METABOLIC REGULATION OF HEALTHY AGING BY DIET, MTOR SIGNALING, AND SKELETAL MUSCLE - PROJECT SUMMARY OBESIT…

Assistance award details

Assistance award identifier

ASST_NON_K00AG083290_075

FAIN

K00AG083290

Recipient

UNIVERSITY OF WISCONSIN SYSTEM

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$169,601

Period

Sep 10, 2023 – Jan 31, 2029

Fiscal year

2025

Place of performance state

WI

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

METABOLIC REGULATION OF HEALTHY AGING BY DIET, MTOR SIGNALING, AND SKELETAL MUSCLE - PROJECT SUMMARY OBESITY, GLUCOSE AND INSULIN RESISTANCE, AND OTHER METABOLIC DISORDERS ARE ON THE RISE DUE IN PART TO THE GROWING AGED POPULATION. DIETARY INTERVENTIONS SUCH AS CALORIE RESTRICTION (CR) CAN IMPROVE AND EVEN REVERSE THESE COMPLICATIONS BUT CR DIETS ARE DIFFICULT FOR MOST PEOPLE TO ADHERE TO. ALTERNATIVE REGIMENS BASED ON RESTRICTION OF SPECIFIC MACRONUTRIENTS, SUCH AS PROTEIN RESTRICTION (PR) OR LIMITATION OF SPECIFIC ESSENTIAL AMINO ACIDS, HAVE SHOWN PROMISE IN IMPROVING METABOLIC HEALTH AND EXTEND LIFESPAN WITHOUT NEEDING TO LIMIT OF CALORIES. I AND THE LAMMING LAB HAVE SHOWN THAT ISOLEUCINE RESTRICTION (ILER) IMPROVES GLUCOSE HOMEOSTASIS, IMPROVE BODY WEIGHT AND ADIPOSITY, AND EVEN EXTENDS THE LIFESPAN OF MICE. ILER INDUCES FIBROBLAST GROWTH FACTOR 21 (FGF21), AN ENERGY EXPENDITURE HORMONE AND SOME BUT NOT ALL OF THE DOCUMENTED BENEFITS OF ILER ARE DEPENDENT ON FGF21. DURING THE F99 PHASE, I WILL DETERMINE FOR THE FIRST TIME IF FGF21 IS REQUIRED FOR LIFESPAN EXTENDING EFFECTS OF ILER BY USING A MOUSE MODEL OF WHOLE BODY FGF21 KNOCKOUT. I WILL ALSO TEST THE NECESSITY OF MTORC1 IN THE ADIPOSE AND SKELETAL MUSCLE – TWO KEY SITES OF ISOLEUCINE CATABOLISM – ON ILER BENEFITS BY DELETING RAPTOR SPECIFICALLY IN THE SKELETAL MUSCLE OR ADIPOSE TISSUE. THIS STUDY WILL NICELY BRIDGE THE GAP BETWEEN MY GRADUATE AND POSTDOCTORAL WORK AS I SHIFT MY FOCUS FROM WHOLE BODY METABOLISM AND PHYSIOLOGY TO BIOLOGY OF AGING MUSCLE. IN THE K00 PHASE, I WILL UTILIZE A VALIDATED MOUSE MODEL OF RESISTANCE EXERCISE TRAINING TO DETERMINE THE INTERACTION BETWEEN TRAINING AND THE MTORC1 INHIBITOR RAPAMYCIN ON SKELETAL MUSCLE OUTCOMES, SUCH AS MUSCLE MASS, FIBER TYPE, STRENGTH AND MITOCHONDRIAL RESPIRATION IN BOTH MALE AND FEMALE MICE OF MIDDLE AND OLD AGE, AS WELL AS ORGANISMAL OUTCOMES INCLUDING FRAILTY. I WILL ALSO UTILIZE BANKED TISSUES TO EXAMINE MUSCULAR OUTCOMES IN OLDER HUMANS FROM