Dr. Huffman is an Assistant Professor of Medicine and Molecular Pharmacology, Co-Director of the Einstein Healthy Aging Physiology Core, and Member of the Einstein Aging Center, Cancer Center, and Diabetes Research Center at the Albert Einstein College of Medicine. Dr. Huffman’s research is focused on three areas:
1) The biology of aging: role of IGF-1 signaling
2) Central insulin and IGF-1 signaling
3) Role of obesity and aging on cancer risk
1) The biology of aging: role of IGF-1 signaling – I am primarily interested in understanding the interplay between endocrine and metabolic systems with aging and age-related diseases. There is a clear link between aging and metabolism across species. In mammalians, aging is characterized metabolically by accretion of visceral fat, insulin resistance, dyslipidemias and metabolic inflexibility. This dysregulation in metabolism has been linked to increased risk for numerous age-related diseases and accelerated aging. Likewise, growth factors and body size have been closely tied to lifespan. Indeed, dwarf mice live longer than normal mice, small dogs live longer than large dogs, and ponies live longer than thoroughbreds. This phenomenon is believed to be attributed to a reduction in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signaling, and less signaling through this axis has been has been linked to improved longevity in model organisms. Furthermore, in humans, high IGF-1 levels are associated with increased cancer risk, but are paradoxically linked with protection from cardiovascular disease, type 2 diabetes and osteoporosis. Thus, the relevance of IGF-1 to aging in humans remains unclear.
Relevant to this paradox, we have recently uncovered novel, beneficial effects of centrally-acting IGF-1 on peripheral metabolism. Furthermore, we have found that as compared to central insulin treatment, central IGF-1 replacement in old, insulin-resistant rats, more effectively restores peripheral insulin action. This has led us to hypothesize that optimally modulating IGF-1 signaling to promote healthy aging and longevity in humans may require shifting the balance of IGF-1 from the periphery to the central nervous system (CNS) in order to maximize the 'good' effects of IGF-1, while minimizing its 'bad' effects on cancer in the periphery. We are currently testing this hypothesis in animal models using a combination of genetic and pharmacologic approaches, combined with several state-of-the-art strategies to evaluate healthy aging in these animals. We are specifically evaluating the potential of IGF-1 receptor (IGF-1R) antibodies, currently used in clinical trials to treat cancer, as a pharmacologic strategy to reduce peripheral (but not central) IGF-1R signaling in hopes that this may serve as a translational tool for treating some manifestations of aging in humans, thus "bridging the gap" between basic biological discovery and human therapeutic strategy.
2) Central insulin and IGF-1 signaling – A second area involves understanding the mechanism(s) whereby insulin and IGF-1 signaling in the brain control peripheral metabolism. Ongoing studies have uncovered novel similarities and differences between insulin and IGF-1 in regards to their ability to regulate glucose metabolism via the CNS. These studies involve tandem central infusion of peptides and/or inhibitors during a euglycemic clamp in awake, unstressed animals. These studies thus far seem to suggest a potentially important role for insulin receptor/IGF-1R hybrids in the brain. In addition, aged animals demonstrate central insulin resistance, but respond remarkably well to central IGF-1, suggesting that IGF-1 may be a better ligand in the brain than insulin for treating some manifestations of aging. Studies are also ongoing using BOLD-fMRI to assess the impact of central insulin and IGF-1 in the brain as well as with Dr. Young-Hwan Jo on the role of insulin, IGF-1, and their receptors, on electrical activity in specific neuronal populations.
3) Role of obesity and aging on cancer risk – A third area involves the role of aging, obesity and diet on cancer risk. In a pre-clinical model of prostate cancer, we have previously found that cancer risk was linked to energy balance and body mass, but independent of food intake. Likewise, using a surgical model of visceral fat removal, we have found that ablating visceral fat stores in male rats extended their longevity, thus uncoupling the effects of fat from nutrients on lifespan for the first time. More recently, we have found that visceral fat removal is protective from adenoma development and improved survival in a female model of intestinal cancer, providing the first causal evidence linking adiposity to this site-specific cancer. Future areas of interest in this area include studies uncovering the mechanisms behind this link, to determine how abdominal obesity and nutrient availability act independently during the various stages of tumor promotion and progression. We are particularly interested in interrogating the epigenetic changes that occur in specific intestinal stem cells with obesity and aging and how these might relate to later cancer risk. We are also employing parabiosis surgery between young and old animals to assess the role of systemic factors from young and old environments on this process.
Huffman DM, Altena TS, Mawhinney TP, and Thomas TR. Effect of n-3 fatty acids on free tryptophan and exercise fatigue. Eur J Appl Physiol 2004 92:584-91.
Huffman DM, Michaelson JL, Thomas TR. Chronic supplementation with fish oil increases fat oxidation during exercise in young men. J Exerc Physiol 2004 7(1):48-56.
Huffman DM, Landy NM, Potter E, Nagy TR, and Gower BA.Comparison of the Lunar DPX-L and Prodigy dual-energy X-ray absorptiometers for assessing total and regional body composition. Int J Body Comp Res 2005 3(1):25-30.
Huffman DM, Johnson MS, Watts A, Elgavish A, Eltoum IA, and Nagy TR. Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake. Cancer Res 2007 67: 417-24.(Included in "Research Highlights" on issue cover)
Huffman DM, Grizzle WE,Bamman MM, Kim JS, Eltoum IA, Elgavish A, and Nagy TR. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 2007 67: 6612-18.
