Dietary restriction, stress resistance, and aging
In models organisms from yeast to rodents, benefits of dietary restriction include extended longevity, improved healthspan and increased resistance to stress. In mammalian models in particular, dietary restriction forestalls, ameliorates or reverses a number of conditions for which age is a prime risk factor, from neurodegeneration to cancer to cardiovascular disease.
Dietary restriction comprises a variety of feeding regimes focused either on reducing total calorie intake (calorie restriction) or enforced periods of fasting between meals (intermittent fasting; e.g. every-other-day fasting). Although dietary restriction was first observed to extend longevity in rats almost 100 years ago, the components of an optimally beneficial diet remain controversial. Similarly, our understanding of the genetic requirements or underlying molecular mechanisms remains far from complete.
We are interested in elucidating the specific role of protein and essential amino acid restriction in the benefits of dietary restriction, and the evolutionarily conserved amino acid sensing pathways involved, including mTORC1 and GCN2. We are also interested in the specific role of sulfur amino acids including methionine and cysteine in the benefits of dietary restriction. Finally, we are interested in the timing of onset and duration of benefits in order to best facilitate translation to the clinic.
We have found that short-term application of various dietary restriction regimens lasting from three days to one week offer significant protection in rodent models of surgical stress, including ischemia reperfusion injury to kidney, liver and brain. Our long-term goal is to translate these benefits to the clinic, starting with the area of preoperative nutrition.
Mitchell JR, Verweij M, Brand K, van de Ven M, Goemaere N, van den Engel S, Chu T, Forrer F, Muller C, de Jong M, van IJcken W, IJzermans JN, Hoeijmakers JH, de Bruin RW. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell, 2009. Volume(1): p. 40-53. PMID: 19878145
Peng W, Robertson L, Gallinetti J, Mejia P, Vose S, Charlip A, Chu T, Mitchell JR. Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in mice. Sci. Transl. Med. 2012 Jan 25 (4):118ra11. PMID: 22277968
Nguyen B, Tao M, Yu P, Mauro C, Seidman MA, Wang YE, Mitchell JR, Ozaki CK. Pre-operative diet impacts the adipose tissue response to surgical trauma. Surgery 2013 Apr:153(4). PMID: 23274098
Varendi K, Airavaara M, Anttila J, Vose S, Saarma M, Mitchell JR, Andressoo JO. Preoperative fasting and short-term dietary protein restriction are neuroprotective in a rat focal stroke model. PLoS One 2014 Apr 4;9(4): e93911. PMID: 24705386
Mauro CR, Tao M, Peng Y, Treviño-Villerreal JH, Longchamp A, Kristal BS, Ozaki CK, Mitchell JR. Pre-operative dietary restriction reduces intimal hyperplasia and protects from ischemia reperfusion injury. J Vasc Surg 2014 Aug 8. pii: S0741-5214(14)01295-6. PMID: 25124359
Harputlugil E, Hine C, Vargas D, Robertson L, Peng W, Manning BD, Mitchell JR. Tsc1 required for benefits of dietary protein restriction on hepatic insulin sensitivity and stress resistance. Cell Reports 2014 Aug 21;8(4):1160-70. PMID: 25131199
Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC, Brace L, Longchamp A, Treviño-Villarreal JH, Mejia P, Ozaki CK, Wang R, Gladyshev VN, Madeo F, Mair WB, Mitchell JR. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 2014. PMID: 25542313
Hine C, Mitchell JR. NRF2 and the phase II response in acute stress resistance induced by dietary restriction. J Clin. Exp. Path. 2012. PMID: 23505614
Mitchell JR, Beckman JA, Nguyen LL, Ozaki CK. Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery 2013 Apr:153(4):594-598. PMID: 23218877
Gallinetti J, Harputlugil E, Mitchell JR. Amino acid sensing and translational control in dietary restriction-mediated longevity and stress resistance: contrasting roles of signal transducing kinases Gcn2 and mTOR. Biochem. J 2013 449:1-10. PMID: 23216249
Robertson LT, Mitchell JR. Benefits of fasting and short-term dietary restriction in mammals. Exp. Gerontol. 2013 Feb 1. pii: S0531-5565(13)00024-7. PMID: 23376627
Hine C, Mitchell JR. Saying no to drugs: fasting protects hematopoietic stem cells from chemotherapy and aging. Cell Stem Cell 2014 Jun 5;14(6): 704-5. PMID: 24905161
Hine C, Mitchell JR. Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Exp Ger 2014 (in press) PMID: 25523462