Research at OFAS
OFAS has spent years researching dietary methionine restriction (MR) as a means of extending lifespan. Our studies have shown that reducing intake of this essential amino acid can lead to a remarkable increase in maximum age. In addition, experimental animals maintained on this dietary intervention have lower body weight, less fat accretion, improved insulin sensitivity, and reduced incidence of age-related disease, including cancer. Having established the effects of MR, we now seek to understand the mechanisms by which they are accomplished.
Previous work at OFAS revealed that dietary MR protects mice from developing diabetes and obesity. Current projects focus on identifying and characterizing the molecular changes MR produces in different organs and how these changes affect whole-body physiology. In addition to examining MR’s mechanistic properties in the bones, we have also examined a paradoxical effect of MR in mice—that it increases levels of homocysteine, a marker for greater cardiovascular disease risk—and found that heart function was not affected. By determining the adaptive responses to MR, we are able to identify cells, pathways, and molecules that help to explain its lifespan-extending effects. Together, our studies imply that MR in humans will lead to lowered risk for developing metabolic diseases and improved healthspan. We have shown that MR in rodent models can improve insulin and glucose levels and reduce body fat, conditions related to diabetes and obesity.
Publications
- Dietary methionine influences therapy in mouse cancer models and alters human metabolism.
Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP Jr, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW
Nature 2019; 572 (7769): 397-401| PubMed ID: 31367041Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Dai Z, Mentch SJ, Gao X, Nichenametla SN, Locasale JW
Nature Communications 2018; 9 (1): 1955| PubMed ID: 29769529Dietary methionine restriction in mice elicits an adaptive cardiovascular response to hyperhomocysteinemia
Ables GP, Ouattara A, Hampton TG, Cooke D, Perodin F, Augie I, Orentreich DS
Scientific Reports 2015; 5: 8886| PubMed ID: 25744495Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice
Malloy VL, Perrone CE, Mattocks DA, Ables GP, Caliendo NS, Orentreich DS, Orentreich N
Metabolism: Clinical and Experimental 2013; 62 (11): 1651-61| PubMed ID: 23928105Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents
Perrone CE, Malloy VL, Orentreich DS, Orentreich N
Experimental Gerontology 2013; 48 (7): 654-60| PubMed ID: 22819757Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density
Ables GP, Perrone CE, Orentreich D, Orentreich N
PloS One 2012; 7 (12): e51357| PubMed ID: 23236485Genomic and metabolic responses to methionine-restricted and methionine-restricted, cysteine-supplemented diets in Fischer 344 rat inguinal adipose tissue, liver and quadriceps muscle
Perrone CE, Mattocks DA, Plummer JD, Chittur SV, Mohney R, Vignola K, Orentreich DS, Orentreich N
Journal of Nutrigenetics and Nutrigenomics 2012; 5 (3): 132-57| PubMed ID: 23052097Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome
Plaisance EP, Greenway FL, Boudreau A, Hill KL, Johnson WD, Krajcik RA, Perrone CE, Orentreich N, Cefalu WT, Gettys TW
The Journal of Clinical Endocrinology and Metabolism 2011; 96 (5): E836-40| PubMed ID: 21346062Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats.
Brind J, Malloy V, Augie I, Caliendo N, Vogelman JH, Zimmerman JA, Orentreich N.
