Rhodiola rosea has been extensively used to improve physical and mental performance and to protect against stress. We, and others, have reported that R. rosea can extend lifespan in flies, worms, and yeast. However, its molecular mechanism is currently unknown. Here, we tested whether R. rosea might act through a pathway related to dietary restriction (DR) that can extend lifespan in a range of model organisms. While the mechanism of DR itself is also unknown, three molecular pathways have been associated with it: the silent information regulator 2 (SIR2) proteins, insulin and insulin-like growth factor signaling (IIS), and the target of rapamycin (TOR). In flies, DR is implemented through a reduction in dietary yeast content. We found that R. rosea extract extended lifespan in both sexes independent of the yeast content in the diet. We also found that the extract extended lifespan when the SIR2, IIS, or TOR pathways were genetically perturbed. Upon examination of water and fat content, we found that R. rosea decreased water content and elevated fat content in both sexes, but did not sensitize flies to desiccation or protect them against starvation. There were some sex-specific differences in response to R. rosea. In female flies, the expression levels of glycolytic genes and dSir2 were down-regulated, and NADH levels were decreased. In males however, R. rosea provided no protection against heat stress and had no effect on the major heat shock protein HSP70 and actually down-regulated the mitochondrial HSP22. Our findings largely rule out an elevated general resistance to stress and DR-related pathways as mechanistic candidates. The latter conclusion is especially relevant given the limited potential for DR to improve human health and lifespan, and presents R. rosea as a potential viable candidate to treat aging and age-related diseases in humans.
References
[1]
Kelly GS (2001) Rhodiola rosea: a possible plant adaptogen. Altern Med Rev 6: 293–302.
[2]
Abidov M, Crendal F, Grachev S, Seifulla R, Ziegenfuss T (2003) Effect of extracts from Rhodiola rosea and Rhodiola crenulata (Crassulaceae) roots on ATP content in mitochondria of skeletal muscles. Bull Exp Biol Med 136: 585–587.
[3]
Boon-Niermeijer EK, van den Berg A, Wikman G, Wiegant FA (2000) Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis. Phytomedicine 7: 389–399.
[4]
Kim SH, Hyun SH, Choung SY (2006) Antioxidative effects of Cinnamomi cassiae and Rhodiola rosea extracts in liver of diabetic mice. Biofactors 26: 209–219.
[5]
Udintsev SN, Schakhov VP (1991) Decrease of cyclophosphamide haematotoxicity by Rhodiola rosea root extract in mice with Ehrlich and Lewis transplantable tumors. Eur J Cancer 27: 1182.
[6]
Jafari M, Felgner JS, Bussel, II, Hutchili T, Khodayari B, et al. (2007) Rhodiola: a promising anti-aging Chinese herb. Rejuvenation Res 10: 587–602.
[7]
Schriner SE, Abrahamyan A, Avanessian A, Bussel I, Maler S, et al. (2009) Decreased mitochondrial superoxide levels and enhanced protection against paraquat in Drosophila melanogaster supplemented with Rhodiola rosea. Free Radic Res 43: 836–843.
[8]
Schriner SE, Avanesian A, Liu Y, Luesch H, Jafari M (2009) Protection of human cultured cells against oxidative stress by Rhodiola rosea without activation of antioxidant defenses. Free Radic Biol Med 47: 577–584.
[9]
Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, et al. (2009) Plant adaptogens increase lifespan and stress resistance in C. elegans. Biogerontology 10: 27–42.
[10]
Bayliak MM, Lushchak VI (2011) The golden root, Rhodiola rosea, prolongs lifespan but decreases oxidative stress resistance in yeast Saccharomyces cerevisiae. Phytomedicine 18: 1262–1268.
[11]
Mattson MP (2008) Hormesis defined. Ageing Res Rev 7: 1–7.
[12]
Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201–204.
[13]
Masoro EJ (2000) Caloric restriction and aging: an update. Exp Gerontol 35: 299–305.
[14]
McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition 10: 63–79.
[15]
Piper MD, Bartke A (2008) Diet and aging. Cell Metab 8: 99–104.
[16]
Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, et al. (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489: 318–321.
[17]
Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101: 15998–16003.
[18]
Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, et al. (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14: 885–890.
