The Evolutionary Theories of Aging.pdf

Experimental Section Gerontology 2009;55:205–216 Received: July 21, 2008...

Experimental Section Gerontology 2009;55:205–216 Received: July 21, 2008 Accepted: December 22, 2008 DOI: 10.1159/000200772 Published online: February 7, 2009 The Evolutionary Theories of Aging Revisited – A Mini-Review Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 Predrag Ljubuncic Abraham Z. Reznick Department of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Key Words Likewise, further attention is suggested regarding the work Evolution ⴢ Aging ⴢ Longevity ⴢ Genomic studies ⴢ Nuclear on telomere shortening, stem cells and studies on under- factor kappa B standing the biochemical and molecular basis for longevity in centenarians. Copyright © 2009 S. Karger AG, Basel Abstract This short review portrays the evolutionary theories of aging in the light of the existing discoveries from genomic and mo- Introduction lecular genetic studies on aging and longevity. At the outset, an historical background for the development of the evolu- Relation between Aging and Darwin’s Evolutionary tionary theories of aging is presented through the works of Theory August Weismann (programmed death and the germ plasm Darwin’s evolutionary theory is based on the concept theories) including his exceptional theoretical postulation, that random and heritable variation of biological traits later experimentally validated by the existence of cell divi- between individuals (caused by mutations) will lead to sion limits. Afterwards, the theory of mutation accumulation natural selection for preferential reproduction of those of Peter Medawar and the theory modification by Charles- individuals who are particularly fit in a given environ- worth (late-life mortality plateau) are presented as well as ment. On the other hand, the process of aging increases the antagonistic pleiotropy hypothesis of George Williams, vulnerability and ultimately leads to the death of organ- and the disposable soma theory of Kirkwood and Holliday. isms. In view of that, evolutionary theories of aging are These theories are discussed in the light of the different re- those theories that try to explain the developmental pro- search studies, which include studies on insulin signaling gram formed by biological evolution and the evolution of and longevity, the possibility that nuclear factor kappa B aging through interplay between the processes of muta- may be a major mediator of aging, studies of anti-aging Sir- tion and selection. They also had an influence on think- tuins and studies on heat shock proteins and longevity and ing about the process of aging patterns, thus forming a on gene sets as biomarkers of aging. Finally, the proposals picture that may explain how longevity is distributed for future research in biogerontology, such as studies on the across the species. Finally, these theories enable us to control of protein synthesis, validation of biomarkers of ag- make theoretical predictions which can be tested in ex- ing, understanding the biochemistry of longevity and re- perimental laboratory and field conditions. search in the field of gerontologic pathology are presented. © 2009 S. Karger AG, Basel A.Z. Reznick 0304–324X/09/0552–0205$26.00/0 Department of Anatomy and Cell Biology, Faculty of Medicine Fax +41 61 306 12 34 Technion – Israel Institute of Technology E-Mail [email protected] Accessible online at: Haifa 31096 (Israel) www.karger.com www.karger.com/ger Tel. +972 4 829 5388, Fax +972 4 829 5403, E-Mail [email protected]  Historical Account and which has been subject to diminished levels of preda- tion pressure and thus less selection for extremely rapid How the Evolutionary Theories of Aging Have reproduction. According to the measurement of longev- Evolved ity as well as the collagen biochemistry, Austad has found Before the theory of evolution, the process of aging that the island population aged more slowly in compari- was conceived in the same way that moving parts wear son to the mainland population. Also, the longevity of out, machines break down and all things deteriorate birds, turtles and porcupines reflects their relative invul- slowly over time. After the development of the theory of nerability to predation. Birds, which live 5–10 times lon- evolution, scientists began to wonder why evolution had ger than comparably sized mammals, have apparently produced such complex and well-adapted creatures that had enough time available to evolve protective mecha- were so successful at surviving from conception through nisms, such as antioxidant pathways and controls of on- Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 to adulthood, but which then fell into decay and died. cogene expression, that may account for their resistance The problem of how aging evolved was first debated to age-related pathology. Accordingly, these studies prove by August Weismann who developed the theory of that different selective pressures on genes alter rates of programmed death which proposed that aging evolved to growth and development. the advantage of the species, not the individual, and that Observations like these are common for many biolog- there must be an evolutionary advantage to having only ical species. In reality, very few individuals of any species a limited lifespan. The evolutionary argument was used living in the wild survive long enough for there to be any to suggest that older members of a species are expected to evolutionary pressure to set an age limit. die of old age by specific death mechanism of natural se- lection meant to eliminate old members of population so Importance of Weismann’s Work that they would no longer compete with younger genera- In order to explain the biological mechanism of his tions for food and other resources. Accordingly, one of theory of programmed death, Weismann came to an the most important concepts provided by Weismann was idea that there is a specific limitation on the number of the necessity of reproduction in a world that invariably divisions that somatic cells might undergo in the course causes degradation of the individual. of an individual life and that this number, like the life On the other hand, there is compelling evidence span of individual generations of cells, is already deter- against the theory of programmed death, such as high mined in the embryonic cell. By this means, the dif- levels of extrinsic mortality observed by Medawar (his ferent life span of animals would be dependent on the work to be discussed in greater detail later). For example, number of cell generations in which there is a specific animals living in harsh conditions in their natural habitat norm for each different species. This exceptional the- survive for only relatively short period of time compared oretical speculation over the existence of a cell division to those living in the protected conditions of captivity, limit was experimentally confirmed in 1961 by Hayflick which is opposite to what would be expected from the and Moorhead who found that normal human em- programmed death theory. For instance, 9 out of 10 mice bryo fibroblasts undergo a finite number of cell divi- living in the wild will die before the age of 10 months, sions, and then they ‘age’ and ‘die’. In the case of the fi- whereas the same mice raised in captivity have an average broblasts the limit was about 50 cell divisions. These re- lifespan of 24 months. Also, the median lifespan of chim- sults have been confirmed in many laboratories for a panzees (Pan troglodytes) living in captivity is between 23 variety of cell types and became known as the Hayflick years (males) and 30 years (females), and almost 20% of limit. It should be noted here that the process of apo- captive female chimpanzees survive to age 50 [3, 4]. In ptosis (programmed cell death), which was distinguished addition to many advantageous environmental factors, from traumatic cell death by John Foxton Ross Kerr , appropriate medical treatment (including vaccinations) or autophagy pathway for cellular death is irrelevant may also be an important life-prolonging factor under to the above discussions focusing on the death-mecha- these circumstances. On the other hand, in wild condi- nism of the whole organism and not to some of its spe- tions, the median lifespan of chimpanzees is only 8 years cific somatic cells. and almost none survive to age 50. Austad com- To conclude, Weismann contributed the first evolu- pared the survival and reproduction of 2 groups of close- tionary theory of aging which drew the attention of other ly related opossums; 1 of those has lived on an isolated researchers. Also, on the basis of theoretical inspiration island, disconnected from the mainland for 4,500 years, alone, he rightly predicted the existence of a cell division 206 Gerontology 2009;55:205–216 Ljubuncic/Reznick limit. Finally, he abandoned his first concept and sug- The probability of an individual reproducing is age de- gested afterward that aging evolved because organisms pendent. It is zero at birth and reaches a peak in young that segregate germ and soma must invest additional re- adults. Then it decreases due to the increased probability sources to reproduce instead of maintaining the soma, of death linked to various external (predators, illnesses, and this renunciation of the soma results in aging. Thus, accidents) and internal (senescence) causes. Under such he formulated the germ plasm theory, i.e. that the body is conditions, deleterious mutations expressed at a young divided into the germ cells (sperm or ova cells), which age are severely selected against because of their highly transmit hereditary information to the offspring and to negative impact on fitness (number of offspring pro- all other (somatic) cells. It should be emphasized that duced). On the other hand, deleterious mutations ex- the disposable soma theory of Thomas Kirkwood, which pressed later in life are relatively neutral to selection be- states that organisms must reach a balance between the cause their bearers have already transmitted their genes Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 resources they invest in soma maintenance and resources to the next generation. Mutation accumulation theory invested in reproduction , is based to a certain extent also predicts that the dependence of progeny lifespan on on Weismann’s ideas. parental lifespan should not be linear. Instead, this de- pendence should have nonlinear shape with an increas- ing slope for the dependence of progeny lifespan on pa- Contemporary Evolutionary Theories of Aging rental lifespan for longer-lived parents. This prediction follows directly from the original statement of the mu- Basically, the evolutionary theory of aging proposes tation accumulation theory that the equilibrium