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Principal Investigator: PAUL L FOX
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $474,473
Funding agency: National Institute on Aging
Project Summary/Abstract
Advanced age is the leading risk factor for Alzheimer's disease (AD). Our program is based on a central tenet of
geroscience that select pathways and mechanisms are shared between advanced age and chronic disease,
and knowledge of one can inform the other. The mTORC1-S6K1 kinase axis is an obesity-activated pathway
that restricts longevity, and targeting this pathway extends lifespan in animal models. This pathway has been
implicated in AD pathogenesis, and pre-clinical intervention studies are promising. However, pharmacological
inhibition causes harmful side-effects, deterring therapeutic application. We have discovered a Cdk5-driven
bifurcation of the mTORC1-S6K1 pathway that contributes to aging and adiposity. We identified a novel, triply-
phosphorylated form of S6K1 (we term S6K1*) phosphorylated at two sites in the C-terminus, as well as at
Thr389, the classical mTORC1 activation site. Multi-site phosphorylated S6K1 directs phosphorylation of novel
targets, including the dual function tRNA synthetase, Glu-Pro tRNA synthetase (EPRS), coenzyme A synthase
(CoASY), and lipocalin-2 (Lcn2). Importantly, mice bearing a phospho-deficient mutation of EPRS at the critical
Ser999 residue are lean and exhibit ~120-day lifespan extension. Ser999 EPRS phosphorylation is required for
elevated adipocyte expression of key longevity-related adipokines, including monocyte chemoattractant protein-
1 (MCP1) and plasminogen-activator-1 (PAI-1). MCP1 is a pro-inflammatory protein predominant in the
senescence-associated secretory phenotype (SASP); PAI-1 is a marker and mediator of cell senescence and
aging, and a null mutation in SERPINE1, the gene encoding PAI-1, protects against biological aging.
Importantly, these novel, age-related targets of S6K1* also are implicated in AD progression. For example,
serum MCP1 level is associated with cognitive decline in mouse AD models and AD patients, and PAI-1
knockout, or pharmacologic inhibition, reduces AD in mice. We hypothesize that the extended mTORC1-S6K1
pathway and its effectors contribute to AD onset and progression, and that genetic inhibition of the pathway will
retard AD onset and reduce its severity with minimal adverse side effects. Also, mice fed a high-fat diet will
show that obesity influences aging and AD progression by a common pathway. We will test these hypotheses in
two Specific Aims. In the first Aim, we will elucidate the role of the S6K1* pathway in AD progression. AD-
susceptible mice will be bred with two genetic mouse models of S6K1* pathway inhibition developed in our
laboratory, namely, EPRS phospho-deficient knock-in mice bearing a Ser999-to-Ala mutation, and our newly
developed S6K1 Ser429-to-Ala mouse model, that lacks the extended S6K1* substrate selection, but exhibits
unaltered canonical S6K1 kinase activity. We will determine effects of S6K1* pathway inhibition on AD
pathology and adverse cognitive side-effects. In the second Aim we will determine the influence of obesity on
S6K1* pathway-mediated AD progression. Our program will establish new mechanisms and molecular targets
for intervention in the aging process and AD.
Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><AD dementia><AD model><AD pathology><Adipocytes><Adipose Cell><Adipose tissue><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's disease risk><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amino Acyl T RNA Synthetases><Amino Acyl-tRNA Ligases><Amino Acyl-tRNA Synthetases><Aminoacyl Transfer RNA Synthetase><Aminoacyl-tRNA Synthetase><Amish><Animal Model><Animal Models and Related Studies><Behavior><Biological Aging><Blood Serum><Brain><Brain Nervous System><Breeding><CCL2><CCL2 gene><Cell Aging><Cell Communication and Signaling><Cell Senescence><Cell Signaling><Cellular Aging><Cellular Senescence><Chemokine, CC Motif, Ligand 2><Chronic><Chronic Disease><Chronic Illness><Clinical Trials><CoA><Coenzyme A><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Communities><Complex><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><Data><Development><Diathesis><Disease Progression><Disease susceptibility><Disturbance in cognition><Elderly><Encephalon><Exhibits><Fat Cells><Fatty Tissue><Gene Modified><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Code><Genetic Diseases><Genetic defect><Geroscience><High Fat Diet><Humulin R><Impaired cognition><Increase lifespan><Inflammation><Inflammatory><Insulin><Insulin Resistance><Intervention><Intervention Strategies><Intervention Studies><Intracellular Communication and Signaling><KI mice><Kinases><Knock-in><Knock-in Mouse><Knock-out><Knockout><Knowledge><LCN2><LCN2 gene><Laboratories><Leanness><Learning><Length of Life><Ligase><Ligase Gene><Lipocalin 2><Lipocytes><Longevity><MCAF><MCP-1><MCP1><Mature Lipocyte><Mature fat cell><Mediating><Mediator><Memory><Metabolic Pathway><Mice><Mice Mammals><Molecular><Molecular Target><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Murine><Mus><Mutant Strains Mice><Mutation><NGAL><Neutrophil Gelatinase-Associated Lipocalin><Novolin R><Obesity><Oncogenic Lipocalin 24P3><Onset of illness><Pathogenesis><Pathway interactions><Phosphorylation><Phosphorylation Site><Phosphotransferase Gene><Phosphotransferases><Plasminogen Activator><Primary Senile Degenerative Dementia><Pro-tRNA><Process><Protein Phosphorylation><Proteins><Regular Insulin><Replicative Senescence><Role><SCYA2><SERPINE1><SERPINE1 gene><Serum><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A2><Synthetases><Testing><Therapeutic><Thinness><Tissue Donors><Tissue Transplantation><Transfer RNA><Transfer RNA Synthetase><Transphosphorylases><Transplantation><Triplet Codon-Amino Acid Adaptor><Uterocalin><Visceral><Wild Type Mouse><accelerated aging><accelerated biological age><accelerated biological aging><adipocytokines><adipokines><adipose><adiposity><advanced age><age acceleration><age associated><age correlated><age dependent><age linked><age related><age specific><aging biological marker><aging biomarker><aging marker><aging process><alzheimer model><alzheimer risk><aminoacid tRNA ligase><biological process of age><biological signal transduction><cdk Proteins><chronic disorder><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><corpulence><developmental><diet-associated obesity><diet-induced obesity><diet-related obesity><disease onset><disorder onset><elongating the lifespan><extend life span><extend lifespan><gene modification><gene null><genetic condition><genetic disorder><genetically modified><genome mutation><geriatric><geroscientific><inhibitor><insulin resistant><insulin tolerance><intervention research><interventional research><interventional strategy><interventional study><interventions research><knockin><knockin mice><liability to disease><lifespan extension><member><model of animal><mouse model><mouse mutant><murine model><neuropathologic><neuropathological><neuropathology><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><null mutation><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><pharmacologic><pre-clinical><preclinical><primary degenerative dementia><programs><proline-tRNA><prolyl-tRNA><senescence associated secretome><senescence associated secretory phenotype><senile dementia of the Alzheimer type><senior citizen><side effect><social role><tRNA><tRNA Synthetase><transfer Ribonucleic acids><transplant><white adipose tissue><wildtype mouse><yellow adipose tissue>