Miller, Benjamin

My 101

It is projected that by 2035, the number of people in the US over the age of 65 years old will be greater than the number of people below 18 years old. This projection illustrates the massive shift in the United States to an aged population. With the aging population comes challenges because of the increase costs and burdens of the diseases that accumulate with age. In our lab, we study the aging process in order to understand how to make people age slower. Our goal is not to make it possible to live 150 years, but rather to extend the period spent free of disease. In other words, rather than increase the lifespan, we aim to increase the healthspan. Of particular interest to our lab is how to maintain muscle, which is important for maintaining independence and a healthy metabolism.

In our laboratory we use models that live longer than they should, to understand what gives rise to increased healthspan. We focus on how to maintain proteins in a “young” state so that cells and tissues can continue to function normally and absent of disease. Of particular interest are mitochondria since these cellular organelles seem to be central to the aging process. Our research seeks to determine if we can maintain the quality of proteins in mitochondria to maintain overall health. In a tissue like muscle, it is our hope that maintaining mitochondria will help preserve muscle function with age. Importantly, it is always our goal to take what we learn in our laboratory experiments and translate them into human treatments that improve human healthspan.

Research

Maintaining proteostasis with aging: The Geroscience Initiative identified proteostasis as one of the seven “pillars” of aging research. Proteostasis refers to the processes that maintain proteome fidelity. My research focuses on the biosynthesis and turnover components of proteostasis. In this regard, we make direct measures of these dynamic processes, not markers or indicators, which has led to important insight into shared characteristics of slowed aging. By using stable isotopes to simultaneously measure both protein synthesis and DNA synthesis in vitro and in vivo we have made two discoveries: 1) mitochondrial proteins are selectively translated in slowed aging models, and 2) when accounting for cell proliferation, the turnover of proteins in existing cells is increased, not decreased. These findings are repeatable in several slowed aging models and slowed aging treatments.
Stress resistance and slowed aging: Like proteostasis, The Geroscience Initiative identified stress resistance as a “pillar” of aging research. My interest in stress resistance spurred from our work with the transcription factor Nrf2. From this work, we proposed a Nrf2 activator to the NIA Interventions Testing Program (ITP), which increased median lifespan in male mice. We followed this up with the proposal of a second-generation Nrf2 activator, which is currently in testing. We have used these Nrf2 activators both as a means to understand the aging process as well as treat it.
Translation of treatments to slow aging: It is my goal to translate our more basic science into potential human treatments to slow aging. We do this using unique animal models and with clinical trials in humans. My work in humans has focused either on exercise, metformin, or Nrf2 activation. More specifically, we have investigated the efficacy of these treatments to slow age-related declines in skeletal muscle mitochondrial function and skeletal muscle mass. For example, some in the aging field are pushing metformin to be the first drug used to treat aging. We have data both in support and against such use. It is clear to us that the field needs more evidence before pushing such an expensive clinical trial.
Approaches: Stable isotopes and mass spec are key features of my research program. In this regard, I consider our lab a leader in the use of D2O to measure in vitro and in vivo biosynthetic processes. We are working on methods to expand these approaches in order to continue to improve measurements of kinetic processes. I also have extensive experience in using stable isotopes for the assessment of metabolic flux. In combination these approaches allow us to explore the interface between protein and energetics.

Brief CV

Education
Ph.D., Integrative Biology, University of California, Berkeley, CA, 2002
M.S., Kinesiology, University of Wisconsin, Madison, WI, 1998
B.S., Kinesiology, University of Wisconsin, Madison, WI, 1995

