Advertisement

The slim, the fat, and the obese: guess who lives the longest?

Abstract

In a modern society that is increasingly older and “heavier,” it is understandable that the majority favors a slimmer body that helps to sail smoothly into the dusk of life. Given the association between obesity and many metabolic and cardiovascular disorders, there are stern criticisms over such a thought of “good fat”. Ironically, a phenomenon called “obesity paradox”, that is, the overweight population purportedly enjoys the lowest all-cause mortality, and baffles open-minded clinicians and scientists. Lipids are essential to all life forms. Fat, in particular, triacylglycerol, also exists in different forms and in different locations in the human body, making any simple statement that vilifies all fat invalid. Whether the phenomenon of obesity paradox, indeed, has its root in a hitherto unrealized pro-survival function of fat deserves a serious look. Indeed, a recent publication using yeast as the model showed that elevation in the cellular storage of triacylglycerol extends lifespan in an energy expenditure independent fashion. In stark contrast, lean cells devoid of triacylglycerol biosynthetic capability die upon entering the senescence phase. Together, a new cytoprotective function of fat emerges. This mini-review aims to discuss potential mechanisms for the observed lifespan preservation function of triacylglycerol.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Allen C, Buttner S, Aragon AD, Thomas JA, Meirelles O, Jaetao JE, Benn D, Ruby SW, Veenhuis M, Madeo F, Werner-Washburne M (2006) Isolation of quiescent and nonquiescent cells from yeast stationary-phase cultures. J Cell Biol 174:89–100. doi:10.1083/jcb.200604072

  2. Bagnato C, Igal RA (2003) Overexpression of diacylglycerol acyltransferase-1 reduces phospholipid synthesis, proliferation, and invasiveness in simian virus 40-transformed human lung fibroblasts. J Biol Chem 278:52203–52211. doi:10.1074/jbc.M305760200

  3. Bailey AP, Koster G, Guillermier C, Hirst EM, MacRae JI, Lechene CP, Postle AD, Gould AP (2015) Antioxidant role for lipid droplets in a stem cell niche of Drosophila. Cell 163:340–353. doi:10.1016/j.cell.2015.09.020

  4. Beach A, Titorenko VI (2013) Essential roles of peroxisomally produced and metabolized biomolecules in regulating yeast longevity. Subcell Biochem 69:153–167. doi:10.1007/978-94-007-6889-5_9 Springer, Netherlands

  5. Binns D, Januszewski T, Chen Y, Hill J, Markin VS, Zhao Y, Gilpin C, Chapman KD, Anderson RG, Goodman JM (2006) An intimate collaboration between peroxisomes and lipid bodies. J Cell Biol 173:719–731. doi:10.1083/jcb.200511125

  6. Carman GM, Han GS (2009) Phosphatidic acid phosphatase, a key enzyme in the regulation of lipid synthesis. J Biol Chem 284:2593–2597. doi:10.1074/jbc.R800059200

  7. Choudhary V, Ojha N, Golden A, Prinz WA (2015) A conserved family of proteins facilitates nascent lipid droplet budding from the ER. J Cell Biol 211:261–271. doi:10.1083/jcb.201505067

  8. Coleman RA, Lee DP (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43:134–176

  9. Dahlqvist A, Stahl U, Lenman M, Banas A, Lee M, Sandager L, Ronne H, Stymne S (2000) Phospholipid:diacylglycerol acyltransferase: an enzyme that catalyzes the acyl-CoA-independent formation of triacylglycerol in yeast and plants. Proc Natl Acad Sci 97:6487–6492. doi:10.1073/pnas.120067297

  10. Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345–357

  11. Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ, Smith SR (2011) Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab 96:1654–1663. doi:10.1210/jc.2011-0585

  12. Fabrizio P, Longo VD (2007) The chronological life span of Saccharomyces cerevisiae. Methods Mol Biol 371:89–95. doi:10.1007/978-1-59745-361-5_8