FASEB Journal 2011; (25): 528.2| PubMed ID: Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase
Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Smith AD, Drevon CA, Refsum H, Perrone CE
Journal of Lipid Research 2011; 52 (1): 104-12| PubMed ID: 20871132Role of β-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction
Plaisance EP, Henagan TM, Echlin H, Boudreau A, Hill KL, Lenard NR, Hasek BE, Orentreich N, Gettys TW
American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2010; 299 (3): R740-50| PubMed ID: 20554934Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states
Hasek BE, Stewart LK, Henagan TM, Boudreau A, Lenard NR, Black C, Shin J, Huypens P, Malloy VL, Plaisance EP, Krajcik RA, Orentreich N, Gettys TW
American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2010; 299 (3): R728-39| PubMed ID: 20538896Nutritional control of aging
Zimmerman JA, Malloy V, Krajcik R, Orentreich N
Experimental Gerontology 2003; 38 (1-2): 47-52| PubMed ID: 12543260Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer’s disease
de Leon MJ, McRae T, Rusinek H, Convit A, De Santi S, Tarshish C, Golomb J, Volkow N, Daisley K, Orentreich N, McEwen B
The Journal of Clinical Endocrinology and Metabolism 1997; 82 (10): 3251-9| PubMed ID: 9329348Low methionine ingestion by rats extends life span
Orentreich N, Matias JR, DeFelice A, Zimmerman JA
The Journal of Nutrition 1993; 123 (2): 269-74| PubMed ID: 8429371Obese men have elevated plasma levels of estrone sulfate
Brind J, Strain G, Miller L, Zumoff B, Vogelman J, Orentreich N
International Journal of Obesity 1990; 14 (6): 483-6| PubMed ID: 2401584In vitro testosterone metabolism in the mouse preputial gland: intercellular co-operation and changes with cell maturation
Brind JL, Marinescu D, Gomez EC, Wheatley VR, Orenteich N
The Journal of Endocrinology 1984; 100 (3): 377-88| PubMed ID: 6699537
Publications
- Pleiotropic responses to methionine restriction
Ables GP, Johnson JE
Experimental Gerontology 2017; (94): 83-88| PubMed ID: 28108330Methionine-restricted diet inhibits growth of MCF10AT1-derived mammary tumors by increasing cell cycle inhibitors in athymic nude mice
Hens JR, Sinha I, Perodin F, Cooper T, Sinha R, Plummer J, Perrone CE, Orentreich D
BMC Cancer 2016; 16 (1): 349| PubMed ID: 27255182Dietary methionine restriction inhibits prostatic intraepithelial neoplasia in TRAMP mice
Sinha R, Cooper TK, Rogers CJ, Sinha I, Turbitt WJ, Calcagnotto A, Perrone CE, Richie JP
The Prostate 2014; 74 (16): 1663-73| PubMed ID: 25250521A functional trinucleotide repeat polymorphism in the 5′-untranslated region of the glutathione biosynthetic gene GCLC is associated with increased risk for lung and aerodigestive tract cancers
Nichenametla SN Muscat JE, Liao JG, Lazarus P, Richie JP
Molecular Carcinogenesis 2012; 45 (10): 791-9| PubMed ID: 22610501Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma
Asgari MM, Tang J, Warton ME, Chren MM, Quesenberry CP, Bikle D, Horst RL, Orentreich N, Vogelman JH, Friedman GD
The Journal of Investigative Dermatology 2010; 130 (5): 1438-43| PubMed ID: 20043012Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies
Roddam AW, Allen NE, Appleby P, Key TJ, Ferrucci L, Carter HB, Metter EJ, Chen C, Weiss NS, Fitzpatrick A, Hsing AW, Lacey JV, Helzlsouer K, Rinaldi S, Riboli E, Kaaks R, Janssen JA, Wildhagen MF, Schrӧder FH, Platz EA, Pollak M, Giovannucci E, Schaefer C, Quesenberry CP, Vogelman JH, Severi G, English DR, Giles GG, Stattin P, Hallmans G, Johansson M, Chan JM, Gann P, Oliver SE, Holly JM, Donovan J, Meyer F, Bairati I, Galan P
Annals of Internal Medicine 2008; 149 (7): 461-71, W83-8| PubMed ID: 18838726Helicobacter pylori infection and development of pancreatic cancer
de Martel C, Llosa AE, Friedman GD, Friedmana GD, Vogelman JH, Orentreich N, Stolzenberg-Solomon RZ, Parsonnet J
