Kristopher John Burkewitz, Ph.D.

Assistant Professor
Faculty Appointments
Assistant Professor of Cell & Developmental Biology
Ph.D., Pharmacology, Vanderbilt University, Nashville, TennesseeB.S., Biology, University of Miami, Coral Gables, Florida
Research Description
A majority of the top causes of mortality in the U.S. are chronic conditions considered to be diseases of old age. These include neurodegenerative diseases, cardiovascular disease, cancer and diabetes, which obviously arise in a variety of cell types and possess distinct proximal etiologies. The Burkewitz lab is interested in understanding what causes the elderly to be at such great risk for these diseases when the young are not. What are the common biological changes that underlie many of these diverse forms of age-dependent pathogenesis, and are there ways to intervene and prevent these changes from occurring?

Fortunately, there is now an abundance of evidence to suggest that aging is not immutable, but rather a plastic process influenced by genes and the environment. One example of this is the drastic variability in the rate of aging between species, which reveals that aging involves physiological processes that are shaped by evolution. While humans begin exhibiting the common signs of aging after decades, the nematode C. elegans ages over weeks, Drosophila over months, and mice over just a couple years. Through these experimentally advantageous models, we also know that single genetic, dietary and pharmacological interventions can successfully extend healthy lifespan and reduce the incidence of multiple age-onset diseases. A common thread among the identified interventions is that they often target core, evolutionarily conserved nutrient-sensing pathways, such as mTOR, insulin signaling, and AMPK, revealing an ancient connection between metabolism and aging. Using a foundation of molecular genetics and quantitative, live imaging in the transparent model C. elegans, we are striving to understand how mimicking a fasting or ‘low-energy’ physiological state translates into longevity, stress resistance and protection from age-related diseases.

We are particularly interested in the roles that organelles like the ER and mitochondria play in these processes for two reasons. First, the architecture and behavior of these organelles begins to shift as animals age, and these aberrant organelle dynamics are correlated with the onset of multiple age-onset diseases—especially in neurons and muscle, tissues which are ‘sensitive’ to age-related pathology. Second, these organelles are both key responders and controllers of cell and organismal metabolism. Fluctuating nutrient levels cause these organelles to remodel their form, thereby allowing them to optimize their function for the changing environment. We will employ cutting-edge genetic techniques such as CRISPR/Cas9 transgenesis to label these organelles and observe their behaviors in living animals. We will then genetically manipulate metabolic functions and the regulators of organelle dynamics to ask (i) how and why the dysregulation of organelle architecture occurs in aging animals, (ii) how long-lived animals are able to better protect organelle form and function, and (iii) can we target organelle dynamics therapeutically to prevent age-onset declines and pathology?
Research Keywords
aging, age-related disease, molecular genetics, metabolism, caloric restriction, dietary restriction, live-cell microscopy, nutrient signaling, calcium signaling, mitochondria, ER, stress
Weir HJ, Yao P, Huynh FK, Escoubas CC, Goncalves RL, Burkewitz K, Laboy R, Hirschey MD, Mair WB. Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab [print-electronic]. 2017 Dec 12/5/2017; 26(6): 884-896.e5. PMID: 29107506, PMCID: PMC5718936, PII: S1550-4131(17)30612-5, DOI: 10.1016/j.cmet.2017.09.024, ISSN: 1932-7420.

Reis Rodrigues P, Kaul TK, Ho JH, Lucanic M, Burkewitz K, Mair WB, Held JM, Bohn LM, Gill MS. Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans. G3 (Bethesda). 2016 Jun 6/1/2016; 6(6): 1695-705. PMID: 27172180, PMCID: PMC4889665, PII: g3.116.026997, DOI: 10.1534/g3.116.026997, ISSN: 2160-1836.

Burkewitz K, Weir HJ, Mair WB. AMPK as a Pro-longevity Target. Exp Suppl. 2016; 107: 227-56. PMID: 27812983, DOI: 10.1007/978-3-319-43589-3_10, ISSN: 1664-431X.

Jacobi D, Liu S, Burkewitz K, Kory N, Knudsen NH, Alexander RK, Unluturk U, Li X, Kong X, Hyde AL, Gangl MR, Mair WB, Lee CH. Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness. Cell Metab [print-electronic]. 2015 Oct 10/6/2015; 22(4): 709-20. PMID: 26365180, PMCID: PMC4598294, PII: S1550-4131(15)00397-6, DOI: 10.1016/j.cmet.2015.08.006, ISSN: 1932-7420.

Burkewitz K, Morantte I, Weir HJM, Yeo R, Zhang Y, Huynh FK, Ilkayeva OR, Hirschey MD, Grant AR, Mair WB. Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal. Cell. 2015 Feb 2/26/2015; 160(5): 842-55. PMID: 25723162, PMCID: PMC4392909, PII: S0092-8674(15)00137-3, DOI: 10.1016/j.cell.2015.02.004, ISSN: 1097-4172.

Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. Cell Metab [print-electronic]. 2014 Jul 7/1/2014; 20(1): 10-25. PMID: 24726383, PMCID: PMC4287273, PII: S1550-4131(14)00106-5, DOI: 10.1016/j.cmet.2014.03.002, ISSN: 1932-7420.

Burkewitz K, Choe KP, Lee EC, Deonarine A, Strange K. Characterization of the proteostasis roles of glycerol accumulation, protein degradation and protein synthesis during osmotic stress in C. elegans. PLoS ONE [print-electronic]. 2012; 7(3): e34153. PMID: 22470531, PMCID: PMC3314593, PII: PONE-D-11-18918, DOI: 10.1371/journal.pone.0034153, ISSN: 1932-6203.

Burkewitz K, Choe K, Strange K. Hypertonic stress induces rapid and widespread protein damage in C. elegans. Am. J. Physiol., Cell Physiol [print-electronic]. 2011 Sep; 301(3): C566-76. PMID: 21613604, PMCID: PMC3174568, PII: ajpcell.00030.2011, DOI: 10.1152/ajpcell.00030.2011, ISSN: 1522-1563.

Flynt AS, Thatcher EJ, Burkewitz K, Li N, Liu Y, Patton JG. MiR-8 microRNAs regulate the response to osmotic stress in zebrafish embryos. J. Cell Biol [print-electronic]. 2009 Apr 4/6/2009; 185(1): 115-27. PMID: 19332888, PMCID: PMC2700511, PII: jcb.200807026, DOI: 10.1083/jcb.200807026, ISSN: 1540-8140.