  13. Fabrizio P, Longo VD (2008) Chronological aging-induced apoptosis in yeast. Biochim Biophys Acta 1783:1280–1285. doi:10.1016/j.bbamcr.2008.03.017

  14. Fabrizio P, Hoon S, Shamalnasab M, Galbani A, Wei M, Giaever G et al (2010) Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet. 6:e1001024. doi:10.1371/journal.pgen.1001024.s011 (Fabrizio P, Hoon S, Shamalnasab M, Galbani A, Wei M, Giaever G et al. (eds))

  15. Fagone P, Jackowski S (2009) Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res 50(Suppl):S311–S316. doi:10.1194/jlr.R800049-JLR200

  16. Fan J, Andre C, Xu C (2011) A chloroplast pathway for the de novo biosynthesis of triacylglycerol in Chlamydomonas reinhardtii. FEBS Lett 585:1985–1991. doi:10.1016/j.febslet.2011.05.018

  17. Farese RV Jr, Walther TC (2009) Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 139:855–860. doi:10.1016/j.cell.2009.11.005

  18. Guo Y, Walther TC, Rao M, Stuurman N, Goshima G, Terayama K, Wong JS, Vale RD, Walter P, Farese RV (2008) Functional genomic screen reveals genes involved in lipid-droplet formation and utilization. Nature 453:657–661. doi:10.1038/nature06928

  19. Hainer V, Aldhoon-Hainerova I (2013) Obesity paradox does exist. Diabetes Care 36(Suppl 2):S276–S281. doi:10.2337/dcS13-2023

  20. Handee W, Li X, Hall KW, Deng X, Li P, Benning C, Williams BL, Kuo MH (2016) An energy-independent pro-longevity function of triacylglycerol in yeast. PLoS Genet 12:e1005878. doi:10.1371/journal.pgen.1005878

  21. Ho YH, Gasch AP (2015). Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling. Curr Genet. 61(4):503–511. doi:10.1007/s00294-015-0491-0

  22. Hu Q, Sommerfeld M, Jarvis E, Ghirardi M, Posewitz M, Seibert M, Darzins A (2008) Microalgal triacylglycerols as feedstocks for biofuel production: perspectives and advances. Plant J 54:621–639. doi:10.1111/j.1365-313X.2008.03492.x

  23. Jagerstrom S, Polesie S, Wickstrom Y, Johansson BR, Schroder HD, Hojlund K, Bostrom P (2009) Lipid droplets interact with mitochondria using SNAP23. Cell Biol Int 33:934–940. doi:10.1016/j.cellbi.2009.06.011

  24. Jiang Y (2016). Regulation of TORC1 by ubiquitin through non-covalent binding. Curr Genet, pp 1–3. doi:10.1007/s00294-016-0581-7

  25. Kaeberlein M (2007) Molecular basis of ageing. EMBO Rep 8:907–911. doi:10.1038/sj.embor.7401066

  26. Kaeberlein M (2010) Lessons on longevity from budding yeast. Nature 464:513–519. doi:10.1038/nature08981

  27. Kaeberlein M, Rabinovitch PS, Martin GM (2015) Healthy aging: the ultimate preventative medicine. Science 350:1191–1193. doi:10.1126/science.aad3267

  28. Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL (1972) Indices of relative weight and obesity. J Chronic Dis 25:329–343

  29. Kohlwein SD (2010) Triacylglycerol homeostasis: insights from yeast. J Biol Chem 285:15663–15667. doi:10.1074/jbc.R110.118356

  30. Kohlwein SD, Veenhuis M, van der Klei IJ (2013) Lipid droplets and peroxisomes: key players in cellular lipid homeostasis or a matter of fat–store ‘em up or burn ‘em down. Genetics 193:1–50. doi:10.1534/genetics.112.143362

  31. Kourtis N, Tavernarakis N (2011). Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J 30(13):2520–2531. doi:10.1038/emboj.2011.162

  32. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594. doi:10.1242/jcs.051011

