A link between phenotypic robustness and life expectancy in Drosophila melanogaster

Long-lived systems are expected to be stable, i. e. resistant to either external influences, or internal failures. Robustness of biological systems can be defined as a reciprocal value to their phenotypic plasticity expressed through a coefficient of variation (C.V.) for positively distributed phenotypic traits. Considering lifespan as phenotype, which integrates all functions of an organism, we showed that its phenotypic robustness correlates positively with life expectancy. We assessed lifespan parameters for a selection of inbred Drosophila melanogaster strains from Drosophila Genetic Reference Panel (DGRP) reared at 29 ºС. The robustness of lifespan phenotype (C.V.–1) correlated positively with estimated life expectancy for these strains. The same relation also holds for the lifespan of all DGRP strains reared at 25 ºС. Also, in agreement with previous observations, upon temperature change (decrease or increase) the survival curves scaled in time (stretched or shrunk respectively). In other words, the average lifespan decreased for flies reared at elevated temperature, but so did the standard deviation, and thus the coefficients of variation remained in the same range. From this we conclude that coefficients of variation correlate with life expectancies and account for the robustness of lifespan phenotype irrespective of accelerated aging caused by temperature.

lifespan, life expectancy, aging, phenotypic plasticity, phenotypic robustness, Drosophila melanogaster

1. Ayyadevara S., Alla R., Thaden J.J., Shmookler Reis R.J. Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell. 2008;7:13-22. DOI 10.1111/j.1474-9726.2007.00348.x.

2. Garinis G.A., van der Horst G.T., Vijg J., Hoeijmakers J.H. DNA damage and ageing: new-age ideas for an age-old problem. Nat. Cell Biol. 2008;10:1241-1247. DOI 10.1038/ncb1108-1241.

3. Gompertz B. On the Nature of the Function Expressive of the Law of Human Mortality, and on a New Mode of Determining the Value of Life Contingencies. Philosophical Transactions of the Royal Society of London. 1825;115:513-583. DOI 10.1098/rstl.1825.0026.

4. Greenwood F.R.S. “Laws” of mortality from the biological point of view. J. Hyg. 1928;28:267-294. DOI 10.1017/S002217240000961X.

5. Gumbel E.J. Statistics of extremes. N. Y.: Columbia University Press, 1958.

6. Huang W., Massouras A., Inoue Y., Peiffer J., Ramia M., Tarone A.M., Turlapati L., Zichner T., Zhu D., Lyman R.F., Magwire M.M., Blan-kenburg K., Carbone M.A., Chang K., Ellis L.L., Fernandez S., Han Y., Highnam G., Hjelmen C.E., Jack J.R., Javaid M., Jayasee-lan J., Kalra D., Lee S., Lewis L., Munidasa M., Ongeri F., Patel S., Perales L., Perez A., Pu L., Rollmann S.M., Ruth R., Saada N., Warner C., Williams A., Wu Y.Q., Yamamoto A., Zhang Y., Zhu Y., Anholt R.R., Korbel J.O., Mittelman D., Muzny D.M., Gibbs R.A., Barbadilla A., Johnston J.S., Stone E.A., Richards S., Deplancke B., Mackay T.F. Natural variation in genome architecture among 205 Drosophila melanogaster genetic reference panel lines. Genome Res. 2014;24:1193-1208. DOI 10.1101/gr.171546.113.

7. Hulbert A.J., Pamplona R., Buffenstein R., Buttemer W.A. Life and death: metabolic rate, membrane composition, and life span of animals. Physiol. Rev. 2007;87:1175-1213. DOI 10.1152/physrev.00047.2006.

8. Ivanov D.K., Escott-Price V., Ziehm M., Magwire M.M., Mackay T.F., Partridge L., Thornton J.M. Longevity GWAS using the Drosophila Genetic Reference Panel. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2015;70:1470-1478. DOI 10.1093/gerona/glv047.

9. Kapahi P., Kaeberlein M., Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res. Rev. 2017;39:3-14. DOI 10.1016/j.arr.2016.12.005.

10. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958;53:457-481. DOI 10.2307/2281868.

11. Kenyon C., Chang J., Gensch E., Rudner A., Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461-464. DOI 10.1038/366461a0.

12. Lopez-Otin C., Galluzzi L., Freije J.M., Madeo F., Kroemer G. Metabolic control of longevity. Cell. 2016;166:802-821. DOI 10.1016/j.cell.2016.07.031.

