(R.prlntcd from Naturc, YoL 250, No. 5465,pp. 3Bt-J85, August 2, 1974)
Theageing,gr.owthanddeathof cells
A. R. Sheldrake
Department of Biochemistry,University of Cambridge, Cambridge, UK.
The ageing and death of cells in higher plants and
higher animals is discussedin relation to cellular
rejuvenation by growth and division.
lation of cytoplasmicbreakdown products, some of which
might be deleteriousto the cell if they accumulatedsufficiently. In all actively metabolisingcells, there is a turnover of cytoplasmic constituents such as proteins and
membranelipids. More is known about their synthesisthan
about their breakdown in vivo; while some of them may
be broken down completely, others may be broken down
only partiallyor not at all. They must thereforeaccumulate.
No celt is immortal. If a cell growsand divides,it becomes
two cells; if it does not divide, sooner or later it dies.
Multicellular organismsare not aggregatesof cells in a
state of exponentialgrowth and division. Some cells divide,
Lipid peroxidation
but most differentiateand do not undergo further division.
Here I shall discussthe ageingand death of cells in vascular
One example of such an accumulation is provided by the
'age pigment'
plants and vertebrate animals in an attempt to explore the
or lipofuscin granules which accumulate in
significanceof these processesin relation to growth and
an age-dependentway in the cells of many mammalian
development,both normal and abnormal.
tissues'.The lipofuscin material contains lipid and protein
It is often convenientto think of cells or living organisms and may be formed in autophagosomalvesicles,for example
as maintaining a more or less steady state; but it ii also
during the digestionof mitochondria;haem groups,released
easyto forget that this is an approximation,an abstraction
as the cytochromesare degraded,may catalysethe peroxiwhich, if realised,would confer on cells and on organisms
dation of unsaturated lipids in the degenerating mitothe doubtful blessingsof eternal life and eternal youth. The
chondrial membranes'whichmay crosslink with eaChother
realities of growth, development,ageing and death cannot
and with denaturedproteinsr.The cells seem to be unable
be understoodin terms of steady state concepts.They are
to destroythese crosslinked polymers.Lipofuscin granules
directionaland irreversiblechangesin time.
do not seem to damage cells directly except when they
Some cells die as tl.:y differentiate, for example xylem
accumulate, as they do in certain diseases,to such an
cells in plants and l:eratinisedepidermal cells in animals;
extent that they mechanicallyinterfere with the structure
some, such as phloem sieve tubes in plants and red blood
and functions of the cell'.
cells in mammals, lose their nuclei; others which retain
Lipid peroxidation does not always result in the formatheir nuclei may lose their ability to divide-as do most
tion of micyoscopicallyvisible lipofuscin granules,nor is it
nerve cells. But even cells which retain their ability to
confined to autophagosomalvesicles;it occurs in all funcdivide will die if they do not do so; they senesce.
tional cell membranes,including the surface membrane.
Any general hypothesisof cellular ageing must not only
Once the peroxidationof unsaturatedlipids is initiated,by
explain cellular ageing itself, but also the way in which
haem groupe, Fe'* ions and other simple catalystsin the
some cell lines do not senesceand die out. The germ cell
presenceof oxygen, it takes place by a free radical chain
line is continuousfrom generationto generation(also many
reaction.It can be inhibited by lipid-solubleantioxidants
plants can be propagatedvegetativelyindefinitely)and some
suchas vitamin E and accelerated
by vitamin E deficiency,
cell lines derivedfrom plant or animal tissuescan be proionising radiation,chloroform and ethanol poisoningand
pagated in vito for an indefinite number of generations.
hyperbaric treatments''o,which can cause irreversible
General hypothesesof ageing basedon genetic mutation
damageto cells.
face two difficulties.First, in explaining the universalityof
The peroxidationof lipids within cell membranesis
the processesof ageing in non dividing cells in terms of a
occurring in vivo all the time. Some peroxidisedlipids may
lethal accumulation of harmful mutations and, second,in
be metabolised'but others, perhapsthose which are cross
accountingfor the facts of sexual and vegetativereproduclinked to other lipids and lipoproteins may not be. The
tion, which show that mutations do not accumulate to a
chain reaction of lipid peroxidation may be terminated by
lethal extent in all cells. The alternative to a geneticthe oxidation of other substanceswhich may themselvesbe
mutation hypothesisof ageingis some sort of 'cytoplasmic'
damagedand accumulateto.Such substancesformed within
hypothesis,the most recent and best known of which is
the surface membrane, for example, may accumulate in
Orgel's'error catastrophe'hypothesis,which postulates situ; if they are removedfrom the surfacemembraneas the
that an accumulation of errors in protein synthesisleads
membraneis recycledby the invaginationof membrane
to a positive feedbackof error as the enrymes involved in
vesicles"-" or by other means,some of them might find
protein synthesis themselves develop errors and thus
their way into residualbodies,but they might also be incorproduce more defective proteinst. For this hypothesisto
porated into intracellular membranes.'.The formation and
account for the continuity of the germ line and the inaccumulationof suchsubstances
within the outer and intradefinite propagationof 'permanent cell lines' in vitro it is
cellular membranes,for exanr,plein the Golgi apparatus,
'cellular
necessary to postulate a process of
selection'
endoplasmic reticulum nuclear membrane and lysosomal
whereby error-containingcells are selectedoutr.
membranes,
could well be deleteriousto normal membrane
Neither the genetic-mutationhypothesisrnor the protein
functioningand could also lead to a positivefeedbackof
synthesis'error catastrophe'hypothesis'of ageingare sup
damage by further lipid peroxidation,and thus to the
ported by sufficientevidenceto rule out the possibilitythat
senescence
and death of the cell. The rate of ageingwould
cellular ageingmay be explicablein terms of the accumube temperaturedependentand would also dependon the
composition,structureand functionsof the cellular memt Presentaddress:International
CropsResearch
Institutefor
500016, branes, the extra- and intracellular environments,antithe Semi-Arid
Tropics,l-ll-256, Begumpet,
Hyderabad
oxidant levelsand so on. Thus, different types of cellswould
A . P . ,I n i i a .
age at different rates but, according to this hypothesis,all
cells would be ageing to a greater or lesserextent all the
'time; alrl cells would bc heading towards senescenceand
death.
The elimination of membranous material from cells
might enable the ageing processto be rctarded and therc
are a few examplesof the sheddingof membranesby cells
which I will discussfurther. But, in general, the only way
in which cells could avoid their otherwise inevitable mortality would be by growing and dividing, thus diluting the
accumulated breakdown products. Although lipid peroxidation may be the most important cause of the formation
of such substances,the following general considerations
could apply to any deleterioussubstanceswhich accumulate
with age.
Growth anil division of cells
An artificiatly simple case is provided by cells dividing
symmetrically with a fixed generation time if these accumulate deleteriousbreakdown products linearly with time,
an am,oun't,x, being formed per cell generationtime (Fig. l).
Successivegenerations contain more of the accumulated
breakdown products but the increments become smaller
and smaller. lf the rate of accumulation is not linear, but
proportional to the amount already accumulated,the content per cell will increase exponentially; and if there is a
progressivelengthening of the cell generation time, there
will be a greater accumulation within individual cells in
succeeding generations. With either or both of these
assumptions,it can be seen that the whole population will
undergo senescenceand sooner or later die out.
But another type of cell division is possible,an asymmetrical division in which one of the daughtercells receives
all or most of the accumulated breakdown products (becoming more 'mortal') while the other is rejuvenated,
receivinglittle or none. The more 'mortal' of the daughter
cells might die or differentiate directly, or it might divide
again unequally,producing a rejuvenatedcell and a cell
'mortal' than itself, or it might undergo one or
even more
more sequentialsymmetrical divisions (as discussedabove)
to producea populationof cells which sooneror later die
(unlessthey can undergo further asymmetricaldivisionsto
produce rejuvenatedcells).
I / ..
I 2.\
Fig. I Cells dividing symmetricallywith a fixed generation
time showing the accumulation of deleteriousbreakdown
prodr cts linearly with time, an .amount, r, being formed
per cell generationtime.
I shall now consider a few aspectsof the growth and
developmentof higher plants and higher animals in the
light of these ideas. Dicotyledonous trees illustrate the
pattern of indefinite growth that is characteristicof plants.
(There are of course plants, such as herbaceousannuals,
which die after they have flowered.But annualsare capable
of growing for much longer than their normal life-span if
they are preventedfrom flowering, indicating that they die
becausethey flower and not becauseof an innate inability
to go on growing".) The life span of trees is limited by a
variety of mechanicalfactors, but cuttings taken from old
trees can give rise to healthy young trees, and this process
can be repeatedindefinitely.The growing points of the tree,
the apical meristems,remain perpetuallyyoung.