  33. Lee S-J, Zhang J, Choi AMK, Kim HP, Lee S-J, Zhang J et al (2013) Mitochondrial dysfunction induces formation of lipid droplets as a generalized response to stress. Oxid Med Cel Longev 2013:1–10 (Hindawi Publishing Corporation)

  34. Li X, Cope MB, Johnson MS, Smith DL Jr, Nagy TR (2009) Mild calorie restriction induces fat accumulation in female C57BL/6J mice. Obesity 18:456–462. doi:10.1038/oby.2009.312 (Nature Publishing Group)

  35. Li X, Benning C, Kuo MH (2012) Rapid triacylglycerol turnover in Chlamydomonas reinhardtii requires a lipase with broad substrate specificity. Eukaryot Cell 11:1451–1462. doi:10.1128/EC.00268-12

  36. Li-Beisson Y, Shorrosh B, Beisson F, Andersson MX, Arondel V, Bates PD, Baud S, Bird D, Debono A, Durrett TP, Franke RB, Graham IA, Katayama K, Kelly AA, Larson T, Markham JE, Miquel M, Molina I, Nishida I, Rowland O, Samuels L, Schmid KM, Wada H, Welti R, Xu C, Zallot R, Ohlrogge J (2013) Acyl-lipid metabolism. Arabidopsis Book 11:e0161. doi:10.1199/tab.0161

  37. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci 100:3077–3082. doi:10.1073/pnas.0630588100

  38. Longo VD, Shadel GS, Kaeberlein M, Kennedy B (2012) Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab 16:18–31. doi:10.1016/j.cmet.2012.06.002 (Elsevier Inc)

  39. Millar JS, Stone SJ, Tietge UJ, Tow B, Billheimer JT, Wong JS, Hamilton RL, Farese RV Jr, Rader DJ (2006) Short-term overexpression of DGAT1 or DGAT2 increases hepatic triglyceride but not VLDL triglyceride or apoB production. J Lipid Res 47:2297–2305. doi:10.1194/jlr.M600213-JLR200

  40. Mortimer RK, Johnston JR (1959) Life span of individual yeast cells. Nature 183:1751–1752

  41. Murphy S, Martin S, Parton RG (2009) Lipid droplet-organelle interactions; sharing the fats. Biochim Biophys Acta 1791:441–447. doi:10.1016/j.bbalip.2008.07.004

  42. Nielsen TS, Jessen N, Jørgensen JOL, Møller N, Lund S (2014) Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol 52:R199–R222. doi:10.1530/JME-13-0277 (BioScientifica)

  43. Ohlrogge J, Browse J (1995) Lipid biosynthesis. Plant Cell 7:957–970. doi:10.1105/tpc.7.7.957

  44. Oreopoulos A, Padwal R, Norris CM, Mullen JC, Pretorius V, Kalantar-Zadeh K (2008) Effect of obesity on short- and long-term mortality postcoronary revascularization: a meta-analysis. Obesity (Silver Spring) 16:442–450. doi:10.1038/oby.2007.36

  45. Pal D, Khozin-Goldberg I, Cohen Z, Boussiba S (2011) The effect of light, salinity, and nitrogen availability on lipid production by Nannochloropsis sp. Appl Microbiol Biotechnol 90:1429–1441. doi:10.1007/s00253-011-3170-1 (Springer-Verlag)

  46. Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777:1249–1262. doi:10.1016/j.bbabio.2008.07.003

  47. Pamplona R, Barja G, Portero-Otin M (2002) Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation? Ann N Y Acad Sci 959:475–490

  48. Petschnigg J, Wolinski H, Kolb D, Zellnig G, Kurat CF, Natter K et al (2009) Good fat, essential cellular requirements for triacylglycerol synthesis to maintain membrane homeostasis in yeast. J Biol Chem 284:30981–30993. doi:10.1074/jbc.M109.024752