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 2008; 17 (5): 1188-94| PubMed ID: 18483341Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies
Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key TJ
Journal of the National Cancer Institute 2008; 100 (3): 170-83| PubMed ID: 18230794Serum ghrelin levels and risk of subsequent adenocarcinoma of the esophagus
de Martel C, Haggerty TD, Corley DA, Vogelman JH, Orentreich N, Parsonnet J
The American Journal of Gastroenterology 2007; 102 (6): 1166-72| PubMed ID: 17378911Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma
de Martel C, Llosa AE, Farr SM, Friedman GD, Vogelman JH, Orentreich N, Corley DA, Parsonnet J
The Journal of Infectious Diseases 2005; 191 (5): 761-7| PubMed ID: 15688293No association between serum levels of tumor necrosis factor-α (TNF-α) or the soluble receptors sTNFR1 and sTNFR2 and breast cancer risk
Krajcik RA, Massardo S, Orentreich N
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 2003; 12 (9): 945-6| PubMed ID: 14504210CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma (letter)
Shibata A, Parsonnet J, Longacre TA, Garcia MI, Puligandla B, Davis RE, Vogelman JH, Orentreich N, Habel LA
Carcinogenesis 2003; 1 (24): 147| PubMed ID: Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer
Krajcik RA, Borofsky ND, Massardo S, Orentreich N
Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 2002; 11 (12): 1566-73| PubMed ID: 12496045CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma
Shibata A, Parsonnet J, Longacre TA, Garcia MI, Puligandla B, Davis RE, Vogelman JH, Orentreich N, Habel LA
Carcinogenesis 2002; 23 (3): 419-24| PubMed ID: 11895856
Publications
- Pleiotropic responses to methionine restriction
Ables GP, Johnson JE
Experimental Gerontology 2017; (94): 83-88| PubMed ID: 28108330Methionine-restricted diet increases miRNAs that can target RUNX2 expression and alters bone structure in young mice
Plummer J, Park M, Perodin F, Horowitz MC, Hens JR
Journal of Cellular Biochemistry 2016; 118 (1): 31-42| PubMed ID: 27191548Methionine restriction alters bone morphology and affects osteoblast differentiation
Ouattara A, Cooke D, Gopalakrishnan R, Huang TH, Ables GP
Bone Reports 2016; 5: 33-42| PubMed ID: 28326345Dietary restrictions, bone density, and bone quality
Huang TH, Ables GP
Annals of the New York Academy of Sciences 2016; 1363 (1): 26-39| PubMed ID: 26881697Effects of methionine restriction and endurance exercise on bones of ovariectomized rats: a study of histomorphometry, densitometry, and biomechanical properties
Huang TH, Su IH, Lewis JL, Chang MS, Hsu AT, Perrone CE, Ables GP
Journal of Applied Physiology (Bethesda, Md. : 1985) 2015; 119 (5): 517-26| PubMed ID: 26159761A methionine-restricted diet and endurance exercise decrease bone mass and extrinsic strength but increase intrinsic strength in growing male rats
Huang TH, Lewis JL, Lin HS, Kuo LT, Mao SW, Tai YS, Chang MS, Ables GP, Perrone CE, Yang RS
The Journal of Nutrition 2014; 144 (5): 621-30| PubMed ID: 24647387Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density
Ables GP, Perrone CE, Orentreich D, Orentreich N
PloS One 2012; 7 (12): e51357| PubMed ID: 23236485
Publications
- Dietary methionine restriction modulates renal response and attenuates kidney injury in mice
Cooke D, Ouattara A, Ables GP
The FASEB Journal 2017; 32 (2): 693-702| PubMed ID: 28970255Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice
Mattocks DA, Mentch SJ, Shneyder J, Ables GP, Sun D, Richie JP Jr, Locasale JW, Nichenametla SN
Experimental Gerontology 2017; (88): 1-8| PubMed ID: 27940170Methionine-restricted diet increases miRNAs that can target RUNX2 expression and alters bone structure in young mice
Plummer J, Park M, Perodin F, Horowitz MC, Hens JR
Journal of Cellular Biochemistry 2016; 118 (1): 31-42| PubMed ID: 27191548Methionine-restricted diet inhibits growth of MCF10AT1-derived mammary tumors by increasing cell cycle inhibitors in athymic nude mice