[19]
Giannakou ME, Goss M, Partridge L (2008) Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response. Aging Cell 7: 187–198.
[20]
Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, et al. (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5: 97–108.
[21]
Spindler SR (2006) Use of microarray biomarkers to identify longevity therapeutics. Aging Cell 5: 39–50.
[22]
Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One 5: e8758.
[23]
Slack C, Foley A, Partridge L (2012) Activation of AMPK by the Putative Dietary Restriction Mimetic Metformin Is Insufficient to Extend Lifespan in Drosophila. PLoS One 7: e47699.
[24]
Grandison RC, Wong R, Bass TM, Partridge L, Piper MD (2009) Effect of a standardised dietary restriction protocol on multiple laboratory strains of Drosophila melanogaster. PLoS One 4: e4067.
[25]
Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18: 12–16.
[26]
Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73: 417–435.
[27]
Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, et al. (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11: 453–465.
[28]
Hagopian K, Ramsey JJ, Weindruch R (2003) Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice. Exp Gerontol 38: 253–266.
[29]
Ingram DK, Roth GS (2011) Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Exp Gerontol 46: 148–154.
[30]
Rogina B, Helfand SL, Frankel S (2002) Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 298: 1745.
[31]
Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429: 562–566.
[32]
Humphrey DM, Toivonen JM, Giannakou M, Partridge L, Brand MD (2009) Expression of human uncoupling protein-3 in Drosophila insulin-producing cells increases insulin-like peptide (DILP) levels and shortens lifespan. Exp Gerontol 44: 316–327.
[33]
Broughton SJ, Piper MD, Ikeya T, Bass TM, Jacobson J, et al. (2005) Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A 102: 3105–3110.
[34]
Magwere T, Goodall S, Skepper J, Mair W, Brand MD, et al. (2006) The effect of dietary restriction on mitochondrial protein density and flight muscle mitochondrial morphology in Drosophila. J Gerontol A Biol Sci Med Sci 61: 36–47.
[35]
Anderson RM, Shanmuganayagam D, Weindruch R (2009) Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol 37: 47–51.
[36]
Archer MA, Bradley TJ, Mueller LD, Rose MR (2007) Using experimental evolution to study the physiological mechanisms of desiccation resistance in Drosophila melanogaster. Physiol Biochem Zool 80: 386–398.
[37]
Schriner SE, Katoozi NS, Pham KQ, Gazarian M, Zarban A, et al. (2012) Extension of Drosophila lifespan by Rosa damascena associated with an increased sensitivity to heat. Biogerontology 13: 105–17.
[38]
Jang YC, Perez VI, Song W, Lustgarten MS, Salmon AB, et al. (2009) Overexpression of Mn superoxide dismutase does not increase life span in mice. J Gerontol A Biol Sci Med Sci 64: 1114–1125.
[39]
Perez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, et al. (2009) The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8: 73–75.
[40]
Orr WC, Sohal RS (2003) Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster? Exp Gerontol 38: 227–230.
[41]
Bai H, Kang P, Tatar M (2012) Drosophila insulin-like peptide-6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain. Aging Cell 11: 978–985.
[42]
Broughton SJ, Slack C, Alic N, Metaxakis A, Bass TM, et al. (2010) DILP-producing median neurosecretory cells in the Drosophila brain mediate the response of lifespan to nutrition. Aging Cell 9: 336–346.
[43]
Panossian A, Wikman G, Sarris J (2010) Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 17: 481–493.
[44]
Martin GM (1989) Genetic modulation of the senescent phenotype in Homo sapiens. Genome 31: 390–397.
[45]
Tu MP, Epstein D, Tatar M (2002) The demography of slow aging in male and female Drosophila mutant for the insulin-receptor substrate homologue chico. Aging Cell 1: 75–80.
[46]
Lee KS, Lee BS, Semnani S, Avanesian A, Um CY, et al. (2010) Curcumin Extends Life Span, Improves Health Span, and Modulates the Expression of Age-Associated Aging Genes in Drosophila melanogaster. Rejuvenation Res 13: 561–70.
[47]
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254.
[48]
Matsumura H, Miyachi S (1980) Cycling assay for nicotinamide adenine dinucleotides. Methods Enzymol 69: 465–470.
