Login Register Cart 0
Generic placeholder image

Current Aging Science

Editor-in-Chief

ISSN (Print): 1874-6098
ISSN (Online): 1874-6128

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Mechanism of Programmed Aging: The Way to Create a Real Remedy for Senescence

Author(s): Alexander G. Trubitsyn*

Volume 13, Issue 1, 2020

Page: [31 - 41] Pages: 11

DOI: 10.2174/1874609812666191014111422

Abstract

Background: Accumulation of various damages is considered the primary cause of aging throughout the history of gerontology. No progress has been made in extending animal lifespan under the guidance of this concept. This concept denies the existence of longevity genes, but it has been experimentally shown that manipulating genes that affect cell division rates can increase the maximum lifespan of animals. These methods of prolonging life are unsuitable for humans because of dangerous side effects, but they undoubtedly indicate the programmed nature of aging.

Objective: The objective was to understand the mechanism of programmed aging to determine how to solve the problem of longevity.

Methods: Fundamental research has already explored key details relating to the mechanism of programmed aging, but they are scattered across different fields of knowledge. The way was to recognize and combine them into a uniform mechanism.

Results: Only a decrease in bioenergetics is under direct genetic control. This causes many different harmful processes that serve as the execution mechanism of the aging program. The aging rate and, therefore, lifespan are determined by the rate of cell proliferation and the magnitude of the decrease in bioenergetics per cell division in critical tissues.

Conclusion: The mechanism of programmed aging points the way to achieving an unlimited healthy life; it is necessary to develop a means for managing bioenergetics. It has already been substantially studied by molecular biologists and is now waiting for researchers from gerontology.

Keywords: Longevity, genetic program, natural selection, bioenergetics, mechanism of aging, aging clock, rate of aging.