Hens JR, Sinha I, Perodin F, Cooper T, Sinha R, Plummer J, Perrone CE, Orentreich D
BMC Cancer 2016; 16 (1): 349| PubMed ID: 27255182Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism
Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D, Gόmez Padilla P, Ables G, Bamman MM, Thalacker-Mercer AE, Nichenametla SN, Locasale JW
Cell Metabolism 2015; 22 (5): 861-73| PubMed ID: 26411344Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase
Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Smith AD, Drevon CA, Refsum H, Perrone CE
Journal of Lipid Research 2011; 52 (1): 104-12| PubMed ID: 20871132Sulfur amino acids in methionine-restricted rats: hyperhomocysteinemia
Elshorbagy AK, Valdivia-Garcia M, Refsum H, Smith AD, Mattocks DA, Perrone CE
Nutrition (Burbank, Los Angeles County, Calif.) 2010; 26 (11-12): 1201-4| PubMed ID: 20080389Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats
Perrone CE, Mattocks DA, Jarvis-Morar M, Plummer JD, Orentreich N
Metabolism: Clinical and Experimental 2010; 59 (7): 1000-11| PubMed ID: 20045141Methionine restriction effects on 11β-HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue
Perrone CE, Mattocks DA, Hristopoulos G, Plummer JD, Krajcik RA, Orentreich N
Journal of Lipid Research 2008; 49 (1): 12-23| PubMed ID: 17909224Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction
Malloy VL, Krajcik RA, Bailey SJ, Hristopoulos G, Plummer JD, Orentreich N
Aging Cell 2006; 5 (4): 305-14| PubMed ID: 16800846Tissue glutathione and cysteine levels in methionine-restricted rats
Richie JP, Komninou D, Leutzinger Y, Kleinman W, Orentreich N, Malloy V, Zimmerman JA
Nutrition (Burbank, Los Angeles County, Calif.) 2004; 20 (9): 800-5| PubMed ID: 15325691Methionine restriction inhibits age-related spontaneous tumorigenesis in F344 rats.
Komninou D, Malloy V, Krajcik R, Rivenson A, Orentreich N, Zimmerman JA, Richie JP Jr
Proceedings of the American Association of Cancer Research 2004; (45): 3919| PubMed ID: Methionine restriction increases blood glutathione and longevity in F344 rats
Richie JP, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA
FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 1994; 8 (15): 1302-7| PubMed ID: 8001743
Several observational studies suggest that vegan or vegan-like diets, low in protein and thus in methionine, confer benefits against obesity, hypertension, type-2 diabetes, and cardiovascular mortality. However, there are no interventional studies confirming whether such benefits are due to low protein in general or, more specifically, to low methionine. We are currently conducting a study with Penn State University investigating whether MR provides beneficial effects in humans similar to those observed in laboratory animals.
Recent studies reaffirm walking as an efficient, cost effective, and equitable preventive measure for obesity and age-related illnesses. However, improvements toward a more walkable environment cannot be made without the proper understanding of the quality of the built environment and human perception of the walking experience. Active living communities for older adults are essential for fostering individual health and longevity. We are currently expanding on a previous case study in three neighborhoods within Manhattan, New York where our research team will study the human perception of the built environment to complement the microscale assessment previously completed. This study uses geographic information systems (GIS) to objectively measure walkability surrounding three older-adult living facilities and as a tool for planning and design of urban pedestrian environments. This data is key to the process of identifying placemaking opportunities that can increase walking, improve health, and extend lifespan.