My research focuses on elucidating the mechanistic bases for differential aging and lifespan among vertebrates with an emphasis on the role of developmental factors and stress resistance. Enhanced resistance to cytotoxic and metabolic insults is a recurring phenomenon within cell lines derived from long-lived laboratory mouse models, and I have shown that this extends to free-living rodents and birds with disparate life spans as well. Work in my lab centers on comparing and contrasting the regulation of candidate pathways in primary cell lines to determine whether they are differentially activated under stressful conditions in long- versus short-lived species.
In addition, I study the role of nutrition and specific hormones (e.g., growth hormone/insulin-like growth factor I) as regulators of stress resistance, metabolic function, inflammation and aging in laboratory mice through outside collaborations with investigators at UTHSCSA, the University of Michigan and Southern Illinois University, and recently showed that a reduction in caloric intake limited to the juvenile period leads to a significant longevity extension. Increased longevity was associated with the maintenance of physiological function at a more “youthful” level, especially immune and adipose biology, insulin signaling and glucose homeostasis, hypothalamic-pituitary-adrenal axis (HPA) function, and stress resistance. Current and future research in this area focuses on the role of the adenosine monophosphate kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway downstream of specific endocrine pathways.
Finally, I have a long-standing interest in physiological ecology, especially the influence of environmental stressors on physiological function. Because capture and handling alters basal function at the physiological level I use a series of established and/or putative (see below) minimally invasive measures; these include: (1) fecal steroid analysis; (2) urinary measures derived from samples collected on absorbent filter paper (akin to newborn dried blood spot screening); and (3) primary cell lines derived from dermal biopsies.
Jimenez, A.G., Harper, J.M., Queenborough, S.A., and Williams, J.B. In press. Linkages between the life-history evolution of tropical and temperate birds and the resistance of their cells to oxidative and non-oxidative chemical injury. Journal of Experimental Biology.
Sadighi-Akha, A.A., Harper, J.M., Salmon, A.B., Schroeder, B.A., Rutkowski, D.T. and Miller, R.A. 2011. Heightened induction of pro-apoptotic signals in response to ER stress in primary fibroblasts from a mouse model of longevity. Journal of Biological Chemistry, 286: 30344 - 30351.
Harper, J.M., Wang, M., Galecki, A.T., Ro, J., Williams, J.B. and Miller, R.A. 2011. Fibroblasts from Long-Lived Bird Species are Resistant to Multiple Forms of Stress. Journal of Experimental Biology, 412: 1902 - 1910.
Miller, R.A., Williams, J.B., Kiklevich, V.J., Austad, S.N. and Harper, J.M. 2011. Comparative Cellular Biogerontology: Primer and Prospectus. Aging Research Reviews, 10: 181 – 190; invited review.
Sun, L., Sadighi-Akha, A.A., Miller, R.A. and Harper, J.M. 2009. Life span extension in mice by pre-weaning food restriction and by methionine restriction in middle age. Journals of Gerontology Biological Sciences and Medical Sciences, 64A: 711 – 722.
Harper, J.M.*, Salmon, A.B.*, Leiser, S.L., Galecki, A., and Miller, R.A. 2007. Skin-Derived Fibroblasts from Long-Lived Species are Resistant to Some, but Not All, Lethal Stresses and to the Mitochondrial Inhibitor Rotenone. Aging Cell, 6: 1 – 13.
Harper, J.M. and Austad, S.N. 2001. Effect of Capture and Season on Fecal Glucocorticoid Levels in Deer Mice (Peromyscus maniculatus) and Red-Backed Voles (Clethrionomys gapperi). General and Comparative Endocrinology 123: 337-344.
Harper, J.M. and S.N. Austad. 2000. Fecal Glucocorticoids: A Noninvasive Method of Measuring Adrenal Activity in Wild and Captive Rodents. Physiological and Biochemical Zoology 73: 12-22.