« Previous Next »
Graphical Abstract

[1]
Weisman A. Essays upon Heredity and Kinder Biological Problems. Oxford: Clarendon Press 1891.
[2]
Medawar PB. An Unsolved Problem of Biology. London: Levis 1952.
[3]
Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11(3): 298-300.
[http://dx.doi.org/10.1093/geronj/11.3.298] [PMID: 13332224]
[4]
Williams GC. Pleiotropy, natural selection and the evolution of senescence. Evolution 1957; 11: 398-411.
[http://dx.doi.org/10.1111/j.1558-5646.1957.tb02911.x]
[5]
Kirkwood TBL. Evolution of ageing. Nature 1977; 270(5635): 301-4.
[http://dx.doi.org/10.1038/270301a0] [PMID: 593350]
[6]
Miquel J, Economos AC, Fleming J, Johnson JE. Mitochondrial role in cell aging. Exp Gerontol 1980; 15(6): 575-91.
[http://dx.doi.org/10.1016/0531-5565(80)90010-8] [PMID: 7009178]
[7]
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(6454): 461-4.
[http://dx.doi.org/10.1038/366461a0] [PMID: 8247153]
[8]
Malone EA, Inoue T, Thomas JH. Genetic analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation. Genetics 1996; 143(3): 1193-205.
[PMID: 8807293]
[9]
Tissenbaum HA, Ruvkun G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 1998; 148(2): 703-17.
[PMID: 9504918]
[10]
Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426(6967): 620.
[http://dx.doi.org/10.1038/426620a] [PMID: 14668850]
[11]
Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004; 14(10): 885-90.
[http://dx.doi.org/10.1016/j.cub.2004.03.059] [PMID: 15186745]
[12]
Gillespie ZE, Pickering J, Eskiw CH. Better living through Chemistry: Caloric Restriction (CR) and CR mimetics alter genome function to promote increased health and lifespan. Front Genet 2016; 7: 142.
[http://dx.doi.org/10.3389/fgene.2016.00142] [PMID: 27588026]
[13]
Carmona JJ, Michan S. Biology of healthy aging and longevity. Rev Invest Clin 2016; 68(1): 7-16.
[PMID: 27028172]
[14]
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663-76.
[http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]
[15]
Choi J, Lee S, Mallard W, et al. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat Biotechnol 2015; 33(11): 1173-81.
[http://dx.doi.org/10.1038/nbt.3388] [PMID: 26501951]
[16]
Hashizume O, Ohnishi S, Mito T, et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep 2015; 5: 10434.
[http://dx.doi.org/10.1038/srep10434] [PMID: 26000717]
[17]
Wilson EO. Group selection and its significance for ecology. Bioscience 1973; 23: 631-8.
[http://dx.doi.org/10.2307/1296775]
[18]
Trubitsyn AG. Species-specific lifespan is under control of natural selection. Adv Gerontol 2006; 19: 13-24.
[PMID: 17152715]
[19]
Mitteldorf J, Pepper J. Senescence as an adaptation to limit the spread of disease. J Theor Biol 2009; 260(2): 186-95.
[http://dx.doi.org/10.1016/j.jtbi.2009.05.013] [PMID: 19481552]
[20]
Goldsmith TC. Evolvability, population benefit, and the evolution of programmed aging in mammals. Biochemistry (Mosc) 2017; 82(12): 1423-9.
[http://dx.doi.org/10.1134/S0006297917120021] [PMID: 29486693]
[21]
Malek MH, Hüttemann M, Lee I. Mitochondrial structure, function, and dynamics: The common thread across organs, disease, and aging. Oxid Med Cell Longev 2018; 20181863414
[http://dx.doi.org/10.1155/2018/1863414] [PMID: 29576844]
[22]
Hayashi J, Ohta S, Kikuchi A, Takemitsu M, Goto Y, Nonaka I. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction. Proc Natl Acad Sci USA 1991; 88(23): 10614-8.
[http://dx.doi.org/10.1073/pnas.88.23.10614] [PMID: 1720544]
[23]
Hayashi J, Ohta S, Kagawa Y, et al. Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects. J Biol Chem 1994; 269(9): 6878-83.
[PMID: 8120050]
[24]
Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell 2016; 61(5): 654-66.
[http://dx.doi.org/10.1016/j.molcel.2016.01.028] [PMID: 26942670]
[25]
Srivastava S. The mitochondrial basis of aging and age-related disorders. Genes (Basel) 2017; 8(12): 398.
[http://dx.doi.org/10.3390/genes8120398] [PMID: 29257072]
[26]
Sebastián D, Palacín M, Zorzano A. Mitochondrial dynamics: Coupling mitochondrial fitness with healthy aging. Trends Mol Med 2017; 23(3): 201-15.
[http://dx.doi.org/10.1016/j.molmed.2017.01.003] [PMID: 28188102]
[27]
Zhang H, Menzies KJ, Auwerx J. The role of mitochondria in stem cell fate and aging. Development 2018; 145(8)143420
[http://dx.doi.org/10.1242/dev.143420] [PMID: 29654217]
[28]
Trubitsyn AG. Bioenergetics theory of aging.Bioenergetics Rijeka: In Tech. 2012; p. 63-94.
[29]
Lipsky MS, King M. Biological theories of aging. Dis Mon 2015; 61(11): 460-6.
[http://dx.doi.org/10.1016/j.disamonth.2015.09.005] [PMID: 26490576]
[30]
Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology 2004; 5(1): 1-10.
[http://dx.doi.org/10.1023/B:BGEN.0000017682.96395.10] [PMID: 15138376]
[31]
Lee HW, Blasco MA, Gottlieb GJ, Horner JW II, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature 1998; 392(6676): 569-74.
