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ISSN 1389-5729, Volume 11, Number 4

REVIEW ARTICLE

Genetic, epigenetic and posttranslational mechanismsof aging

L. Robert • J. Labat-Robert • A. M. Robert

Received: 14 September 2009 / Accepted: 15 January 2010 / Published online: 16 February 2010

� Springer Science+Business Media B.V. 2010

Abstract Gerontological experimentation is and

was always strongly influenced by ‘‘theories’’. The

early decades of molecular genetics inspired deter-

ministic 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 posttransla-

tional 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 pro-

duction 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 posttrans-

lational processes together with environmentally

influenced genetic pathways play key-roles in aging

and strongly influence gene expression.

Keywords Aging � Genetics � Epigenetics �Posttranslational changes � Maillard reaction �Receptor-aging � Proteolysis � Fibronectin �mi-RNA-s � Elastin � Atherosclerosis

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

Corresponding to a lecture delivered at the Congress of the

International Association of Gerontology and Geriatrics

(IAGG) in Paris in July 2009.

L. Robert (&) � J. Labat-Robert � A. M. Robert

Laboratoire de Recherche Ophtalmologique, Hopital

Hotel Dieu, Universite Paris 5, 1 Place du Parvis Notre

Dame, 75181 Paris cedex 04, France

e-mail: lrobert5@wanadoo.fr

123

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DOI 10.1007/s10522-010-9262-y

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Introduction

The elucidation of the structure and function of DNA,

the ‘‘double helix’’ resulted during the first decades

after 1953 in a rigid, deterministic thinking which

penetrated also experimental gerontology. See for

instance the chapters on developmentally ‘‘pro-

grammed’’ aging in Warner et al. (1987), and the

critical remarks of Hayflick (1987). The elucidation

of the genetic code, closely followed by the ‘‘Central

Dogma’’ (DNA ? RNA ? Protein) further rigidi-

fied by Beadle and Tatum’s ‘‘one gene—one

enzyme’’ thesis outlawed for several decades envi-

ronmental effects or any other mechanisms outside

direct gene-action. This limited knowledge of gene

action gave rise to the only acceptable theories of

aging, mutations, which at that time were recognised

as the major mechanism capable of changing nucle-

otide sequences and were proposed to be causally

involved in aging (Medawar 1952; Burnet 1974 and

Carnes et al. 2003 for a recent review). During the

later decades of the twentieth century several impor-

tant discoveries complicated progressively this pic-

ture: retrotranscription, alternative splicing and

finally RNA-interference definitely outlawed the

simplistic approach to gene-action, as first proposed

(for details on gene-action and inheritance see for

instance Levin 2008; Pierce 2008). Some decades

before the turn of the twentyfirst century epigenetics

invaded the arena. First proposed for the interpreta-

tion of evolutionary processes in the embryo by

Waddington (1968), it rapidly arose interest in

experimental biology outside the field of embryonic

development. The recent organisation of international

symposia and publication of treatises (see for instance

Stillmann and Stewart 2004; Allis et al. 2007) further

confirmed the recognition of the importance of

epigenetic mechanisms in a wide range of biological

and pathological processes, as for instance the

development of malignant tumors (see for instance

Verma et al. 2003). The most recent and rapidly

spreading field is RNA-interference which showed

that nearly all steps from gene-action to protein

production can be controlled by RNA-interference

(see for instance Grosshans and Slack 2002; Morris

2008a). Some of the experimental findings of geron-

tology further displaced the site of action, far from

the genes, to what has to be designated as

posttranslational processes. The first to be described

and the last to be interpreted in these terms is the

Maillard reaction (Ikan 1996; Baynes et al. 2005;

Robert 2009 for reviews). But most data published on

this topic concern ‘‘molecular aging’’, a designation

which concerns posttranslationally modified proteins

(Adelman and Roth 1983). This trend was initiated by

the discovery made by the Gershons demonstrating

inactive enzymes, modified proteins in aging cells

(Gershon and Rott 1988 for a review). Attributed first

to age-dependent increase in errors of aminoacid

incorporation in proteins (the Error-Catastrophe

Theory of Orgel), it was shown later convincingly

that the above modifications and inactivations are all

of a posttranslational nature. The accumulation of

such modified, inactive proteins could be attributed to

a slow-down of their turnover leaving time for

modifications not seen in more rapidly renewed

proteins. Several other age-related processes, as for

instance the proteolytic production of harmful

peptides (Labat-Robert 2002, 2003, 2004) and the

age-dependent loss of elastin’s elasticity with its

consequences on cardiovascular aging (Robert et al.

2008) are of more recent recognition and increase the

number of well documented posttranslational mech-

anisms of aging.

This succinct enumeration of some examples

which came to complicate the interpretation of

gene-action and aging shows clearly that this review

can not be exhaustive. We consider it as illustrative

of the evolution of genetic thinking as applied to

experimental gerontology over the last decades

around the turn of the century.

Genetic inheritance and aging

The Mendelian discovery on the inheritance of

relatively simple traits, its rapid complication by

recessive genes, transposons etc. could not be easily

applied to the field of aging. The first major obstacle

is a precise definition of aging. The still most used

definition is the endpoint, age at death. This actuarian

approach is still important but insufficient. It resulted,

however, in the first quantitative description of life

statistics by Gompertz, further refined by the first

generation of geriatricians (see for a review of early

applications Comfort 1979). This definition is, how-

ever, not satisfactory for studies on the genetic level,

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unless a convincing demonstration of relatively

simple transmission of life expectancy or age at

death can be achieved. This is not the case as best

exemplified by the identical twin studies which

reduced the role of direct genetic transmission of

age-limit to about 3%, from the previous estimation

of about 25% (Browner et al. 2004 for a review).