Cell divisionswithin the apical meristemsof the shoots
give rise to daughtercellswith differentfates: someremain
meristematic,others give rise to the differentiated structures of the stemsand the leaves.Some of thesecells die
as they differentiateinto vasculartissuesand fibres,others,
for example the leaf mesophyll and pith parenchyma,
remain alive for sometime, but, unlessthey are stimulated
to divide again in a regenerativeresponseto wounding or
damage,they eventuallydie. The leavessenesceand fall
from the tree; the pith breaks down. The root meristems
give rise to the primary tissues of the root which, apart
from those which divide to produce further root meristems,
sooner or later die. In secondarily thickening stems the
divisions of the cambial cells give rise to cells which die
as they differentiateinto xylem or undergo further asymmetrical divisionsto produce phloem companion cells and
sievetubes. Thesecells eventually die and are sloughedoff
in the bark. Cell divisionsin the cork cambium give rise to
cork cells which die as they differentiate; divisions of the
root cap initials give rise to root cap cells which die and
are sloughed off. Thus, in the various meristems of the
plant the continued growth and continued rejuvenation of
the meristemsis associatedwith the production of cells
which die during or after differentiation.
Vertebrates
unlike trees,do not go on growingindefinitely,
Vertebrates,
nor can they be propagatedvegetatively.At first, fertilised
which rapidly increasethe number
eggsundergocleavages
of cells, but this rate of increaseof cell number declines
progressively
as the animaldevelops,and as cellsand tissues
Throughoutthe developmentof the embryo
differentiate'".
many tissuesand groupsof cells regressand die"'". Some
of these cell deaths are associatedwith tissue differentiaand
tiontt, some occur during morphogeneticprocesses'o,
others may representthe regressionof phylogenetically
vestigial structures", but the significanceof other cell
deathsis obscurett.As the animal develops,the cells oT
sometissues,suchas nerveand muscle,differentiateand to
a large extent lose the ability to undergofurther division.
Someof thesecells die as the animal grorvsolder and are
not replaced"'"but in the adult animal a number of other
tissuescontinue to grow, for example the epidermis,the
intestinallining, the liver and blood cells continue to be
formed. In all theseexamplesthe productionof new cells
in the basal la)'ersof
is offsetby cell death. Cell diyisio5rs
the mammalianepidermisgive risd to daughtercellswhich
remain in the basal layers and divide again, and other
daughtercells which differentiateand keratinise,dying as
they do so. Cell divisionsin the crypts of the intestinalvilli
replenishthe populationof crypt cells capableof further
divisionand produceother daughtercells which move up
the villi where they die and are sloughedoff". Asymmetricaldivisionsof the early precursorsof all cellsof the
blood occur throughout life and give rise to further precursorcellsas well as to the maturing and mature cellsof
the blood, all of which have a limited life span. During
thc fornrationof red blood cells" and granulocytest'inthe
bone marrow, and lymphocytesin the thymus:', considerable numbersof cellsdie in situ soonafter they are formed.
The reasons for this 'ineffective' erythropoiesis,granulopoiesisand lymphopoiesis
are unknown.
The mortality of at least some of the cells which die in
developinganimal embryos and in mature animals may
representthe price that is paid for the rejuvenationof other
cells which continueto grow and divide.But unfortunately
too little is known about cell lineagesin animals,especially
in embryos, for it tq'hsyrirmetrical
be possibleto decide how general is
the phenomenonof
cell divisionsgiving rise
to daughter cells of unequal mortality. The recognition of
this pattern is complicatedby the fact that by no meansall
cell death takes place as a result of cellular senescence.
Some cells die as they differentiateand others may die
becausethey find themselvesin the wrong placesat the
wrong times". Cell deaths may be controlled chemically,
for exampleby steroid hormones: the injection of glucocorticoidscan causelarge num,bersof lym.phocytes
to dier?,
the regressionof Mullerian and Wolffian ducts is controlled by androgensand oestrogens'n'"
and the regression
of the lining of the femalegenitaltract is under the control
of oestrogens".But, under the hypothesisthat asymmetrical
cell divisions lead to a rejuvenation of 'meristematic'
daughter cells at the price of the increasedmortality of
their sistercells,it doesnot matter whether the latter die
as a result of senescence,
or whether they die as they differentiateor for any other reason.
lost. The best example,and the only'one for which conclusive ultrastructural evidence exists, is in the secretion
of lipid dropletsby the cellsof lactatingmammaryglands.
