Aging and energetics' 'Top 40' future research opportunities 2010-2013

Abstract

Background: As part of a coordinated effort to expand our research activity at the interface of Aging and Energetics a team of investigators at The University of Alabama at Birmingham systematically assayed and catalogued the top research priorities identified in leading publications in that domain, believing the result would be useful to the scientific community at large.

Objective: To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years.

Design: The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive.

Results: Ten research categories were identified from the 40 papers. These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart, and (10) mitochondria, reactive oxygen species, and cellular energetics.

Conclusion: The field is rich with exciting opportunities to build upon our existing knowledge about the relations among aspects of aging and aspects of energetics and to better understand the mechanisms which connect them.

Figure 1.. Upstream of mTOR: classical and non-classical inputs.

a | Growth factors such as insulin stimulate PI3K to generate phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P ₃), which promotes the phosphorylation (P) of AKT at Thr308 by phosphoinositide-dependent kinase 1 (PDK1). AKT phosphorylates tuberous sclerosis complex 2 (TSC2) on multiple sites to inhibit its GTPase-activating protein (GAP) activity for the small GTPase RAS homologue enriched in brain (RHEB). GTP-loaded RHEB then activates mammalian TOR complex 1 (mTORC1). Growth factors also stimulate mTORC2 by promoting its association with ribosomes in a PI3K-dependent manner. b | Amino acids stimulate mTORC1 by promoting the conversion of RAS-related GTP-binding protein (RAG) heterodimers to the active conformation, in which RAGA or RAGB is loaded with GTP and RAGC or RAGD is loaded with GDP. c | In response to low energy (high AMP/ATP ratio), AMP-activated protein kinase (AMPK) phosphorylates regulatory-associated protein of mTOR (RAPTOR) at Ser792 and TSC2 at Ser1387, leading to the inhibition of mTORC1. d | During the inhibition of the Hippo pathway component large tumour suppressor homologue (LATS) kinase, hypophosphorylated Yes-associated protein (YAP) translocates to the nucleus and promotes the expression of the microRNA miR-29. miR-29 targets PTEN mRNA and inhibits PTEN translation, which leads to increased levels of PtdIns(3,4,5)P ₃ and the activation of both mTORC1 and mTORC2. Dashed arrows represent translocation of the molecule. e | Glycogen synthase kinase 3β (GSK3β) activates the TSC complex by phosphorylating TSC2 at Ser1379 and Ser1383. Phosphorylation of these two residues requires priming by AMPK-dependent phosphorylation of Ser1387. WNT signalling inhibits GSK3β and the TSC complex, and thus activates mTORC1. mTORC2 is activated by WNT in a manner dependent on the small GTPase RAC1. Proteins shown in green promote mTOR activity or their activity is promoted by mTOR. Proteins shown in red inhibit mTOR activity or their activity is inhibited by mTOR. Phosphorylation depicted in yellow is an activation signal and phosphorylation depicted in orange is an inhibitory signal. 4E-BP, eIF4E-binding protein; APC, adenomatous polyposis coli; GPCR, G protein-coupled receptor; GRB10, growth factor receptor-bound protein 10; IGF, insulin-like growth factor 1;IRS1, insulin receptor substrate 1; LRP, low-density lipoprotein receptor-related protein; mLST8, mammalian lethal with SEC thirteen 8; RICTOR, rapamycin-insensitive companion of mTOR; S6K, ribosomal S6 kinase; SIN1, SAPK-interacting 1; TBC1D7, TBC1 (TRE2–BUB2–CDC16) domain family member 7; ULK1, UNC-51-like kinase 1. This figure has been reproduced with kind permission from Shimobayashi M, Hall M. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nature Reviews Molecular Cell Biology 2014;15:155–162.

Figure 2.. mTOR controls metabolism.

Mammalian TOR complex 1 (mTORC1) promotes anabolic processes, such as the biosynthesis of proteins, nucleotides and lipids, and inhibits catabolic processes such as autophagy. Aa | mTORC1 phosphorylates (P) the hydrophobic motif (Thr389) in ribosomal S6 kinase (S6K), thereby activating it to subsequently phosphorylate ribosomal protein S6 at the sites indicated to promote ribosome biogenesis. mTORC1 also phosphorylates eIF4E-binding protein (4E-BP) at multiple sites to inhibit it. Inhibition of 4E-BP stimulates translation initiation, especially of 5′ oligopyrimidine tract (termed a 5′ TOP) and pyrimidine-rich translational element (PRTE) containing mRNAs. Ab | mTORC1 stimulates nucleotide and lipid synthesis. mTORC1 promotes the gene expression of key enzymes in the pentose phosphate pathway (PPP), at least in part by activating sterol regulatory element-binding proteins (SREBPs). mTORC1 also stimulates CAD (Gln-dependent carbamoyl-phosphate synthase, Asp carbamoyltransferase, dihydroorotase) by S6K-mediated phosphorylation at Ser1859, which leads to CAD activation and the stimulation of de novo pyrimidine synthesis. Furthermore, mTORC1 promotes lipogenic gene expression by activating S6K or by inhibiting the nuclear translocation of LIPIN1, both of which activate the transcription factor SREBP. Ac | mTORC1 inhibits autophagy by phosphorylating UNC-51-like kinase 1 (ULK1) at Ser758 and ATG14 at multiple sites. During mTORC1 inhibition, AMPK phosphorylates ULK1 at Ser317, and thereby activates ULK1, which phosphorylates Beclin 1 in the vacuolar protein sorting 34 (VPS34)–Beclin 1–ATG14 complex to initiate autophagy. mTORC1 also inhibits autophagy indirectly by blocking lysosome biogenesis, by phosphorylating and inhibiting the nuclear translocation of transcription factor EB (TFEB). B | mTORC2 co-translationally phosphorylates AKT at Thr450 to prevent its ubiquitylation and degradation. mTORC2 also post-translationally phosphorylates ATK at Ser473 to promote lipogenic gene expression by activation of SREBP1c. Moreover, mTORC2 co-translationally phosphorylates IGF2 mRNA-binding protein 1 (IMP1) at Ser181, which stimulates insulin-like growth factor 2 (IGF2) production. The activity of proteins shown in green is promoted by mTOR. The activity of proteins shown in red is inhibited by mTOR. Phosphorylation depicted in yellow is an activation signal and phosphorylation depicted in red is an inhibitory signal. Dashed arrows represent translocation of the protein. mLST8, mammalian lethal with SEC thirteen 8; PDK, phosphoinositide-dependent kinase 1; RAPTOR, regulatory-associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR; SIN1, SAPK-interacting 1. This figure has been reproduced with kind permission from Shimobayashi M, Hall M. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nature Reviews Molecular Cell Biology 2014;15:155–162.