A further complication, still not resolved in a

satisfactory manner, is the relationship between aging

and disease. Dying of old age is still an ill-defined

concept (see for instance Carnes et al. 2008). The

strongest arguments against genetic transmission of

life expectancy is derived from evolutionary theory.

Evolutionary constraints are supposed to act essen-

tially on early reproduction and survival to reproduc-

tive age. Although the ‘‘grandmother effect’’ was

proposed to alleviate the rigor of this evolutionary

argument, at least for the human species, its selective

strength is hard to prove (Hawks 2003). The potential

role of individual differences, such as single nucleo-

tide polymorphisms (SNP-s), copy number variations

(CNV) and others as life course determinants is still in

its early beginnings. Remains as the only survival of

the evolutionary arguments proposed previously the

potential role of antagonistic pleiotropy (Williams

1957). But here again the few processes elucidated at

the cellular-molecular level which play an important

role in the decline of physiological functions is not in

favour of such mechanisms (Robert and Labat-Robert

2000; Robert and Miquel 2004; Robert et al. 2008).

This argument will be developed in the following

articles of this review.

All these critical remarks do not have to be pushed

too far, however, if one wants to give an objective

(although provisory) picture on genetics and aging.

Thanks to the rapid progress in molecular genetics

more and more genes were shown to be involved in the

regulation of physiological processes which decline

with age. The web-site on Human Aging Genomic

Resources (genomics.senescence.info) lists C261

genes identified as important in such processes,

derived from more than 2,461 references. The review

by Browner et al. (2004) on the Genetics of Human

Longevity proposes a list of seven classes of genes

involved in the most important regulatory processes

related to life support mechanisms (Table 1). The most

convincing arguments for genes involved in the

regulation of longevity are derived from genotypes

favouring life threatening diseases, in particular

cardiovascular diseases. This is the case for instance

for the e4/e4 genotype coding apolipoprotein E4, shown

to be accompanied by early onset athero-arterioscle-

rosis and also of neurodegenerative diseases, Alzhei-

mer’s disease and Creutzfeld–Jakob disease (Assmann

et al. 1984; Amouyel et al. 1994; Jacotot 1993).

Several other examples could be cited as for instance

the genetic regulation of a1-antiprotease expression as

related to early onset and severe emphysema (Robert

et al. 1980). These examples can, however, not be

considered as arguments in favour of the genetic

regulation of life expectancy. They belong to the still

open question of the relationship between aging and

age-related pathologies as mentioned before. In this

respect the proposition of Martin et al. (1996) is of

interest. He proposed to distinguish ‘‘public’’ and

‘‘private’’ genetic pathways regulating the aging

process of a variety of species. ‘‘Public’’ genetic

pathways concerne defence mechanisms against life-

threatening processes common to many if not all

species. This is the case for enzymes and molecular

processes protecting cells and tissues against damage

by reactive oxygen species (ROS). Table 2 taken from

the above cited review of Martin et al. (1996) shows

a list of such ‘‘public’’ genetic mechanisms shared by

a large number of species. On the other hand,

age-associated processes depending on mutation accu-

mulations might well be considered as ‘‘private’’

mechanisms, not necessarily shared by a large number

of organisms. We agree with these authors to consider

aging as a ‘‘…mere epiphenomena or passive by-

product of evolution’’ (Martin et al. 1996).

Epigenetics and aging

This term, introduced by Waddington (1968) for the

interpretation of embryonic development concerns

processes which do not modify directly gene-struc-

ture (nucleotide sequences) but processes which

regulate the timing of gene-accessibility for expres-

sion. Such mechanisms were described as self-

perpetuating structural modifications of chromatin

modulating the availability of genes for transcription.

Its mechanisms comprise DNA-methylation, histone

acetylation, imprinting, RNA-interference, gene-

silencing and paramutations (for definitions see

references by Stillmann and Stewart 2004; Allis

et al. 2007). Such epigenetic marks exhibit some

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remarkable properties, as for instance their environ-

mental dependence (rehabilitating Lamarck) and their

temporal variations. These last two properties illus-

trate their relevance for aging. There are several

examples of age-related epigenetic regulations as for

instance studies on sirtuins. Some of these genes

(as SIR-2 in yeast) were shown, when overexpressed,

to increase life-expectancy in some model-animals

(Bishop and Guarente 2007 for a review). It is

certainly interesting to remember that these studies

were undertaken in order to understand the mecha-

nism of calorie-restriction (CR) on longevity, as first

shown by McCay et al. on the rat (1939). These

experiments extended to several other species, clearly

demonstrated the importance of environmental fac-

tors in the regulation of longevity, discovered well

before the elucidation of the structure of DNA. A

more recent example of external influence on the

aging process is the life-prolonging effect of rapa-

mycin-feeding in rats (Harrison et al. 2009 and

Kaeberlein and Kapahi 2009 for comments). The

feeding of this drug was shown to extend significantly

the average and maximal life expectancy of mice,

even when feeding of rapamycin started on day 600

of their life (corresponding approximately to 60 years

old men). Similarly Selman et al. (2009) showed that

besides the mTOR pathway triggered by rapamycin,

the ribosomal protein S6-kinase triggered signalling

regulates significantly mammalian life-span. In their

comments on this work, Kaeberlein and Kennedy

(2009) proposed the following longevity pathways:

CR or rapamycin! mTOR! S6K1 ! longevity

with a possible interference at this last step by AMP-

dependent protein kinase (AMPK) in mice lacking

S6K1. This kinase integrates energy balance with

metabolism and stress resistance and was shown to

function in this respect as a longevity factor in

C. elegans also (see Kaeberlein and Kapahi 2009 for

further details).

Table 1 Genetic mechanisms involved in the regulation of (human) longevity

Genetic mechanisms Potential candidate genes in humana

DNA-repair, nuclear structure and function WRN, LMNA

Telomere—telomerase hTR, DKC1

Stress-resistance, oxidative damage Genes for SOD, insulin—IGF-1R, PI3 K

Mitochondrial DNA mt—haplotypes

Caloric restriction Sirtuinsb

Insulin signalling Genes for insulin—IGF1R, insulinR—substrate and others

Inflammation Genes for toll-like receptors, MIF-s, IL-6, CRP and others

Modified after Table 1 of Browner et al. (2004). Genetic mechanisms favouring diseases which might shorten lifespan are excludeda The role of these genes in aging may be attributed to mutations or also to epigenetic regulations probably for other animal species

alsob More recent results point to mTOR and S6 Kinase 1 signaling

Table 2 The seven classes of genetic loci involved in the protection of organisms against oxidative damage (ROS-defence

mechanisms; modified from Box 2, p 27 of Martin et al. 1996)

Class I. Structural and regulatory genes modulating ROS-production

Class II. Structural and regulatory genes for scavenger enzymes (Ex: SOD-s, catalase etc.)

Class III. Genes regulating flux of non-enzymatic free ROS-scavengers (Ex: c-glutamyl cysteine, and uric-acid synthesis)

Class IV. Genes regulating target copy number (Ex: regulation of mt DNA replicationa)

Class V. Genes specifying target structure (Ex: structural genes for chromatin proteins and membrane lipoproteins)

Class VI. Structural and regulatory genes for target repair processes (Ex: reversal, repair or tolerance of DNA-damage)

Class VII. Genes specifying the orderly replacement of effete cells (Ex: genes modulating DNA replication, cell cycle

progression, apoptosis GF-s and GFR-s)

a And more recently CNV-s

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Holliday insisted from the nineteen nineties on the

importance of epigenetic mechanisms in aging. He

proposed transmission of epigenetic mechanisms by

epimutations (Holliday 1991, 1993, 1998). Our own

experiments on the aging of elastic tissues and

especially of blood vessels also pointed to epigenetic

mechanisms (Robert and Labat-Robert 2000; Robert

and Miquel 2004).

Another interesting and well studied example is the

epigenetic regulation of the longevity of honeybee

workers and queens (Apis mellifera; Amdam and

Seehus 2006; Seehus et al. 2006; Munch et al. 2008;

Rascon et al. 2009). Honeybee workers, according to

their social role such as foraging or brood rearing,

exhibit an exceptional plasticity of their life cycle.

Aging becomes for these insects a function of behav-

ioral control. In their hypopharingeal head glands

workers synthesise ‘‘royal gelly’’, an important ingre-

dient of queen-food. Although eating much more than

the workers, queens live longer. Apparently the

calorie-restriction (CR) paradigm does not hold up in

this society. Hundreds of genes were identified as

differentially expressed in queen- and worker-destined

larvae (Rascon et al. 2009 for a review). Among the

overexpressed genes in queen-larvae are the Insulin-

Insulin-like signalling and Target-Rapamycin (TOR)

pathway regulator genes. These pathways mediate

caste-identity via Juvenile Hormone (JH) as down-

stream metabolic regulator. DNA-methylation pat-

terns appear to play a key role in these regulatory

processes which, at the end determine life-span. DNA-

methyltransferase-3 (Dnmt3), part of the CpG-epige-

netic regulatory machinery, is lower in queen-larvae

than in worker larvae. RNAi-mediated silencing of

Dnmt3 can induce queen-like traits in worker-destined

larvae, showing the importance of DNA-methylation

for caste-regulation. Epigenetic regulation of the

quality and quantity of food intake plays a key-role

in the determination of the life-span of these insects.

Such epigenetic regulation enabled this highly organ-

ised insect society to integrate environmental signals

in their genome, rehabilitating definitively Lamarck.

The downregulation of vitellogenin production, an

important vital factor, by the JH results in the

‘‘pyknotik’’ death of hemocytes, compromising their

immune-system by reducing the availability of Zn, an

important cofactor for Vitellogenin. The longevity

determination of the honeybee worker can therefore

be represented by the sequence:

JH! Vitel log enin! Zn! hemocyte pycnosis

! loss of immundefence

! loss of somatic maintenance:

The plasticity of this life-cycle underlies the

influence of environmental factors on this causal

chain of longevity, as shown clearly by the important

variations of the life expectancy of the honeybee

worker class and their diutinus stage, strongly

influenced also by weather conditions besides nutri-

ent availability. The authors conclude, that ‘‘aging in

honeybees is not merely a collection of nonadaptative

deleterious events that happen in the shadow of

natural selection, but that natural selection has shaped

the aging pattern to come under strict regulatory

control that answers impaired allocation of resources

at the colony level’’. This epigenetic and posttrans-

lational sequence can indeed regulate life span from a

few weeks to 2 years. According to Amdam et al.

similar causal chains can be found for several other

species as Drosophila and also Caenorhabditis ele-

gans with its dauer larval stage. With the recent

sequencing of the honeybee genome more details can

soon be expected on these interesting age-regulatory

process, integrating highly specialised individuals in

a complex society (Rueppell et al. 2004).

Another recent example of the importance of

epigenetic regulations in age-dependent decline of

function for vertebrates was reported by Wolffe and

Matzke (1999), which concerns among others the

regulation of the biosynthesis of extracellular matrix

(ECM) components such as elastin, as well as of its

age-dependent variation. The availability of lysyloxi-

dase, LOXL-1, important for the crosslinking of

ECM-components, collagen and elastin appears also

to be regulated by epigenetic mechanisms (Debret

et al. 2009).

These few examples clearly demonstrate the

relevance of epigenetic, posttranslational mecha-

nisms of aging in far related species of evolution.

Non-coding RNA-s

A number of important mechanisms were attributed to

non-coding RNA-s in the regulation of gene-expres-

sion and the definition of phenotypes. Such RNA-s are

coded in the genome, their synthesis is regulated by as

yet incompletely defined mechanisms. They act at

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several crucial steps of gene-expression, from gene

silencing to destruction of messenger RNA-s (Grosshans

and Slack 2002; Morris 2008a for reviews). These

mechanisms can be considered as part of epigenetic

modulations of gene-expression, because they do not

involve modifications of nucleotide sequences in geno-

mic DNA. Mechanisms mediated by non-coding RNA-s

are, however, quite different from those attributed to

DNA-methylation or histone acetylation, the classical

mechanisms of epigenetic regulations. It was, however,

demonstrated that nuclear RNAi controls among others

heterochromatin assembly and transcriptional gene

silencing, mechanisms close to classical epigenetic

regulations of gene expression (Vavasseur et al. 2008).

RNA mediated transcriptional gene silencing was also

proposed as a mechanism of ‘‘writing the histone code’’

(Morris 2008b).

More direct implication of non-coding RNA-s in

the regulation of age-related processes was also

produced recently, among others by Frank Slack and

colleagues (Pincus and Slack 2008; Budovskaya et al.

2008). RNAi against GATA—family transcription

factors, elt-5 or elt-6 can increase longevity of

C. elegans in an elt-3 dependent manner. elt-3

suppression by RNAi eliminates the long-lifespan

phenotype of mutations in both daf-2 and eat-2

animals, models of calorie-restriction. The elt-3/elt-5/

elt-6 circuit appears therefore to modulate the insulin-

IGF1 pathway, shown to control lifespan in C.

elegans. ncRNA-s were shown also to regulate

stress-response, an important modulator of longevity

(The New York Ac. Sci. e-briefing on short RNA-s in

stress and longevity by the Non Coding RNA Biology

Discussion Group, ref. Don Monroe, Oct. 13, 2009).

We also mentioned in a former section of this review

the RNAi-mediated silencing of Dnmt-3, a DNA

methyl transferase, involved in the epigenetic regu-

lation of honey-bee life course. This rapidly expand-

ing field of RNA-i will undoubtedly contribute a

great deal to our understanding of age-regulatory

mechanisms.

Aging in spare parts

Since the birth of experimental gerontology a number

of laboratories reported reliable determinations of the

age-dependent decline of physiological functions.

These data were collected by Weale (1993). A

simplified linear extrapolation of such correlations

will eventually reach zero value (total loss of the

considered function) at widely different ages (Robert

1995). This graphical representation confirms We-

ale’s suggestion of the selective and relatively

independent rate of decline of a number of physio-

logical functions (Fig. 1).

These data represent a strong argument against

aging as a general process acting simultaneously on

the whole organism indistinctively of individual

functions. Aging in ‘‘spare parts’’ is best exemplified

by the preservation of some ‘‘long lived’’ functions as

for instance musical or intellectual gifts, although

most body functions such as those of the musculo-

skeletal system and others are strongly affected by

age. On Fig. 1 only one line represents embryonic

and early postnatal development. This symbolises the

fact that embryonic development is a ‘‘robust’’

process, as defined by Fox-Keller (2000), a fertilised

human ovule gives only humans and no other species.

With, however, relatively large individual variations

in morphology and function. Such variations are

further amplified during the age-dependent decline of

the organism as represented by the lines on this

figure, declining towards zero function with different

slopes. The elastic functions decline fast, the speed of

nerve-conduction slowly.

Posttranslational mechanisms of aging

This chapter of experimental gerontology started with

the discovery of the Gershon-s, as mentioned in the

Introduction, describing the accumulation of modified

proteins, inactive enzymes in aging cells (Gershon

and Rott 1988 for a review). The accumulation of such

inactive, modified macromolecules was attributed to

delayed turnover leaving time for posttranslational

modifications. A number of such modifications were

described, such as oxidations, S-nitrosylation, dephos-

phorylation and others, reviewed by several authors

(Adelman and Roth 1983). Such mechanisms deprive

aging cells from important cell-and tissue constitu-

ents. Their accumulation is an indirect proof of

important functional modifications in aging cells,

leading to slowdown of biosynthesis and of degrada-

tion of macromolecules.

The situation is different with the Maillard reac-

tion. Although discovered early during the twentieth

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century (Maillard 1912), the recognition of its

importance for aging took several decades. This

was the case for calorie-restriction also, described

during the first half of the twentieth century and

‘‘explained’’ recently by epigenetic mechanisms,

although the final proof of the explanation of calorie

restriction is not yet at hand.

Processes described during the second half of the

previous century, the proteolytic degradation of

macromolecules, essentially of the extracellular

matrix, with the production of harmful peptides and

the creation of vicious circles with age-dependent

amplification belong also to posttranslational mech-

anisms and will be shortly reviewed (Labat-Robert

2002, 2003, 2004).

The third and final example which will be

described in this article concerns the postsynthetic

aging of elastic fibers, studied in our laboratory over

several decades. It represents an example of postsyn-

thetic aging, susceptible to be analysed in terms of

molecular mechanisms (Robert et al. 2008). It also

concerns another important mechanism of posttrans-

lational modifications, the age-dependent loss of

receptors (Roth 1995; Robert 1998).

The Maillard reaction

The first experiments, demonstrating its importance

for connective tissue aging, were performed by

Verzar during the 1950s (Robert 2006 for a review),

but its correct interpretation came several decades

later. As several recent symposia and books were

devoted to this reaction (Ikan 1996; Baynes et al.

2005; Robert 2009), we shall only shortly describe its

mechanisms, insisting on its role in aging. The

reaction itself is quite well understood in its details,

starting by the formation of glycosylamines (for

instance from glucose and free amino groups on

proteins, nucleotide bases), their Amadori-type of

rearrangement and stabilisation, followed by a series

of reactions, only some of them being well under-

stood, and leading to the formation of a number of

organic molecules, described jointly as advanced

glycation end-products (or AGE-s; Robert 2009 for

review). Some of the steps leading to AGE-s and

several reactions engaging AGE-s are mediated by

ROS and called glycoxidation. Such ROS-mediated

reactions explain probably the cytotoxic properties of

AGE-s. The structure and chemical composition of a

Fig. 1 Illustration of ‘‘aging in spare-parts’’. The abscissa

represents a relative time-scale. The ordinates give the percent

remaining activity of a variety of quantifiable physiological

functions. The ascending line on the left illustrates the

evolution of functions during embryonic development and

early childhood, followed by a horizontal portion at early

adulthood. The last part of the graph represents the selective

and differential decline of functions during aging. The first twoportions of the graph are oversimplifications. The development

of functions might well be different for different individuals.

Those differences are, however, negligible compared to those

of the age-dependent decline of functions. Some might be

nearly completely lost, while others are still quite well retained

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number of well identified AGE-s can be found in the

cited references. Here is a short description of the

Verzar-experiments which largely proved the role of

the Maillard reaction in aging of connective tissues.

Verzar’s experiment consisted in measuring the

resistance of collagen fibers to thermal denaturation

as a function of age. He found an age-dependent

exponential increase of this resistance attributed

rightly to an increase of crosslinking of collagen

fibers (Robert 2006 for review). The nature of these

crosslinks was, however, elusive in his time and took

several decades to be elucidated. It appeared that the

AGE-products are the culprits of this regular, age-

dependent increase of collagen crosslinking. As

AGE-products are present in all tissues of the

organism, an age-dependent increase of AGE-

induced post-synthetic modifications of proteins

concern the whole organism and most of its macro-

molecular components. Besides proteins, nucleotide

bases are also affected, as suggested by the genotoxic

effect of AGE-products. When in vitro prepared

AGE-products are added to fibroblast cultures, an

immediate increase of cytotoxicity could be demon-

strated, as shown by the number of dead cells floating

above the adherent cell layer (Peterszegi et al. 2006).

This effect was shown to be transmitted to (at least)

the next cell-generation. The elimination of the AGE-

containing culture medium, its replacement by fresh

medium with no further AGE-s added, still resulted in

a strongly increased cytotoxicity. The rate of cell

proliferation was also affected. What makes the

Maillard reaction an important factor for age-depen-

dent loss of cell and tissue structure and function is

the fact, that besides the in vivo generation of AGE-s

there is also a strong contribution from processed

food, as shown by the quantification of AGE-s in a

variety of food-products (Goldberg et al. 2004).

Acting on the quality of food is one way to alleviate

the nocivity of the Maillard reaction. Routinely used

anti-diabetic drugs as metformin is another. Another

important feature of this reaction is the fact that it

starts early in life, reducing sugars and derivatives are

taken up and produced constantly in the living

organism. It is their accumulation with time what

makes them important for the age-dependent modi-

fications of tissue structure and function. It also

shows that vital molecules as glucose can avoid

classical metabolic pathways and engage in organic

chemical reactions, harmful for the organism with no

efficient scavenging mechanisms which could have

evolved during evolution.

Proteolytic generation of harmful peptides

The role of proteolytic generation of harmful degra-

dation products was convincingly demonstrated dur-

ing the last decades of the twentieth century. As this

subject was also reviewed recently (Labat-Robert

2002, 2003, 2004), we shall shortly remind its most

relevant facets for the subject of this review.

The proteolytic degradation of fibronectin was

shown to result in the formation of several large

peptides endowed with unexpected biological activ-

ity. One large fragment was shown to behave as a

protease, although intact fibronectin is devoid of such

activity (Keil-Dlouha and Planchenault 1986).

Another fragment was shown by Barlati et al.

(1981) to potentiate malignant transformation. The

team of Homandberg demonstrated an active role of

fibronectin fragments in the generation of inflamma-

tion, especially in articular cartilage (Xie et al. 1994).

Another proteolytic fragment of fibronectin induced

an increased synthesis of fibronectin and of TNFarelease (Lopez-Armada et al. 1997). We could show

in our laboratory that fibronectin biosynthesis by

fibroblasts (the tissue form of fibronectin), as well as

by hepatocytes (circulating form in the blood plasma)

increase with age (Labat-Robert et al. 1981). Prote-

olytic activity in several tissues was also shown to

increase with age as well as with passage number in

cell cultures (Robert and Labat-Robert 1988).

All these data add up to a vicious circle with age-

dependent amplification of harmful effects (Fig. 2).

Fibronectin is, however, only one of the proteins of

the extracellular matrix to yield such peptides on

proteolytic degradation, endowed with harmful

effects and an age-dependent amplification. Similar

mechanisms were demonstrated for other macromol-

ecules of the extracellular matrix also (Labat-Robert

2004). Some authors proposed conformational

modifications uncovering cryptic sites for proteo-

lytic attack (matricryptic sites). It is, however,

highly probable that post-proteolytic conformational

changes are involved in the generation of peptides

capable of producing such harmful effects with age-

dependent amplification. In vivo evidence of the role

of such peptides in age-dependent decline of

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functions is still lacking. The presence of fibronectin-

derived peptides was, however, demonstrated in the

blood plasma of elderly inpatients of a geriatric ward,

all suffering of age-related diseases (Labat-Robert

et al. 2000). The plasma of several centenarians in

relatively acceptable health-conditions was also stud-

ied during these same experiments These samples did

not exhibit the presence of comparable fibronectin

degradation products.

Postsynthetic aging of elastic fibers

This process, as that described by Maillard, is among

the age-related processes with loss of structure and

function, elucidated in most of its details (Robert

et al. 2008 for a recent review). It shows also the

important role of the conformation and structure of

biological macromolecules directly involved in their

age-dependent loss of function. Elastin is a strongly

hydrophobic protein. This property is largely respon-

sible for its mainly entropy-driven elasticity (Robert

and Robert 1980). This property is also directly

responsible for its strong affinity for lipids. Most

classes of lipids were shown to accumulate in elastin

fibers, essentially cholesterol and free fatty acid

(Claire et al. 1976). As a result of the specific

sequence of some peptides, part of the elastin forms

ring-like structures with a high affinity for calcium

which was also shown to accumulate with age in the

elastic fibers (Lansing 1959). These two processes,

the progressive accumulation of lipids and calcium

result in a progressive loss of elasticity and in an

increase of its susceptibility to proteolytic degrada-

tion (Hornebeck et al. 1976). Since the early decades

of microscopic pathology it was shown that aorta-

elastic fibers appear fragmented in older autopsy

samples, contrasting with mainly continuous fibers in

young specimens. Elastin derived peptides could be

demonstrated in the circulating blood (Bizbiz et al.

1997). Such peptides were shown to act as high

affinity agonists with the elastin receptor and induce

an increased release of elastolytic proteases as well as

of ROS-s as superoxide (Fulop et al. 1998; Robert

1998). The intracellular transmission pathway of this

receptor coupled to a Gi-protein is altered in cells

taken from old individuals. Superoxide release is

increased in presence of elastin peptides, but no more

inhibited in ‘‘old’’ cells by pertussis toxin, a known

antagonist of Gi-proteins, as was shown to be the case

in cells from young individuals (Fulop et al. 1992;

Robert 1999). The coupling of the elastin receptor

with iNOS in endothelial cells is also lost with age,

accompanied by a progressive loss of vasodilatation

produced by elastin peptides added to rat aorta rings

(Faury et al. 1997). Other age-dependent loss of

functions of the elastin receptor were also demon-

strated as the loss of dose-dependent inhibition by

elastin peptides of cholesterol synthesis in monocytes

from older individuals (Varga et al. 1997). This age-

dependent uncoupling of the elastin receptor goes

together with the loss of its protective functions such

as vasodilatation and limitation of cholesterol bio-

synthesis. On the contrary, it is accompanied by an

increase of its harmful effects, such as release of

elastolytic proteases and free radicals. This sequence

of events leads also to a vicious circle with age-

dependent auto-amplification (Fig. 3).

It can be noticed that the loss of elasticity by

progressive accumulation of lipids and calcium is the

direct consequence of the specific structure and

conformation of the elastin protein (Urry 1980). No

external factors are needed for the age-dependent loss

of elastin-elasticity. These modifications increase the

susceptibility of elastic fibers for proteolytic degra-

dation. The released elastin peptides reach a plasma-

tissue concentration several log-units above the

affinity constant (KD) of the elastin receptor, shown

to be in the nanomol range. The overload of the

elastin receptor by its agonists, elastin peptides, and

Proteolytic degradation

These processes are up-regulated with age

FIBRONECTIN

(age-dependent increase)

PEPTIDES

WITH POTENTIAL HARMFUL EFFECTS

PROTEOLYTIC ACTIVITY

INFLAMMATION

MALIGNANT TRANSFORMATION

Up-REGULATION OF FN BIOSYNTHESIS

Fig. 2 Vicious circle generated by the age-dependent increase

of fibronectin (FN) biosynthesis and its proteolytic degrada-

tion. Several of the proteolytically generated peptides exhibit

harmful properties, such as novel proteolytic activity, poten-

tiation of malignant transformation and mediation of inflam-

mation. Some peptides further increase fibronectin

biosynthesis. For more details see Labat-Robert (2004)

Biogerontology (2010) 11:387–399 395

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its uncoupling from its normal intracellular transmis-

sion pathway (with no change in KD) results in a

progressive upregulation of further elastin degrada-

tion accompanied by the amplification of its harmful

effects (Fig. 3).

Conclusions and perspectives

We attempted in this short review to explore argu-

ments for or against genetic determinism in the aging

process. Although the classic era of molecular

genetics following the elucidation of the structure

and function of DNA suggested rigid genetic deter-

minism, no convincing arguments could be found in

favour of such claims that ‘‘aging is coded in the

genome’’. This negative finding does not distract,

however, from the experimental evidence that a large

number of genes were shown to be involved in

reactions associated with age-dependent decline of

tissue structure and function. Studies on identical

twins furnished also arguments against a strong

inheritance of life expectancy. The best confirmed

life-increasing manipulations as calorie-restriction

pointed to the importance of epigenetic factors in

the regulation of life expectancy. Further experimen-

tal exploration of such mechanisms will forseeably

confirm the importance of epigenetic and posttrans-

lational mechanisms in aging. The environmental and

temporal influence of such mechanisms is in favour

of their potential role in life-course determination.

We summarised in some detail some of the postsyn-

thetic processes involved in aging, RNA interference,

the Maillard reaction, proteolytic degradation prod-

ucts of matrix macromolecules with production of

peptides producing harmful effects and the aging of

elastin with its molecular details comprising the role

of the elastin receptor in the age-dependent amplifi-

cation of the harmful effects. All these examples are

in favour of the evolutionary argument against direct

genetic determinism of life expectancy.

The age-related mechanisms with the most

detailed knowledge of their molecular details are

not in favour of the role of antagonistic pleiotropy in

aging as proposed by Williams (Robert and Labat-

Robert 2000; Robert and Miquel 2004). The above

detailed mechanisms are much more in favour of the

proposition made by Jacob (1997) that evolutionary

processes are imperfect, correspond more to tinkering

than to the production of masterpieces. The elastin

gene does not have to change with age, neither in its

structure or function to explain the progressive

accumulation of lipids and calcium in the peptide

folds of the protein it codes for. The same could be

sad about the structure of fibronectin. The harmful

role of its degradation products do not reflect an age-

dependent modification of the gene coding for this

protein. Its proteolytic degradation with the produc-

tion of harmful peptides is nowhere ‘‘coded in the

genome’’, neither do we have to claim a tissue

specific pleiotropic effect. The Maillard reaction can

also be considered as a result of ‘‘tinkering’’ by the

evolutionary development of the intermediary metab-

olism of reducing sugars. A non negligible fraction of

free glucose (together with other reducing metabo-

lites) reacts freely with macromolecular amino

groups, resulting in AGE-products exhibiting harmful

effects. Their age-dependent accumulation was

clearly shown by the Verzar phenomenon and by a

number of more recent experiments (Peterszegi et al.

2006; Robert 2009). It is important to emphasize that

some nutritional ingredients as glucose can bypass

standard metabolic pathways (catalysed by enzymes

‘‘coded’’ in the genome) and react, just as they would

in a test-tube with biological macromolecules, with

no efficient inhibitory mechanisms which could have

evolved during the course of evolution of living

species. So in our opinion no tissue- and age-

dependent shifts of gene-action (antagonistic pleiot-

ropy) should be claimed to play a role in aging.

Nature did a lousy job during evolution as proposed

by the ‘‘tinkering’’ hypothesis of Francois Jacob.

ELASTIN

Ca Lipids

Further degradation of elastin Loss of elasticity

Elastases

Elastin peptides Action on the Upregulation of Elastin receptor elastase production

and ROS release

Fig. 3 Vicious circle started by the saturation of elastin with

Ca and lipids, loss of elasticity, degradation of elastic fibers by

elastases, liberation of elastin peptides, their action on the

elastin receptor, followed by the upregulation of elastase (and

free radical) production. For more details see Robert et al.

(2008)

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Although aging is not ‘‘coded in the genome’’, a

large number of genes are somehow involved in the

age-dependent decline of tissue structure and func-

tion. The widely different rates of decline of func-

tions with time is in itself a strong argument against a

strict genetic determinism. This is probably the

reason of the flexibility of human life-expectancy,

which increased significantly over the last decades,

essentially thanks to improved nutrition (and not to

calorie restriction) and other environmental factors.

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.

References

Adelman RC, Roth GS (1983) Altered proteins and aging. CRC

Press, Boca Raton

Allis DC, Jenuwein T, Reinberg D, Caparros M-L (eds) (2007)

Epigenetics. CSHL Press, New York

Amdam GV, Seehuus SC (2006) Order, disorder, death: les-

sons from a superorganism. Adv Cancer Res 95:31–60

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

Assmann G, Schmitz G, Menzel HJ, Schulte H (1984) Apoli-

poprotein E polymorphism and hyperlipidemia. Clin

Chemistry 30:641–643

Barlati S, de Petro G, Vartio T, Vaheri A (1981) Transfor-

mation-enhancing activity of proteolytic fragments of

fibronectin. Proc Natl Acad Sci USA 78:4965–4969

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

Bishop NA, Guarente L (2007) Genetic links between diet and

lifespan: shared mechanisms from yeast to humans. Nat

Rev Genet 8:835–844

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 cardio-

vascular risk factor. The EVA study. Atherosclerosis

131:73–78

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

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 ele-gans. Cell 134:291–303

Burnet MF (1974) Intrinsic mutagenesis: a genetic approach to

aging. Wiley, Chichester

Carnes BA, Olshansky SJ, Grahn D (2003) Biological evidence

for limits to the duration of life. Biogerontology 4:31–45

Carnes B, Staats DO, Sonntag WE (2008) Does senescence

give rise to disease? Mech Aging Develop 2008(129):

693–699

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

Comfort A (1979) The biology of senescence. Churchill Liv-

ingstone, Edinburgh

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 pep-

tides. Mech Aging Develop 95:31–42

Fox-Keller E (2000) The century of the gene. Harvard Uni-

versity Press, Cambridge

Fulop T Jr, Barabas G, Varga Z, Csongor J, Hauck M, Szucs S,

Seres I, Mohacsi A, Kekessy D, Despont JP, Robert L,

Penyige A (1992) Transmembrane signalling changes

with aging. Ann New York Acad Sci 673:165–171

Fulop T, Jacob MP, Khalil A, Wallach J, Robert L (1998)

Biological effects of elastin peptides. Pathol Biol 46:497–

506

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, Stahelin HB (eds) The 1988

Sandoz lectures in gerontology. Academic Press, New

York, pp 25–33

Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri

J, Vlassara H (2004) Advanced glycoxidation end prod-

ucts in commonly consumed food. J Am Diet Assoc

104:1287–1291

Grosshans H, Slack FJ (2002) Micro-RNA-s: small is plentiful.

