Skip to main content
SpringerLink
Log in

Genetic, epigenetic and posttranslational mechanisms of aging

  • Review Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Gerontological experimentation is and was always strongly influenced by “theories”. The early decades of molecular genetics inspired deterministic thinking, based on the “Central Dogma” (DNA → RNA → Proteins). With the progress of detailed knowledge of gene-function a much more complicated picture emerged. Regulation of gene-expression turned out to be a highly complicated process. Experimental gerontology produced over the last decades several “paradigms” incompatible with simple genetic determinism. The increasing number of such detailed experimental “facts” revealed the importance of epigenetic factors and of posttranslational modifications in the age-dependent decline of physiological functions. We shall present in this review a short but critical analysis of genetic and epigenetic processes applied to the interpretation of the more and more precisely elucidated experimental paradigms of aging followed by some of the most relevant aging-mechanisms at the post-translational level, the posttranslational modifications of proteins such as the Maillard reaction, the proteolytic production of harmful peptides and the molecular mechanisms of the aging of elastin with the role of the age-dependent uncoupling of the elastin receptor, as well as the loss of several other receptors. We insist also on the well documented influence of posttranslational modifications on gene expression and on the role of non-coding RNA-s. Altogether, these data replace the previous simplistic concepts on gene action as related to aging by a much more complicated picture, where epigenetic and posttranslational processes together with environmentally influenced genetic pathways play key-roles in aging and strongly influence gene expression.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

JH:

Juvenile hormone

ECM:

Extracellular matrix

CR:

Calorie restriction

nc-RNA:

Non coding RNA-s

RNAi :

RNA-interference

mTOR:

Mammalian target of rapamycin

S6K1 :

A ribosomal S6-protein kinase

CNV:

Copy number variation

SNP:

Single nucleotide polymorphism

References

  • Adelman RC, Roth GS (1983) Altered proteins and aging. CRC Press, Boca Raton

    Google Scholar 

  • Allis DC, Jenuwein T, Reinberg D, Caparros M-L (eds) (2007) Epigenetics. CSHL Press, New York

    Google Scholar 

  • Amdam GV, Seehuus SC (2006) Order, disorder, death: lessons from a superorganism. Adv Cancer Res 95:31–60

    Article  PubMed  Google Scholar 

  • Amouyel P, Vidal O, Launay J-M, Laplanche J-L (1994) The apolipoprotein E alleles as major susceptibility factors for Creutzfeld–Jacob disease. Lancet 344:1315–1318

    Article  PubMed  CAS  Google Scholar 

  • Assmann G, Schmitz G, Menzel HJ, Schulte H (1984) Apolipoprotein E polymorphism and hyperlipidemia. Clin Chemistry 30:641–643

    CAS  Google Scholar 

  • Barlati S, de Petro G, Vartio T, Vaheri A (1981) Transformation-enhancing activity of proteolytic fragments of fibronectin. Proc Natl Acad Sci USA 78:4965–4969

    Article  PubMed  Google Scholar 

  • Baynes JW, Monnier VM, Ames JM, Thorpe SR (eds) (2005) The Maillard reaction. Chemistry at the interface of nutrition, aging and disease, vol 1043. Annual New York Academic Science, New York

    Google Scholar 

  • Bishop NA, Guarente L (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8:835–844

    Article  PubMed  CAS  Google Scholar 

  • Bizbiz L, Alperovitch A, Robert L, the EVA Group (1997) Aging of the vascular wall: serum concentration of elastin peptides and elastase inhibitors in relation with cardiovascular risk factor. The EVA study. Atherosclerosis 131:73–78

    Article  PubMed  CAS  Google Scholar 

  • Browner WS, Kahn AJ, Ziv E, Reiner AP, Oshima J, Cawthon RM, Hsueh W-C, Cummings SR (2004) The genetics of human longevity. Review. Am J Med 117:851–860

    Article  PubMed  CAS  Google Scholar 

  • Budovskaya YV, Wu K, Southworth LK, Jiang M, Tedesco P, Johnson TE (2008) Kim SK An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in Caenorhabditis elegans. Cell 134:291–303

    Article  PubMed  CAS  Google Scholar 

  • Burnet MF (1974) Intrinsic mutagenesis: a genetic approach to aging. Wiley, Chichester

    Google Scholar 

  • Carnes BA, Olshansky SJ, Grahn D (2003) Biological evidence for limits to the duration of life. Biogerontology 4:31–45

    Article  PubMed  Google Scholar 

  • Carnes B, Staats DO, Sonntag WE (2008) Does senescence give rise to disease? Mech Aging Develop 2008(129):693–699

    Article  Google Scholar 

  • Claire M, Jacotot B, Robert L (1976) Characterisation of lipids associated with macromolecules of the intercellular matrix of human aorta. Connect Tissue Res 4:61–71

    Article  PubMed  CAS  Google Scholar 

  • Comfort A (1979) The biology of senescence. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Debret R, Claus S, Cenizo V, Aimond G, Andre V, Megarbane A, Devillers M, Damour O, Sommer P (2009). Silencing of elastic fibers related genes in Cutis Laxa as model of human accelerated skin aging. Summary SA8 185-5 (p 101) IAGG 2009 Paris

  • Faury G, Chabaud A, Ristori MT, Robert L, Verdetti J (1997) Effect of age on the vasodilatory action of elastin peptides. Mech Aging Develop 95:31–42

    Article  CAS  Google Scholar 

  • Fox-Keller E (2000) The century of the gene. Harvard University Press, Cambridge

    Google Scholar 

  • Fülöp T Jr, Barabas G, Varga Z, Csongor J, Hauck M, Szücs S, Seres I, Mohacsi A, Kékessy D, Despont JP, Robert L, Penyige A (1992) Transmembrane signalling changes with aging. Ann New York Acad Sci 673:165–171

    Article  Google Scholar 

  • Fülöp T, Jacob MP, Khalil A, Wallach J, Robert L (1998) Biological effects of elastin peptides. Pathol Biol 46:497–506

    PubMed  Google Scholar 

  • Gershon D, Rott R (1988) Studies on the nature of faulty protein molecules and their diminished degradation in cells of aging organisms: functional implications. In: Bergener M, Ermini M, Stähelin HB (eds) The 1988 Sandoz lectures in gerontology. Academic Press, New York, pp 25–33

    Google Scholar 

  • Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H (2004) Advanced glycoxidation end products in commonly consumed food. J Am Diet Assoc 104:1287–1291

    Article  PubMed  CAS  Google Scholar 

  • Grosshans H, Slack FJ (2002) Micro-RNA-s: small is plentiful. J Cell Biol 156:17–21

    Article  PubMed  CAS  Google Scholar 

  • Harrison DE, Strong R, Sharp ZD et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395

    PubMed  CAS  Google Scholar 

  • Hawks K (2003) Grandmothers and the evolution of human longevity. Am J Human Biol 15:380–400

    Article  Google Scholar 

  • Hayflick L (1987) Origins of longevity. In: Warner HR, Butler RN, Sprott RL, Schneider EL (eds) Modern biological theories of aging. Raven Press, New York, pp 21–34

    Google Scholar 

  • Holliday R (1991) Mutations and epimutations in mammalian cells. Mutat Res 250:351–363

    PubMed  CAS  Google Scholar 

  • Holliday R (1993) Epigenetic inheritance based on DNA-methylation. EXS 64:452–468

    PubMed  CAS  Google Scholar 

  • Holliday R (1998) Endogenous DNA-methylation and epimutagenesis. Mutat Res 422:97–100

    PubMed  CAS  Google Scholar 

  • Hornebeck W, Derouette J-C, Roland J, Chatelet F, Bouissou H, Robert L (1976). Corrélation entre l’âge, l’artériosclérose et l’activité élastolytique de la paroi aortique humaine. C R Ac Sci 292: 2003–2006

  • Ikan R (ed) (1996) The Maillard reaction. Consequences for the chemical and life sciences. Wiley, Chichester

    Google Scholar 

  • Jacob F (1997) Evolution and tinkering. Science 196:1161–1166

    Article  Google Scholar 

  • Jacotot B (ed) (1993) Atherosclerose. Sandoz, Paris

    Google Scholar 

  • Kaeberlein M, Kapahi P (2009) Aging Is RSKy business. Science 326:55–56

    Article  PubMed  CAS  Google Scholar 

  • Kaeberlein M, Kennedy BK (2009) A midlife longevity drug. Nature 460:331–332

    Article  PubMed  CAS  Google Scholar 

  • Keil-Dlouha V, Planchenault T (1986) Potential proteolytic activity of human plasma fibronectin. Proc Natl Acad Sci USA 83:5377–5381

    Article  PubMed  CAS  Google Scholar 

  • Labat-Robert J (2002) Fibronectin in malignancy. Effect of aging. Sem Cancer Biol 12:187–195

    Article  CAS  Google Scholar 

  • Labat-Robert J (2003) Age-dependent remodeling of connective tissue: role of fibronectin and laminin. Pathol Biol 51:563–568

    Article  PubMed  CAS  Google Scholar 

  • Labat-Robert J (2004) Cell-matrix interactions in aging: role of receptors and matricryptins. Aging Res Rev 3:233–247

    Article  CAS  Google Scholar 

  • Labat-Robert J, Potazman JP, Derouette JC, Robert L (1981) Age-dependent increase of human plasma fibronectin. Cell Biol Int Rep 5:969–973

    Article  PubMed  CAS  Google Scholar 

  • Labat-Robert J, Marques MA, N’Doye S, Alperovitch A, Moulias R, Allard M, Robert L (2000) Plasma fibronectin in French centenarians. Arch Gerontol Geriat 31:95–105

    Article  CAS  Google Scholar 

  • Lansing AI (ed) (1959) The arterial wall. The Williams & Wilkins Company, Baltimore

    Google Scholar 

  • Levin B (2008) Genes IX. Jones and Bartlett Publishers, Sudbury

    Google Scholar 

  • Lopez-Armada LP, Gonzales E, Gomez-Guerrero C, Egido J (1997) The 80-kDa fibronectin fragment increases the production of fibronectin and tumor necrosis factor alpha (TNF-α) in cultured mesangial cells. Clin Exp Immunol 107:398–403

    Article  PubMed  CAS  Google Scholar 

  • Maillard L-C (1912). Action des acides aminés sur les sucres: formation des mélanoïdines par voie méthodique. C R Ac Sci 154:66–68

  • Martin GM, Austad SN, Johnson TE (1996) Genetic analysis of aging: role of oxidative damage and environmental stresses. Nat Genet 13:25–34

    Article  PubMed  CAS  Google Scholar 

  • McCay CM, Maynard LA, Sperling G, Barnes LL (1939) Retarded growth, lifespan, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. J Nutr 18:1–13

    CAS  Google Scholar 

  • Medawar PB (1952) An unsolved problem in biology. Lewis, London

    Google Scholar 

  • Morris KV (ed) (2008a). RNA and the regulation of gene expression. A hidden layer of complexity. Caister Academic Press, Norfolk

  • Morris KV (2008b). RNA-mediated transcriptional gene silencing: mechanism and implications in writing the histone code. In: Morris KV (ed) RNA and the Regulation of Gene Expression. Caister Academic Press, Norfolk

  • Münch D, Adam GW, Wolschin F (2008) Aging in a eusocial insect: molecular and physiological characteristics of lifespan plasticity in the honeybee. Funct Ecol 22:407–421

    Article  PubMed  Google Scholar 

  • Péterszegi G, Molinari J, Ravelojaona V, Robert L (2006) Effect of advanced glycation end-products on cell proliferation and cell death. Pathol Biol 54:396–404

    Article  PubMed  CAS  Google Scholar 

  • Pierce BA (2008) Genetics, a conceptual approach. W.H.Freeman and Co, New York

    Google Scholar 

  • Pincus Z, Slack FJ (2008) Transcriptional (dys)regulation and aging in Caenorhabditis elegans. Genome Biol 9:233–236

    Article  PubMed  CAS  Google Scholar 

  • Rascon B, Navdeep MS, Tolfsen C, Amdam GV (2009). Honey bee life-history plasticity—development, behaviour, ageing. In: Flatt T, Heymand A (eds) Mechanisms of life history evolution. Oxford University Press (in print)

  • Robert L (1995) Le vieillissement. Faits et Théories. Flammarion, Paris

    Google Scholar 

  • Robert L (1998) Mechanisms of aging of the extracellular matrix: role of the elastin-laminin receptor. Gerontology 44:307–317

    Article  PubMed  CAS  Google Scholar 

  • Robert L (1999) Interaction between cells and elastin, the elastin-receptor. For the 80th birthday of Ines Mandl. Connective Tissue Res 40:75–82

    Google Scholar 

  • Robert L (2006) Fritz Verzar was born 120 years ago: his contribution to experimental gerontology through the collagen research as assessed after half a century. Arch Gerontol Geriat 43:13–43

    Article  Google Scholar 

  • Robert L (2009) The Maillard reaction. Path Biol. doi:10.1016/j.patbio.2009.09.004

  • Robert L, Labat-Robert J (1988) Aging of extracellular matrix, its role in the development of age-associated diseases. In: Bergener M, Ermini M, Stähelin HB (eds) Crossroads of aging. The 1988 Sandoz lectures in gerontology. Academic Press, London, pp 105–126

    Google Scholar 

  • Robert L, Labat-Robert J (2000) Aging of connective tissues, from genetic to epigenetic mechanisms. Biogerontology 1:123–131

    Article  PubMed  CAS  Google Scholar 

  • Robert L, Miquel P-A (2004) Bio-Logiques du Vieillissement. Editions Kimé, Paris

    Google Scholar 

  • Robert L, Robert AM (1980) Elastin, elastase and arteriosclerosis. Front matrix biology, vol 8. Karger, Basel, pp 130–173

    Google Scholar 

  • Robert L, Bellon G, Hornebeck W (1980) Characterisation of different elastases. Their possible role in the genesis of emphysema. Bull Eur Physiopathol Resp 16:199–206

    CAS  Google Scholar 

  • Robert L, Robert AM, Fülöp T (2008) Rapid Increase in human life expectancy: will it soon be limited by the aging of elastin? Biogerontology 9:119–133

    Article  PubMed  CAS  Google Scholar 

  • Roth GS (1995) Changes in tissue responsiveness to hormones and neurotransitters during aging. Exp Gerontol 30:361–368

    Article  PubMed  CAS  Google Scholar 

  • Rueppell O, Amdam GV, Page RE Jr, Carey JR (2004). From genes to societies. Sci Aging Knowledge Environ 5:pe5

    Google Scholar 

  • Seehuus SC, Krekling T, Amdam GV (2006) Cellular senescence in honey bee brain is largely independent of chronological age. Exp Gerontol 41:1117–1125

    Google Scholar 

  • Selman C, Tullet JMA, Wieser D et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326:140–144

    Article  PubMed  CAS  Google Scholar 

  • Stillmann B, Stewart D (eds) (2004) Epigenetics. Cold Spring Harb Symp Quant Biol, LWIX. CSHL Press, New York

    Google Scholar 

  • Urry DW (1980). Sequential Polypeptides of elastin: structural properties and molecular pathologies. Front Matrix Biol 8:78–103

    Google Scholar 

  • Varga Zs, Jacob MP, Robert L, Csongor J, Fülöp T (1997) Age-dependent changes of κ-elastin stimulated effector functions of human phagocytic cells: relevance for atherosclerosis. Exper Gerontol 32:653–662

    Article  CAS  Google Scholar 

  • Vavasseur A, Touat-Todeschini L, Verdel A (2008). Heterochromatin assembly and transcriptional gene silencing under the control of nuclear RNAi: lessons from fission yeast. In: Morris KV (ed) RNA and the regulation of gene expression. Caister Academic Press, pp 45–57

  • Verma M, Dunn BK, Umar A (eds) (2003). Epigenetics in cancer prevention. Early detection and risk assessment. Ann New York Acad Sci 983

  • Waddington CH (ed) (1968) Towards a theoretical biology. 1. Prolegomena. An IUBS symposium. Edinburgh University Press, UK

    Google Scholar 

  • Warner HR, Butler RN, Sprott RL, Schneider EL (eds) (1987) Modern biological theories of aging. Aging vol 31. Raven Press, New York

    Google Scholar 

  • Weale RA (1993) Have human biological functions evolved in support of life-span? Mech Age Develop 69:65–77

    Article  CAS  Google Scholar 

  • Williams GC (1957) Pleiotropy, natural selection and the evolution of senescence. Evolution 11:398–411

    Article  Google Scholar 

  • Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286:481–486

    Article  PubMed  CAS  Google Scholar 

  • Xie DL, Hui F, Meyers R, Homandberg GA (1994) Cartilage chondrolysis by fibronectin fragments is associated with release of several proteinases: stromelysin plays a major role in chondrolysis. Arch Biochem Biophys 311:205–212

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The original experiments reported in this review were carried out in our CNRS Laboratory at University Paris XII and at the Hotel Dieu Hospital, Univ. Paris 5, Paris, supported by Institut DERM. The hospitality of Prof. Gilles Renard, Head of Ophthalmology at Hotel Dieu is thankfully acknowledged.

Author information

Authors and Affiliations

  1. Laboratoire de Recherche Ophtalmologique, Hôpital Hôtel Dieu, Université Paris 5, 1 Place du Parvis Notre Dame, 75181, Paris cedex 04, France

    L. Robert, J. Labat-Robert & A. M. Robert

Authors
  1. L. Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Labat-Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. M. Robert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Robert.

Additional information

Corresponding to a lecture delivered at the Congress of the International Association of Gerontology and Geriatrics (IAGG) in Paris in July 2009.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robert, L., Labat-Robert, J. & Robert, A.M. Genetic, epigenetic and posttranslational mechanisms of aging. Biogerontology 11, 387–399 (2010). https://doi.org/10.1007/s10522-010-9262-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-010-9262-y

Keywords

Search

Navigation