  49. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH, American Heart A, Obesity Committee of the Council on Nutrition PA, Metabolism (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113: 898–918 doi:10.1161/CIRCULATIONAHA.106.171016

  50. Rahmouni K, Correia ML, Haynes WG, Mark AL (2005) Obesity-associated hypertension: new insights into mechanisms. Hypertension 45:9–14. doi:10.1161/01.HYP.0000151325.83008.b4

  51. Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci 98:7037–7044. doi:10.1073/pnas.121145898

  52. Reddy JK, Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21:193–230. doi:10.1146/annurev.nutr.21.1.193

  53. Saarikangas J, Barral Y (2016). Protein aggregation as a mechanism of adaptive cellular responses. Curr Genet, pp 1–14. doi:10.1007/s00294-016-0596-0

  54. Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17:422–427. doi:10.1016/j.tcb.2007.07.009

  55. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 91:1033–1042

  56. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135. doi:10.1038/nature07976

  57. Spindler SR (2010) Caloric restriction: from soup to nuts. Ageing Res Rev 9:324–353. doi:10.1016/j.arr.2009.10.003

  58. Watt MJ, Steinberg GR (2008) Regulation and function of triacylglycerol lipases in cellular metabolism. Biochem J 414:313–325. doi:10.1042/BJ20080305

  59. Weindruch R, Walford RL (1982) Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Sci 215:1415–1418

  60. Wilfling F, Wang H, Haas JT, Krahmer N, Gould TJ, Uchida A, Cheng JX, Graham M, Christiano R, Frohlich F, Liu X, Buhman KK, Coleman RA, Bewersdorf J, Farese RV Jr, Walther TC (2013) Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell 24:384–399. doi:10.1016/j.devcel.2013.01.013

  61. Yang L, Ding Y, Chen Y, Zhang S, Huo C, Wang Y, Yu J, Zhang P, Na H, Zhang H, Ma Y, Liu P (2012) The proteomics of lipid droplets: structure, dynamics, and functions of the organelle conserved from bacteria to humans. J Lipid Res 53:1245–1253. doi:10.1194/jlr.R024117

  62. Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV Jr (2008) Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 49:2283–2301. doi:10.1194/jlr.R800018-JLR200

  63. Yoon K, Han D, Li Y, Sommerfeld M, Hu Q (2012) Phospholipid:diacylglycerol acyltransferase is a multifunctional enzyme involved in membrane lipid turnover and degradation while synthesizing triacylglycerol in the unicellular green microalga Chlamydomonas reinhardtii. Plant Cell 24:3708–3724. doi:10.1105/tpc.112.100701

  64. Younce C, Kolattukudy P (2012) MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy. Cell Physiol Biochem 30:307–320. doi:10.1159/000339066 (Karger Publishers)

  65. Yu YH, Ginsberg HN (2005) Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ Res 96:1042–1052. doi:10.1161/01.RES.0000165803.47776.38

  66. Zasedatelev B (1988) A habit that takes away health|Privychka, unosiashchaia zdorov’e. Meditsinskaia sestra 47:10–13

  67. Zhang M, Fan J, Taylor DC, Ohlrogge JB (2009) DGAT1 and PDAT1 acyltransferases have overlapping functions in Arabidopsis triacylglycerol biosynthesis and are essential for normal pollen and seed development. Plant Cell 21:3885–3901. doi:10.1105/tpc.109.071795

  68. Ziegler DV, Wiley CD, Velarde MC (2015) Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell 14:1–7. doi:10.1111/acel.12287

Download references

Author information

Correspondence to Min-Hao Kuo.

Additional information

X. Li and W. Handee equal contribution.

Communicated by M. Kupiec.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, X., Handee, W. & Kuo, M. The slim, the fat, and the obese: guess who lives the longest?. Curr Genet 63, 43–49 (2017). https://doi.org/10.1007/s00294-016-0617-z

Download citation

Keywords

  • Aging
  • Lifespan regulation
  • Triacylglycerol
  • Obesity paradox
  • Free radicals