J Cell Biol 156:17–21

Harrison DE, Strong R, Sharp ZD et al (2009) Rapamycin fed

late in life extends lifespan in genetically heterogeneous

mice. Nature 460:392–395

Hawks K (2003) Grandmothers and the evolution of human

longevity. Am J Human Biol 15:380–400

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

Holliday R (1991) Mutations and epimutations in mammalian

cells. Mutat Res 250:351–363

Holliday R (1993) Epigenetic inheritance based on DNA-

methylation. EXS 64:452–468

Holliday R (1998) Endogenous DNA-methylation and epimu-

tagenesis. Mutat Res 422:97–100

Hornebeck W, Derouette J-C, Roland J, Chatelet F, Bouissou

H, Robert L (1976). Correlation entre l’age, l’art-

eriosclerose et l’activite elastolytique 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

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

1166

Biogerontology (2010) 11:387–399 397

123

Author's personal copy

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

Kaeberlein M, Kapahi P (2009) Aging Is RSKy business.

Science 326:55–56

Kaeberlein M, Kennedy BK (2009) A midlife longevity drug.

Nature 460:331–332

Keil-Dlouha V, Planchenault T (1986) Potential proteolytic

activity of human plasma fibronectin. Proc Natl Acad Sci

USA 83:5377–5381

Labat-Robert J (2002) Fibronectin in malignancy. Effect of

aging. Sem Cancer Biol 12:187–195

Labat-Robert J (2003) Age-dependent remodeling of connec-

tive tissue: role of fibronectin and laminin. Pathol Biol

51:563–568

Labat-Robert J (2004) Cell-matrix interactions in aging: role of

receptors and matricryptins. Aging Res Rev 3:233–247

Labat-Robert J, Potazman JP, Derouette JC, Robert L (1981)

Age-dependent increase of human plasma fibronectin.

Cell Biol Int Rep 5:969–973

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

Lansing AI (ed) (1959) The arterial wall. The Williams &

Wilkins Company, Baltimore

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

Sudbury

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-a) in cultured mesangial cells. Clin Exp Immunol

107:398–403

Maillard L-C (1912). Action des acides amines sur les sucres:

formation des melanoıdines par voie methodique. 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

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

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

London

Morris KV (ed) (2008a). RNA and the regulation of gene

expression. A hidden layer of complexity. Caister Aca-

demic 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

Munch 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

Peterszegi G, Molinari J, Ravelojaona V, Robert L (2006)

Effect of advanced glycation end-products on cell prolif-

eration and cell death. Pathol Biol 54:396–404

Pierce BA (2008) Genetics, a conceptual approach.

W.H.Freeman and Co, New York

Pincus Z, Slack FJ (2008) Transcriptional (dys)regulation and

aging in Caenorhabditis elegans. Genome Biol 9:233–236

Rascon B, Navdeep MS, Tolfsen C, Amdam GV (2009).

Honey bee life-history plasticity—development, behav-

iour, ageing. In: Flatt T, Heymand A (eds) Mechanisms of

life history evolution. Oxford University Press (in print)

Robert L (1995) Le vieillissement. Faits et Theories. Flam-

marion, Paris

Robert L (1998) Mechanisms of aging of the extracellular

matrix: role of the elastin-laminin receptor. Gerontology

44:307–317

Robert L (1999) Interaction between cells and elastin, the

elastin-receptor. For the 80th birthday of Ines Mandl.

Connective Tissue Res 40:75–82

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

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, Stahelin HB (eds) Crossroads of

aging. The 1988 Sandoz lectures in gerontology. Aca-

demic Press, London, pp 105–126

Robert L, Labat-Robert J (2000) Aging of connective tissues,

from genetic to epigenetic mechanisms. Biogerontology

1:123–131

Robert L, Miquel P-A (2004) Bio-Logiques du Vieillissement.

Editions Kime, Paris

Robert L, Robert AM (1980) Elastin, elastase and arterioscle-

rosis. Front matrix biology, vol 8. Karger, Basel, pp 130–

173

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

Robert L, Robert AM, Fulop T (2008) Rapid Increase in human

life expectancy: will it soon be limited by the aging of

elastin? Biogerontology 9:119–133

Roth GS (1995) Changes in tissue responsiveness to hormones

and neurotransitters during aging. Exp Gerontol 30:361–

368

Rueppell O, Amdam GV, Page RE Jr, Carey JR (2004). From

genes to societies. Sci Aging Knowledge Environ 5:pe5

Seehuus SC, Krekling T, Amdam GV (2006) Cellular senes-

cence in honey bee brain is largely independent of chro-

nological age. Exp Gerontol 41:1117–1125

Selman C, Tullet JMA, Wieser D et al (2009) Ribosomal

protein S6 kinase 1 signaling regulates mammalian life

span. Science 326:140–144

Stillmann B, Stewart D (eds) (2004) Epigenetics. Cold Spring

Harb Symp Quant Biol, LWIX. CSHL Press, New York

Urry DW (1980). Sequential Polypeptides of elastin: structural

properties and molecular pathologies. Front Matrix Biol

8:78–103

Varga Zs, Jacob MP, Robert L, Csongor J, Fulop T (1997)

Age-dependent changes of j-elastin stimulated effector

functions of human phagocytic cells: relevance for ath-

erosclerosis. Exper Gerontol 32:653–662

Vavasseur A, Touat-Todeschini L, Verdel A (2008). Hetero-

chromatin assembly and transcriptional gene silencing

under the control of nuclear RNAi: lessons from fission

398 Biogerontology (2010) 11:387–399

123

Author's personal copy

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 Univer-

sity Press, UK

Warner HR, Butler RN, Sprott RL, Schneider EL (eds) (1987)

Modern biological theories of aging. Aging vol 31. Raven

Press, New York

Weale RA (1993) Have human biological functions evolved in

support of life-span? Mech Age Develop 69:65–77

Williams GC (1957) Pleiotropy, natural selection and the

evolution of senescence. Evolution 11:398–411

Wolffe AP, Matzke MA (1999) Epigenetics: regulation through

repression. Science 286:481–486

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

Biogerontology (2010) 11:387–399 399

123

Author's personal copy