mass. (A) Bodyweights during 14 days of hindlimb suspension and average food consumption (inset) for 6-month-old mice fed either a standard diet (SD) or SD supplemented with SRT2104 for 6 weeks. (B) Muscle weights. (C) Trabecular bone volume, trabecular connectivity, and trabecular bone mineral density (BMD). (D) Alkaline phosphatase (AP) activity in C2C12 cells infected with SIRT1 shRNA or nontargeting shRNA control and treated with 1 and 3 μ

m

SRT2104 for 24 h. (E) Osteoclast (OC) number in bone marrow-derived osteoblastic cells from wild-type (WT) mice and SIRT1f/f mice and treated with 1 and 3 μ

m

SRT2104 for 4 days. (F) Cortical thickness in femurs from wild-type (WT) and SIRT1KO mice. Data are mean ± SEM. *P < 0.05. SOL, soleus; PL, plantaris; GAS, gastrocnemius; BV, bone volume; TV, total volume; Tb, trabecular.

Similar articles

Cited by

References

    1. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE. 2008;3:e2264. - PMC - PubMed
    1. Baur J, Pearson K, Price N, Jamieson H, Lerin C, Kalra A, Prabhu V, Allard J, Lopez-Lluch G, Lewis K, Pistell P, Poosala S, Becker K, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein K, Spencer R, Lakatta E, Le Couteur D, Shaw R, Navas P, Pueigserver P, Ingram K, de Cabo R, Sinclair D. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. - PMC - PubMed
    1. Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R. Are sirtuins viable targets for improving healthspan and lifespan? Nat. Rev. Drug Discov. 2012;11:443–461. - PMC - PubMed
    1. Bernier M, Paul RK, Martin-Montalvo A, Scheibye-Knudsen M, Song S, He H-J, Armour SM, Bohr VA, Wang L, Zong Y, Sinclair DA, de Cabo R. Negative regulation of STAT3-mediated cellular respiration by SirT1. J. Biol. Chem. 2011;286:19270–19279. - PMC - PubMed
    1. Bordone L, Cohen D, Robinson A, Motta MC, Van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell. 2007;6:759–767. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources