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.From a purelybiological point of view, there seems to be no reason why humanbeings could not develop lethal cancers in the first few years of life, andindeed a few rare (and deadly) pediatric cancers such as retinoblastomaand neuroblastoma continue to plague our offspring.One of the ways humans have managed to defer the onset of cancerhas been through the development of the powerful tumor-suppressorgenes we have discussed in this and the previous chapter.These genesmake it difficult to trigger unscheduled cell division, even under theinfluence of virally carried oncogenes.And it appears that humans alsohave multiple backup tumor suppressor systems, since viruses that areknown to neutralize individual tumor suppressors rarely cause cancerin humans.Tumor suppressor genes would thus clearly qualify as senes-cence repressing genes.Regulatory genes preventing telomerase fromadding telomeres to the ends of chromosomes in rapidly dividing cellsmay play a similar role in inhibiting the emergence of tumors fromtransformed cells, and thus in repressing senescence.Telomerase itself poses an interesting dilemma in terms of inducersand repressors of senescence.From the point of view of individual cells,telomerase helps them escape from senescence, and so could be viewedas a senescence repressor.Yet from the organism's point of view, thisescape from cellular senescence results in cancer, a form of organismalsenescence, so telomerase looks like a senescence effector mechanism.128 REPLICATIVE IMMORTALITYCancer is one of the few instances when cellular and organismal senes-cence would seem to be at odds.The apparent dilemma resolves whenwe remember that the role of senescence in both cells and organismsis to enhance the transmission of germline DNA; the survival oforganisms and the somatic cells of which they are mostly composed isalways secondary to that role.The connection between cancer and senescence, particularly replica-tive senescence, continues to fascinate us.Cancer is a disease uniqueto multicellular organisms.When cells gave up their individuality totake advantage of a communal life-style, they had to learn to livetogether; they had to become socialized.If any one of them chose totake a shot at immortality, it could compromise the mission of theentire organism transmission of germline DNA to the next genera-tion.But this is a critical consideration only before reproductive matu-rity; once DNA has been passed on, the need for safeguards againstrunaway cells is less compelling.In fact, the powerful restraints againstexcessive cell division that evolved to protect us against cancer whenwe are young are the very mechanisms that force our cells into replica-tive senescence when we are old.It is certainly clear from many differ-ent types of experiments that the molecular machinery in the two casesis identical.And it is also increasingly clear that replicative senescenceis a feature of all senescent cells, whether or not they actively divideduring most of their lifetime.Exactly how replicative senescence wouldbecome manifest as a more generalized senescence in these cells (orvice versa) is unclear at present, but remains one of the more interest-ing and exciting areas of aging research.129 8Caloric Restriction andMaximum LifespanBehind our quest for a clearer understanding of the agingprocess in animals doubtless lies the hope that we may somehow beable to use this information to extend our own maximum possiblelifespan.For some single-cell species, maximum lifespan is to someextent a plastic quantity: It may not be defined at all in terms of cal-endar time, as our own lives are, but rather as a fixed number of celldivisions.In times of depleted resources, single-cell organisms can evengo into a death-like state to prolong life, where they may stay for years,further complicating a precise definition of maximum lifespan.Forsome invertebrate species, even when maximum lifespan is defined inyears or months, it can often be manipulated by relatively simplemeans such as changing growth temperatures.For warm-bloodedmammals such as ourselves, maximum lifespan, at least in the wild,seems to be a genetically regulated property of each species, eventhough it may only be observable in highly artificial environments suchas zoos or laboratories.Still, the fact that in organisms like round- A MEANS TO AN ENDworms and fruit flies, mutations in a single gene can result in substan-tial increases in maximal as well as average lifespan of 50 percent ormore has led at least some researchers to ask just how predeterminedmaximum lifespan may be.That maximal lifespan in warm-blooded animals although seem-ingly fixed in the wild might not be an absolutely unalterable quan-tity was first suggested in a believable way by experiments carried outwith rats in the 1930s by the nutritionist Clive McCay at Cornell Uni-versity.The type of studies McCay engaged in were stimulated at leastindirectly by Buffon's suggestion in the eighteenth century that themaximal lifespan of a species could be predicted from the time it takesfor members of that species to reach full physical maturity; in manymammalian species maximal lifespan is approximately five times aslong as the time required for completion of body growth.McCay thusset out to determine whether postponing full physical maturity wouldincrease maximum lifespan.To his delight and satisfaction, it seemedto do just that.The means McCay used to retard growth in his rats was initiallycalled dietary restriction.Although by no means the first to observe aneffect of undernutrition on growth, McCay's studies were unusuallywell controlled, and are cited today as the true starting point for seri-ous investigation of the interaction between nutrition and longevity.McCay allowed a portion of his rats unrestricted access to a nutrition-ally balanced diet.The remaining rats were fed the same diet, butrestricted to about half the total amount of food.Importantly, McCayadded extra vitamins and minerals to the food of those receiving arestricted diet, so that the levels of these important dietary adjunctswere the same in all groups.McCay's insistence on undernutrition butnot malnutrition set his studies apart from earlier experiments alongthese lines, and has been followed by all serious investigators sincehis time.As expected, rats fed the restricted diet from the time they wereweaned grew more slowly, and in fact never reached the size of fullyfed rats, even if the restricted rats were allowed unlimited access tofood later on as young adults.Nevertheless, the underfed rats appearedquite healthy, and showed no signs of physiological abnormality upontheir eventual death.While alive, they had excellent coats (a sensitivesign of health problems in rodents) and later studies proved them to132 CALORIC RESTRICTION AND MAXIMUM LIFESPANbe quite vigorous in all exercise regimens [ Pobierz całość w formacie PDF ]