Honors and Awards
2003 United States National Institute of Health Ruth L. Kirschstein Post Doc Fellowship - Turnover of Musculotendinous Collagen Following Exercise
2004 American Physiological Society Young Investigator Award, Environmental and Exercise Physiology, Washington DC
2006 University of Auckland Early Career Research Excellence Award, Auckland, New Zealand
2006 National Institute on Aging, Summer Institute on Aging Research, Maryland
2008 Fellow, American College of Sports Medicine
2010 National Institutes of Health Loan Repayment Program
2010 College of Applied Human Sciences Tenure-Track Faculty Scholarly Excellence Award, Colorado State University
2010 Selection, Eighteenth Annual Summer Training Course in Experimental Aging Research. NIA and The Buck Institute, UT Health Science Center, San Antonio, TX
2010 Selection, Marine Biology Laboratory, Summer Program in Molecular Biology of Aging (declined)
2012 Journal of Physiology Century Citation Club – publications that receive 100 or more citations in less than 10 years.
2012 National Institutes of Health Loan Repayment Program-Renewal
2014 National Institutes of Health Loan Repayment Program-Renewal
2014 American Physiological Society (APS) Journals Star Reviewer
2015 American Physiological Society (APS) Journals Star Reviewer
2017 MVP Associate Editor, Exercise and Sport Science Reviews
2020 Impact Award (Midcareer award) American Physiological Society

Memberships
Fellow, American Physiological Society 2018-present
American Aging Association 2019-present
Fellow, American Gerontological Society 2007-present

Joined OMRF’s Scientific Staff in 2018

Publications

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Recent Publications

Hettinger ZR, Hamagata K, Confides AL, Lawrence MM, Miller BF, Butterfield TA, Dupont-Versteegden EE. Age-related susceptibility to muscle damage following mechanotherapy in rats recovering from disuse atrophy. J Gerontol A Biol Sci Med Sci, 2021 June, PMID: 34181006

Brown JL, Lawrence MM, Borowik A, Oliver L, Peelor Iii FF, Van Remmen H, Miller BF. Tumor burden negatively impacts protein turnover as a proteostatic process in non-cancerous liver, heart, and muscle, but not brain. J Appl Physiol (1985), 2021 May, PMID: 34013745

Abbott CB, Lawrence MM, Kobak KA, Lopes EBP, Peelor FF 3rd, Donald EJ, Van Remmen H, Griffin TM, Miller BF. A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis. Function (Oxf) 2:zqab028, 2021 May, PMID: 34124684, PMCID: PMC8187230

Selected Publications

Abbott CB, Lawrence MM, Kobak KA, Lopes EBP, Peelor FF 3rd, Donald EJ, Van Remmen H, Griffin TM, Miller BF. A Novel Stable Isotope Approach Demonstrates Surprising Degree of Age-Related Decline in Skeletal Muscle Collagen Proteostasis. Function (Oxf). 2021 May 10;2(4):zqab028. doi: 10.1093/function/zqab028. eCollection 2021. PMID: 34124684, PMCID: PMC8187230

Wolff CA, Lawrence MM, Porter H, Zhang Q, Reid JJ, Laurin JL, Musci RV, Linden MA, Peelor FF 3rd, Wren JD, Creery JS, Cutler KJ, Carson RH, Price JC, Hamilton KL, Miller BF. Sex differences in changes of protein synthesis with rapamycin treatment are minimized when metformin is added to rapamycin. Geroscience. 2020 Aug 5. Epub ahead of print. PMID: 32761290, PMCID: PMC8110668

Miller BF, Reid JJ, Price JC, Lin HL, Atherton PJ, Smith K. CORP: The use of deuterated water for the measurement of protein synthesis. J Appl Physiol (1985). 2020;128(5):1163-1176. PMID: 32213116

Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019 Feb;18(1):e12880. PMID: 30548390, PMCID: PMC6351883

Miller BF, Drake JC, Naylor B, Price JC, Hamilton KL. The measurement of protein synthesis for assessing proteostasis in studies of slowed aging. Ageing Res Rev. 2014 Nov;18:106-11. PMID: 25283966, PMCID: PMC4258117

Miller BF, Hamilton KL. A perspective on the determination of mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E496–9. PMID: 22205627 PMCID: PMC3311289