The secreted lipid droplets are surrounded by a unit
membranederivedin part from the surface membraneand
in part from Golgi vesicle membranest'.
Second, membrane-bounded
vesiclesof cytoplasmcan
break away from mammalian macrophagesboth in vitro
and in yiyott, This process,known as clasmotosis,is of
unknown significance.Lymphocyteswhich are activatedin
immunological reactions or as a result of phytohaemagglutinin stimulation form 'tails' (uropods) which can btJb
off vesiculated buds in vivo and in vitro".. Again, the
significanceof this processis unknown. Clasmotosisis also
frequently observedin cultures of fibroblasts.
Third, many typesof animal virusesare buddedoff from
host cells in membrane-bounded
vesicles.The protein in
the membraneof the vesiclesis largelyviral, at leastin the
case of RNA tumour viruses,but the lipids are derived
from the host cell membrane".Viral particlesboundedby
membraneare also buddedoff from the cells of a number
of spontaneously
canceroustissues"and from many of the
cell strainsand permanentcell lines which are commonly
cultured in laboratories".
Tissuecultures
Many plant callus cultures can be grown indefinitelyin
vilro. During the early stagesof the growth of some calluses,an exponentialincreasein cell number takesplaceat
a rate which suggests
that many of the cells may undergo
Sexualreproduction
a limited numberof sequentialsymmetricaldivisionsbefore
In the sexual reproduction of both higher plants and
the growth rate declines"''o
but in most plant tissuecultures
higher animals almost all the cytoplasmfrom which the
the rate of increaseof cell number is more or lesslinear
embryo and the new organismdevelopsis providedby the
for most of the growth period"'''. Linear growth characegg. In both cases,the egg cells are formed as a result of
teristics would be compatible with a meristematic pattern
asymmetricaldivisionsof the egg mother cell. In the great
of cell division such that some daughter cells continue to
majority of higher plants, the meiotic divisions of the egg
grow and divide while their sister cells age and sooner or
mother cell produce four cells, three of which die. The
later die. Unfortunately nothing is known in detail about
fourth undergoesfurther divisions to produce the cells of
cell lineageswithin thesecultures, nor are there any quanthe embryo sac, most of which die before or shortly after
titative data on cell death. Nevertheless,
dead and dying
fertilisation.In somespecies,
one or more of the threesister
cellsare by no meansuncommon.
'Permanent'
cells of the cell which gives rise to the egg may undergo
mammaliancell lines capableof indefinite
further division to produceshort-livedembryo sac cellsrt. propagationin vitro can be derivedfrom canceroustissues
In animalsthe first and secondmeiotic divisionsof the egg
and also from cells which have undergonea spontaneous
mother cell give rise to the first and secondpolar bodies, 'transformation'during culture. Diploid fibroblastcultures
rvhich regressand dieto.tt.
can be propagated,however,only for a finite number of
I t i s p a r t i c u l a r l ys t r i k i n gt h a t i n b o t h p l a n t sa n d a n i m a l s , subculturings,more (up to about 60) if the cells are
only one of the progenyof the egg mother cell givesrise
derivedfrom embryonictissues,fewer if they are derived
to an egg while the sister cells die (or if they divide give
from mature organisms". The number of generations
rise to short-livedprogeny).By contrast,there is no comthrough which the cells can be passedbefore the populaparablecell lossin male gametogenesis
associated
with the
tion senesces
and dies out is reducedif the period of time
meiotic divisions of the pollen mother cells and
betweenthe subculturings
is increased".Fibroblastsof the
spermatogonia.
mouseL strain havebeenobservedto divide symmetrically
The many examplesin both higher plants and higher
over six to sevencell generations
with a more or lessconanimals(and many more can be found in the lower plants
stant generationtime"; if the cells in the diploid fibroblast
and lower animals)of the productionof rejuvenatedmeriscultures also divide symmetrically,deleteriousbreakdown
tematic,stem or egg cellsby asymmetricaldivisionsdo not
products might accumulatein the cells of succeeding
of course prove that these divisions involve an asymgenerations,as discussedabove, and account for the
metrical distribution of deleteriousbreakdown products; senescence
of these cultures. It is impossible,however,to
but the availablefacts appear to be consistentwith this
make any detailed interpretation of the senescenceof
hypothesis.
these cultures in the absenceof quantitative information
about the proportionsof dividing and nondividing cells,the
Loss of membranousmaterial by animal cells
incidenceof cell death,and the extent and significance
of
clasmotosiswithin these cultures---orindeed with cultures
If the accumulationof deleteriousbreakdownproductsof
'transformed'
and 'permanent' cell lines.