gene effectively 2 models for how aging can evolve: (1) the the- frequency for deleterious mutations should increase ory of mutation accumulation and (2) the antagonistic with age at onset of mutation action because of weaker pleiotropy hypothesis. The theory of mutation accumula- (postponed) selection against later-acting mutations. tion originates from Peter Medawar’s ideas in which he Thus, it was argued, if the ages at death were indeed de- argued that diminishing selection would lead to the ac- termined by accumulated late-acting deleterious muta- cumulation of late-acting harmful genes. In George Wil- tions, one would expect this slope to become steeper with liams’s model of antagonistic pleiotropy, aging evolves higher parental ages at death. Indeed, the analysis of due to the pleiotropic effect of genes that are beneficial the reliable and accurate genealogical data on familial early in life and then harmful at late ages. longevity in European royal and noble families found that the regression slope for the dependence of offspring The Mutation Accumulation Theory Suggested by lifespan on parental lifespan increases with parental life- Medawar span, as predicted by the mutation accumulation theory The basic observations that the force of natural selec-. tion declines with age were developed by Peter Medawar According to Strehler’s criteria for the aging process,. Since all organisms eventually die from different it is cumulative, universal, progressive, intrinsic and det- causes (e.g. diseases, accidents, predation), genes benefi- rimental, which means it is omnipresent. In addition, cial early in life are favored by natural selection over genes according to the predictions of the mutation accumula- beneficial late in life. Consequently, the greatest con- tion theory, mechanisms that limit lifespan may be placed tribution to create a new generation comes from young, into 3 categories: all aging mechanisms that involve a not from old organisms. Thus, the power of natural selec- gradual deterioration of cellular and metabolic processes tion fades with age, making it possible for hazardous late- with age through the appearance of cellular and molecu- acting genes to exist. lar damage late in the life (oxidative damage, somatic The mutation accumulation theory of aging of DNA mutation, telomere shortening, etc.); other mecha- Medawar considers aging as a byproduct of natural selec- nisms that are linked to young adulthood (cell senes- tion. According to this theory, aging has no adaptive cence, caloric restriction and insulin-signaling pathway traits because natural selection does not occur in long- which regulates caloric restriction), and external mecha- lived animals and provides little additional contribution nisms which are unavoidable consequences of old age to offspring numbers. In other words, old age is not under such as inflammation response, caused by infection and selective pressure per se, and there is no evolutionary pathogenic invasion in old age. While categories 2 mechanism to rid a population of mutations that cause and 3 might be similar among species, the first category detrimental effects only in old animals. is different between various species. Evolutionary Theories of Aging Gerontology 2009;55:205–216 207  Late-Life Mortality Plateau: Charlesworth’s decreases the chances of dying at age 10 or 20. Thus, Modified Mutation Accumulation Theory harmful late-acting genes can remain in a population if Under traditional evolutionary models mortality rates they have a beneficial effect early in life such as increas- should increase monotonically after sexual maturity. ing fitness at early ages or increasing reproductive suc- However, the equilibrium frequencies of deleterious al- cess. However, it was argued by Williams that natural leles affecting late life are lower than predicted under tra- selection will frequently maximize vigor in youth at the ditional models. The discovery of late-life mortality pla- expense of vigor later on and thereby produce a declin- teaus [19, 20], in which cohort mortality rates appear to ing vigor (aging) during adult life. One frequently plateau or even decrease at late ages, challenged the valid- quoted example is that of Zahavi about the costly sexual ity of evolutionary explanations of aging. In that way, ornaments of male birds that are crucial to attracting fe- Charlesworth presented a modified mutation accu- males, and thus vital to passing on genes to the next gen- Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 mulation model in which mortality plateaus are predict- eration. However, these ornaments can be considered ed to occur at late ages if alleles affecting fitness do so for handicaps, e.g. the extravagant feathers of male peacocks more than 1 specific age range class (moderate age speci- limit the bird’s movements, which can deter their ability ficity). Under the modified mutation accumulation mod- to escape predators. Therefore, the stipulation of the el, late-life mortality plateaus were predicted whether del- existence of pleiotropic antagonistic genes could explain eterious alleles affected fitness during a ‘window’ of just the aging process. Such genes will be maintained in the a few age classes or affected fitness cumulatively at all population due to their positive effect on reproduction ages after a given age. Computer simulations testing this at young