[http://dx.doi.org/10.1038/33345] [PMID: 9560153]
[32]
Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 1994; 91(21): 9857-60.
[http://dx.doi.org/10.1073/pnas.91.21.9857] [PMID: 7937905]
[33]
Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997; 91(1): 25-34.
[http://dx.doi.org/10.1016/S0092-8674(01)80006-4] [PMID: 9335332]
[34]
Herrera E, Samper E, Martín-Caballero J, Flores JM, Lee HW, Blasco MA. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J 1999; 18(11): 2950-60.
[http://dx.doi.org/10.1093/emboj/18.11.2950] [PMID: 10357808]
[35]
Dilman VM. The Grand Biological Clock Moscow: Mir. 1998.
[36]
Reppert SM, Weaver DR. Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 2001; 63: 647-76.
[http://dx.doi.org/10.1146/annurev.physiol.63.1.647] [PMID: 11181971]
[37]
Karasek M. Melatonin, human aging, and age-related diseases. Exp Gerontol 2004; 39(11-12): 1723-9.
[http://dx.doi.org/10.1016/j.exger.2004.04.012] [PMID: 15582288]
[38]
Gubin DG, Gubin GD. Daily administration of melatonin reduces circadian rhythm disturbances in older people. Curr Aging Sci 2016; 9: 5-13.
[http://dx.doi.org/10.2174/1874609809666151130220011] [PMID: 26632428]
[39]
Panda S. Circadian physiology of metabolism. Science 2016; 354(6315): 1008-15.
[http://dx.doi.org/10.1126/science.aah4967] [PMID: 27885007]
[40]
Tevy MF, Giebultowicz J, Pincus Z, Mazzoccoli G, Vinciguerra M. Aging signaling pathways and circadian clock-dependent metabolic derangements. Trends Endocrinol Metab 2013; 24(5): 229-37.
[http://dx.doi.org/10.1016/j.tem.2012.12.002] [PMID: 23299029]
[41]
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14(10): R115.
[http://dx.doi.org/10.1186/gb-2013-14-10-r115] [PMID: 24138928]
[42]
Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018; 19(6): 371-84.
[http://dx.doi.org/10.1038/s41576-018-0004-3] [PMID: 29643443]
[43]
Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25: 585-621.
[http://dx.doi.org/10.1016/0014-4827(61)90192-6] [PMID: 13905658]
[44]
Trubitsyn AG. The Mechanism of phenoptosis: 2. the hayflick limit is caused by programmed decrease of the bioenergetics level. Adv Gerontol 2011; 1: 134-9.
[http://dx.doi.org/10.1134/S2079057011020147]
[45]
Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol 2006; 7: 14.
[http://dx.doi.org/10.1186/1471-2121-7-14] [PMID: 16529651]
[46]
Kasper G, Mao L, Geissler S, et al. Insights into mesenchymal stem cell aging: involvement of antioxidant defense and actin cytoskeleton. Stem Cells 2009; 27(6): 1288-97.
[http://dx.doi.org/10.1002/stem.49] [PMID: 19492299]
[47]
Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007; 8(9): 703-13.
[http://dx.doi.org/10.1038/nrm2241] [PMID: 17717515]
[48]
Campisi J. From cells to organisms: can we learn about aging from cells in culture? Exp Gerontol 2001; 36(4-6): 607-18.
[http://dx.doi.org/10.1016/S0531-5565(00)00230-8] [PMID: 11295503]
[49]
Hornsby PJ. Cellular senescence and tissue aging in vivo. J Gerontol A Biol Sci Med Sci 2002; 57(7): B251-6.
[http://dx.doi.org/10.1093/gerona/57.7.B251] [PMID: 12084795]
[50]
Ho AD, Wagner W, Mahlknecht U. Stem cells and aging. EMBO Rep 2005; 6: S35-8.
[http://dx.doi.org/10.1038/sj.embor.7400436] [PMID: 15995659]
[51]
McCay CM, Crowell MF, Maynard LA. The Effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 1935; 10: 63-79.
[http://dx.doi.org/10.1093/jn/10.1.63]
[52]
Koubova J, Guarente L. How does calorie restriction work? Genes Dev 2003; 17(3): 313-21.
[http://dx.doi.org/10.1101/gad.1052903] [PMID: 12569120]
[53]
Grandison RC, Piper MDW, Partridge L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 2009; 462(7276): 1061-4.
[http://dx.doi.org/10.1038/nature08619] [PMID: 19956092]
[54]
Heestand BN, Shen Y, Liu W, et al. Dietary restriction induced longevity is mediated by nuclear receptor NHR-62 in Caenorhabditis elegans. PLoS Genet 2013; 9(7)e1003651
[http://dx.doi.org/10.1371/journal.pgen.1003651] [PMID: 23935515]
[55]
Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R. Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res 2008; 102(5): 519-28.
[http://dx.doi.org/10.1161/CIRCRESAHA.107.168369] [PMID: 18340017]
[56]
Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273(5271): 59-63.
[http://dx.doi.org/10.1126/science.273.5271.59] [PMID: 8658196]
[57]
Wolf NS, Penn PE, Jiang D, Fei RG, Pendergrass WR. Caloric restriction: conservation of in vivo cellular replicative capacity accompanies life-span extension in mice. Exp Cell Res 1995; 217(2): 317-23.
[http://dx.doi.org/10.1006/excr.1995.1092] [PMID: 7698231]
[58]
Pendergrass WR, Li Y, Jiang D, Fei RG, Wolf NS. Caloric restriction: conservation of cellular replicative capacity in vitro accompanies life-span extension in mice. Exp Cell Res 1995; 217(2): 309-16.
[http://dx.doi.org/10.1006/excr.1995.1091] [PMID: 7698230]