membranelipids is one of the causesof cellular senescence, of
the loss of membranousmaterial might be of considerable
importancein enablingcells to rid themselves
of such sub_ Cancer
stances.The sheddingof membranousmaterial by living
Malignancymust not only involvethe freeing of cellsfrom
cells does not seem to be of common occurrencebut ca;
the normal controls on their proliferation, but also the
t a k e p l a c ei n m a m m a l i a nc e l l sa s f o l l o w s .
avoidanceof senescence
by at least a part of the cell
First, in apocrinesecretionspart of the cell membraneis
population.Many animal tumours contain a stem cell or
'meristematic' population which gives
rise to daughtercells
which may or may not differentiate, but which sooncr or
later die", There are numerous examples of cell death
within canceroustissues"-tt, Some of the cell deaths can
be explained in terms of an iriadequatevascularisationof
the tumour tissue,but in most tumours this is by no means
the only cause and does not apply at all to leukaemias;
many of the cells may die as a result of ageing'r.
Little attention has been paid to the incidence of cell
death within cultures of cancerouscells and it is therefore
at present impossibleto know to what extent the patterns
of cell division, ageing and death within these cultures
resemble those within in vivo cancers. It is sometimes
assumed,if only implicitly, that overatl exponentialgrot"ih
characteristicsof cell cultures mean that there is a homogeneous population of symmetrically dividing cells. This
assumption is not justified: a heterogeneouspopulation
c-ontaining proliferating, nonproliferating and dying cells
can also grow exponentially if the proportion of cells that
die is constant with time",''.
It is conceivablethat the loss of membranousmaterial
either spontaneously,as in certain types of mammary gland
tumours", or as a result of the budding off of viruses
(such as RNA tumour viruses)could play a significantrole
in the retardation of cellular senescencein certain types
of cancer.
Effects of cell death
Very little is known about the biochemistry of dying cells.
Such cells probably release all sorts of proteins, glycoproteins, peptides,amino acids, amino acid breakdownproducts, nucleic acids and nucleic acid breakdownproducts,
lipids and lipid breakdown products as well as salts and
other substanceswhich were sequesteredinside the cells.
It has recently been found that in higher plants the
hormone auxin (indole-3-aceticacid) is formed as a consequenceof cell death as tryptophan, releasedby proteolysis,
is broken down. Dying cells in differentiating vascular
tissue, regressingnutritive tissuesand so on, are probably
the major source of this hormone within the plant". Other
plant hormones may also be produced by damagedand
dying cells: ethylene from the breakdown of methionine
and cytokinins by the hydrolysis of transfer RNA". In
higher plants the normal production of hormones as a
consequenceof cell death and the production of 'wound
hormones' by darnagedcells can be seen as two aspectsof
the same phenomonomtt.
Wound and regenerativeresponsesin vertebratescannot
be explainedsimply in terms of wound hormones,but there
is evidencethat dying cells releasesubstancesthat stimulate
phagocytosis",and affect growth and developmentin both
normaltt'tt and canceroustissuest'.And at least some of
the cell deaths which occur during normal embryonic
development may well result in the production or release
of substancesinvolved in the control of differentiationand
development.
Dying cells may not only have a chemical effect on
neighbouring cells but also a physical effect as cell to cell
contacts are broken. Cell deaths within a tissue may also
affect the functioningof the tissueas a whole: for example,
the death of nerve cells within the brain" seemslikely to
affect pathwaysor patterns of nervous conduction, perhaps
leading to the formation of new pathwaysor patterns.Such
cell deathscould act as a sourceof random changewithin
the nervoussystemthat might not alwaysbe deleterious".
So little attention has been paid to the ageingand death
of cells during growth and development,both normal and
abnormal, that detailedinformation about these processes
is scarce. Where facts are few, speculationcan flourish.
Most of the speculationsadvancedin this article could be
opposod by alternativespeculations,but they illustrate the
view that growth and development cannot be understood
in isolation from ageingand death. This is by no meansan
original concept, but at the cellular level it provides a
perspectivein which many familiar facts take on a new
significance and suggests a new approach to familiar
problems.
I am indebtedto Dr A. Gliicksmann,Dr W. Jacobsonand
ProfessorE. N. Willmer for helpful comments,criticismand
discussion.
ReceivedFebruary5, 1974.
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