13. Mackay T.F., Richards S., Stone E.A., Barbadilla A., Ayroles J.F., Zhu D., Casillas S., Han Y., Magwire M.M., Cridland J.M., Richard- son M.F., Anholt R.R., Barron M., Bess C., Blankenburg K.P., Carbone M.A., Castellano D., Chaboub L., Duncan L., Harris Z., Javaid M., Jayaseelan J.C., Jhangiani S.N., Jordan K.W., Lara F., Lawrence F., Lee S.L., Librado P., Linheiro R.S., Lyman R.F., Mackey A.J., Munidasa M., Muzny D.M., Nazareth L., Newsham I., Perales L., Pu L.L., Qu C., Ramia M., Reid J.G., Rollmann S.M., Rozas J., Saada N., Turlapati L., Worley K.C., Wu Y.Q., Yamamoto A., Zhu Y., Bergman C.M., Thornton K.R., Mittelman D., Gibbs R.A. The Drosophila melanogaster genetic reference panel. Nature. 2012; 482:173-178. DOI 10.1038/nature10811.

14. Mair W., Goymer P., Pletcher S.D., Partridge L. Demography of dietary restriction and death in Drosophila. Science. 2003;301:1731-1733. DOI 10.1126/science.1086016.

15. Markov A.V., Naimark E.B., Yakovleva E.U. Temporal scaling of age-dependent mortality: dynamics of aging in Caenorhabditis el-egans is easy to speed up or slow down, but its overall trajectory is stable. Biochemistry (Moscow). 2016;81:906-911. DOI 10.1134/S0006297916080125.

16. Missov T.I., Lenart A., Nemeth L., Canudas-Romo V., Vaupel J.W. The Gompertz force of mortality in terms of the modal age at death. Demographic Res. 2015;32:1031-1048. DOI 10.4054/DemRes.2015.32.36.

17. Moore D.F. Applied Survival Analysis Using R. Springer International Publishing, 2016.

18. Pan H., Finkel T. Key proteins and pathways that regulate lifespan. J. Biol. Chem. 2017;292:6452-6460. DOI 10.1074/jbc.R116.771915.

19. Proshkina E.N., Shaposhnikov M.V., Sadritdinova A.F., Kudryavtseva A.V., Moskalev A.A. Basic mechanisms of longevity: A case study of Drosophila pro-longevity genes. Ageing Res. Rev. 2015;24: 218-231. DOI 10.1016/j.arr.2015.08.005.

20. Rigby R.A., Stasinopoulos D.M. Generalized additive models for location, scale and shape. J. Royal Statistical Society: Series C (Applied Statistics). 2005;54:507-554. DOI 10.1111/j.1467-9876.2005.00510.x.

21. Rogina B. INDY-A New link to metabolic regulation in animals and humans. Front. Genet. 2017;8:66. DOI 10.3389/fgene.2017.00066.

22. Shaw R.F., Bercaw B.L. Temperature and life-span in poikilothermous animals. Nature. 1962;196:454-457. DOI 10.1038/196454a0.

23. Speakman J.R. Body size, energy metabolism and lifespan. J. Exp. Biol. 2005;208:1717-1730. DOI 10.1242/jeb.01556.

24. Stasinopoulos D.M., Rigby R.A. Generalized additive models for location scale and shape (GAMLSS). J. Stat. Softw. 2007;23:46. DOI 10.18637/jss.v023.i07.

25. Stroustrup N., Anthony W.E., Nash Z.M., Gowda V., Gomez A., Lo-pez-Moyado I.F., Apfeld J., Fontana W. The temporal scaling of Caenorhabditis elegans ageing. Nature. 2016;530:103-107. DOI 10.1038/nature16550.

26. Tacutu R., Craig T., Budovsky A., Wuttke D., Lehmann G., Tara-nukha D., Costa J., Fraifeld V.E., de Magalhaes J.P. Human ageing genomic resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 2013;41:D1027-D1033. DOI 10.1093/nar/gks1155.

27. Therneau T.M., Grambsch P.M. Modeling Survival Data: Extending the Cox Model. N. Y.: Springer-Verlag, 2000.

28. Van Raamsdonk J.M. Mechanisms underlying longevity: A genetic switch model of aging. Exp. Gerontol. 2017. Ahead of print. DOI 10.1016/j.exger.2017.08.005.

29. Vermeij W.P., Dolle M.E., Reiling E., Jaarsma D., Payan-Gomez C., Bombardieri C.R., Wu H., Roks A.J., Botter S.M., van der Eer-den B.C., Youssef S.A., Kuiper R.V., Nagarajah B., van Oos-trom C.T., Brandt R.M., Barnhoorn S., Imholz S., Pennings J.L., de Bruin A., Gyenis A., Pothof J., Vijg J., van Steeg H., Hoeij-makers J.H. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature. 2016;537:427-431. DOI 10.1038/nature19329.

30. Zane L., Sharma V., Misteli T. Common features of chromatin in aging and cancer: cause or coincidence? Trends Cell Biol. 2014;24:686-694. DOI 10.1016/j.tcb.2014.07.001.