[59]
Bhattacharyya TK, Jackson P, Patel MK, Thomas JR. Epidermal cell proliferation in calorie-restricted aging rats. Curr Aging Sci 2012; 5(2): 96-104.
[http://dx.doi.org/10.2174/1874609811205020096] [PMID: 21834786]
[60]
Zimmerman JA, Malloy V, Krajcik R, Orentreich N. Nutritional control of aging. Exp Gerontol 2003; 38(1-2): 47-52.
[http://dx.doi.org/10.1016/S0531-5565(02)00149-3] [PMID: 12543260]
[61]
Solon-Biet SM, McMahon AC, Ballard JW, et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab 2014; 19(3): 418-30.
[http://dx.doi.org/10.1016/j.cmet.2014.02.009] [PMID: 24606899]
[62]
Trubitsyn AG. The lag of the proliferative aging clock underlies the lifespan-extending effect of calorie restriction. Curr Aging Sci 2015; 8(3): 220-6.
[http://dx.doi.org/10.2174/1874609808666151002111632] [PMID: 26428550]
[63]
Anisimov VN, Bartke A. The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol 2013; 87(3): 201-23.
[http://dx.doi.org/10.1016/j.critrevonc.2013.01.005] [PMID: 23434537]
[64]
Lee SH, Min KJ. Caloric restriction and its mimetics. BMB Rep 2013; 46(4): 181-7.
[http://dx.doi.org/10.5483/BMBRep.2013.46.4.033] [PMID: 23615258]
[65]
Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature 1996; 384(6604): 33.
[http://dx.doi.org/10.1038/384033a0] [PMID: 8900272]
[66]
Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 2001; 98(12): 6736-41.
[http://dx.doi.org/10.1073/pnas.111158898] [PMID: 11371619]
[67]
Bartke A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 2003; 78(4): 210-6.
[http://dx.doi.org/10.1159/000073704] [PMID: 14583653]
[68]
Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science 2010; 328(5976): 321-6.
[http://dx.doi.org/10.1126/science.1172539] [PMID: 20395504]
[69]
Bartke A, Quainoo N. Impact of growth hormone-related mutations on mammalian aging. Front Genet 2018; 9: 586.
[http://dx.doi.org/10.3389/fgene.2018.00586] [PMID: 30542372]
[70]
Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol 2009; 21(2): 209-18.
[http://dx.doi.org/10.1016/j.ceb.2009.01.024] [PMID: 19261457]
[71]
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168(6): 960-76.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[72]
Wipperman MF, Montrose DC, Gotto AM, Hajjar DP. Mammalian target of rapamycin: A metabolic rheostat for regulating adipose tissue function and cardiovascular health. Am J Pathol 2019; 189(3): 492-501.
[http://dx.doi.org/10.1016/j.ajpath.2018.11.013] [PMID: 30803496]
[73]
Loewith R, Hall MN. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 2011; 189(4): 1177-201.
[http://dx.doi.org/10.1534/genetics.111.133363] [PMID: 22174183]
[74]
Kenyon CJ. The genetics of ageing. Nature 2010; 464(7288): 504-12.
[http://dx.doi.org/10.1038/nature08980] [PMID: 20336132]
[75]
Gruber J, Yee Z, Tolwinski NS. Developmental drift and the role of Wnt signaling in aging. Cancers (Basel) 2016; 8(8): 73.
[http://dx.doi.org/10.3390/cancers8080073] [PMID: 27490570]
[76]
Lithgow G. Small molecules that suppress protein aggregation and slow aging. Abstracts of reports of 3rd international conference. Sochi. 2014.
[77]
Conti B, Sanchez-Alavez M, Winsky-Sommerer R, et al. Transgenic mice with a reduced core body temperature have an increased life span. Science 2006; 314(5800): 825-8.
[http://dx.doi.org/10.1126/science.1132191] [PMID: 17082459]
[78]
Xiao R, Zhang B, Dong Y, et al. A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell 2013; 152(4): 806-17.
[http://dx.doi.org/10.1016/j.cell.2013.01.020] [PMID: 23415228]
[79]
Munshi-South J, Wilkinson GS. Bats and birds: Exceptional longevity despite high metabolic rates. Ageing Res Rev 2010; 9(1): 12-9.
[http://dx.doi.org/10.1016/j.arr.2009.07.006] [PMID: 19643206]
[80]
Browe BM, Vice EN, Park TJ. Naked mole-rats: Blind, naked, and feeling no pain. Anat Rec (Hoboken) 2018; 303(1): 77-88.
[http://dx.doi.org/10.1002/ar.23996] [PMID: 30365235]
[81]
Shatilovich AV, Tchesunov AV, Neretina TV, et al. Viable nematodes from late pleistocene permafrost of the kolyma river lowland. Dokl Biol Sci 2018; 480(1): 100-2.
[http://dx.doi.org/10.1134/S0012496618030079] [PMID: 30009350]
[82]
Shi T, Reeves RH, Gilichinsky DA, Friedmann EI. Characterization of viable bacteria from Siberian permafrost by 16S rDNA sequencing. Microb Ecol 1997; 33(3): 169-79.
[http://dx.doi.org/10.1007/s002489900019] [PMID: 9115180]
[83]
Kadenbach B, Ramzan R, Wen L, Vogt S. New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms. Biochim Biophys Acta 2010; 1800(3): 205-12.
[http://dx.doi.org/10.1016/j.bbagen.2009.04.019] [PMID: 19409964]
[84]
Kadenbach B, Ramzan R, Vogt S. High efficiency versus maximal performance--the cause of oxidative stress in eukaryotes: a hypothesis. Mitochondrion 2013; 13: 1-6.

Rights & Permissions Print Cite
Article Metrics
14
2
© 2024 Bentham Science Publishers | Privacy Policy