Huffman DM, Moellering DM, Grizzle WE, Stockard CR, Johnson MS and Nagy TR. Effect of exercise and calorie restriction on biomarkers of aging in mice. Am J Physiol Regul Integr Comp Physiol 2008 294(5): R1618-27. PMID: 18321952 (paper selected for media release by the journal)
Muzumdar RH, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein F, Fishman S, McVei T, Keith SW, and Barzilai N. Visceral adipose tissue modulates mammalian longevity. Aging Cell 2008 7(3): 438-40. PMCID: PMC2504027
Einstein FH, Fishman S, Bauman J, Thompson RH, Huffman DM, Atzmon G, Barzilai N and Muzumdar RH. Enhanced activation of a ‘nutrient-sensing’ pathway with age contributes to insulin resistance. FASEB J 2008 Oct;22(10):3450-57. PMCID: PMC2537426
Huffman DM and Barzilai N. Role of visceral adipose tissue in aging. (Invited review) Biochemical and Molecular Mechanisms of Aging: from Model Systems to Human Longevity. Biochemica et Biophysica Acta 2009 Oct; 1790(10):1117-23. PMCID: PMC2779572
Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Budagov T, Cui L, Einstein F, Fishman S, Poduval A, Hwang D, Barzilai N and Cohen P. Humanin: A novel central regulator of peripheral insulin action. PLOS One 2009 Jul 22;4(7):e6334. PMCID: PMC2709436
Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Shaw JW, Huffman DM, Barzilai N and Suh Y. Telomere length and telomerase gene variation are associated with human longevity. Proc Natl Acad Sci U S A2010 107:1710-1717. PMCID: PMC2868292
Huffman DM*, Einstein FH*, Fishman S*, Atzmon G, Jerschow E, Heo HJ, Budagov T, Barzilai N, and Muzumdar RH. Aging per se increases the susceptibility to free fatty acid-induced insulin resistance. J Gerontol A Biol Sci Med Sci 201065(8):800-808. PMCID: PMC2537426
Muzumdar RH, Huffman DM, Calvert JW, Jha S, Weinberg Y, Cui L, Nemkal A, Atzmon G, Klein L, Gundewar S, Yong S, Lavu M, Predmore BL and Lefer D. Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice. Arterioscler Thromb Vasc Biol2010 30(10):1940-1948. PMCID: PMC2941397
Huffman DM and Calvert JW. Exercise to the rescue. J Physiol 2011 589(24): 5919-5920. PMCID: PMC3286671
Huffman DM. Editorial Comment to Inhibition of cortactin and SIRT1 expression attenuates migration and invasion of prostate cancer DU145 cells: Making sense of SIRT1 and prostate cancer. Int J Urol 2012 19(1) 79-80.
Barzilai N, Huffman DM, Muzumdar RH, and Bartke A. Perspectives in Diabetes: The Critical Role of Metabolic Pathways in Aging. Diabetes 2012 61(6): 1315-22. PMCID: PMC3357299
Huffman DM, Deelen J, Ye K, Bergman A, Slagboom EP, Barzilai N, and Atzmon G. Distinguishing between longevity and buffered-deleterious genotypes for exceptional human longevity: The case of the MTP gene. J Gerontol A Biol Sci Med Sci 2012 Nov;67(11):1153-60. PMCID: PMC3474468
Huffman DM, Augenlicht LH, Zhang XY, Lofrese JJ, Atzmon G, Chamberland JP and Mantzoros CS. Abdominal obesity, independently from caloric intake, accounts for the development of intestinal tumors in Apc1638N/+ female mice Cancer Prev Res 2013 Mar;6(3): 177-87. PMCID: PMC3595118 (featured press release by AACR)
Huffman DM, Farias-Quipildor G, Mao K, Zhang X, Wan J, Apontes P, Cohen P, Barzilai N. Central IGF-1 Restores Whole-Body Insulin Action in a Model of Age-Related Insulin Resistance and IGF-1 Decline Aging Cell. 2016 Feb;15(1):181-86.
Chusyd DE, Wang D, Huffman DM, Nagy TR. Relationships between rodent white adipose fat pads and human white adipose fat depots Front Nutr April 2016
Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK, Mehta HH, Gao Q, Ashur C, Huffman DM, Wan J, Muzumdar RH, Barzilai N, Cohen P. Naturally-occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers Aging (accepted)
Huffman DM and Barzilai N. Animal Models of Visceral Obesity. Book Chapter from Abdominal Obesity and the Endocannabinoid System: From Basic Aspects to Clinical Management of Related Cardiometabolic Risk. Editor: Jean-Pierre Despres, PhD. Informa Healthcare.
Barzilai N, Huffman DM, Cohen P and Muzumdar RH. The role of IGF-1 and its partners in central and peripheral metabolism: Considerations for extending healthy lifespan. Book Chapter from Research and Perspectives in Endocrine Interactions: IGFs: Local Repair and Survival Factors Throughout the Life Span. Springer Publishing.
Huffman DM and Barzilai N. Contribution of Adipose Tissue to Health-Span and Longevity. Book Chapter from Body Composition and Aging. Editor: Charles Mobbs, PhD, Karger Publishing. Interdiscip Top Gerontol. 2010;37:1-19.
Huffman DM. Exercise as a Calorie Restriction Mimetic: Implications for Improving Healthy Aging and Longevity. Book Chapter from Body Composition and Aging. Editor: Charles Mobbs, PhD, Karger Publishing. Interdiscip Top Gerontol. 2010;37:157-174.
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