ages, despite their negative effects at old, postre- model of age specificity were consistent with existing productive age by having negative effects that look ex- data on late-life mortality. Recently, Reynolds et al. actly like the aging process. These initially verbal argu- evaluated the mutation accumulation model by test- ments were later proved mathematically by Charles- ing the degree of age specificity of segregating alleles af- worth. fecting fitness in Drosophila melanogaster. They assessed An example of antagonistic pleiotropy refers to repli- age specificity by measuring the homozygous fitness ef- cative cellular senescence (cell division limit), which is fects of segregating alleles across the adult life span and known to suppress tumorigenesis by arresting cell growth then calculated genetic correlations of these effects across. This process, which suppresses tumorigenesis early age classes. The authors found for both males and females in life, may promote cancer in later life because senescent that allelic effects were age specific with effects extending cells stimulate other premalignant and malignant cells to over 1–2 weeks across all age classes, which was consis- proliferate and to form tumors [26, 25]. Thus, there is a tent with modified mutation accumulation theory. trade-off between the earlier protective effect of growth Thus, these results point out that Charlesworth’s modi- arrest because of cellular senescence and the later detri- fied mutation accumulation theory can both explain the mental effect caused by cancer promotion. origin of senescence and predict late-life mortality pla- The antagonistic pleiotropy theory may also explain teaus. the so called idea of reproductive cost or, more generally, of trade-offs between different traits of the organism in Antagonistic Pleiotropy Model Suggested by which reproduction may come with a cost for species lon- Williams gevity. The mutations favoring more intensive reproduc- The antagonistic pleiotropy model by Williams (‘pay tion (more offspring produced) will be propagated in fu- later’ theory) proposes that some genes are beneficial at ture generations even if these mutations have some del- earlier ages but harmful at later ages. The genes with age- eterious effects in later life. For example, mutations related opposite effects are called pleiotropic genes. causing overproduction of sex hormones, which may in- Accordingly, the theory of antagonistic pleiotropy is crease the sex drive, libido, reproductive efforts and suc- based on 2 assumptions. First, it is assumed that a par- cess, may be favored by selection despite causing sex-re- ticular gene may have an effect not only on 1 feature but lated cancers (prostate and ovarian cancer) later in life. on several traits of an organism (pleiotropy). The second The trade-offs between reproduction and longevity assumption is that these pleiotropic effects may affect was also predicted by Williams, who was arguing that individual fitness in antagonistic ways. For example, a reproductive maturation is the most important landmark gene that increases survival to reproductive age or repro- in the life-cycle for the evolution of senescence and that ductive output will be favored by natural selection if it senescence may already theoretically begin right after re- 208 Gerontology 2009;55:205–216 Ljubuncic/Reznick productive maturation stage in development is reached. The Disposable Soma Theory by Kirkwood and This prediction was tested in the fruit fly D. melanogaster Holliday and, contrary to this prediction, no linear relationship There were attempts to find a better name for the an- was found between the speed of development and longev- tagonistic pleiotropy theory and to specify in more detail ity. Also, the search for the trade-offs between lon- how one and the same gene could have both deleterious gevity and reproduction was made in experiments with and beneficial effects. The disposable soma theory, which the nematode Caenorhabditis elegans where a number of was proposed by Kirkwood and Holliday , predicts long-lived mutants have been identified. When long-lived that aging occurs due to the accumulation of damage mutants were put under standard culture conditions to- during life and that failures of defensive or repair mecha- gether with normal wild-types individuals, neither of nisms contribute to aging [12, 35, 36]. It postulated a spe- them exhibited a competitive advantage, contrary to the- cial class of gene mutations with antagonistic pleiotropic Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 oretical evolutionary predictions [28, 29]. However, when effects in which hypothetical mutations save energy for nematode cultures were alternatively fed and starved, reproduction (positive effect) by partially disabling mo- mimicking cyclic field conditions in nature, the wild- lecular proofreading and other accuracy promoting de- type worms outcompeted (outnumbered) the long-lived vices in somatic cells (negative effect). In other words, mutant. These findings, demonstrating that increas- given finite resources, the more an animal expends on ing lifespan may exhibit some fitness cost only in harsh bodily maintenance, the less it can expend on reproduc- conditions, provided limited support for the antagonistic tion, and vice versa. The distinction between somatic and pleiotropy theory of aging. reproductive tissues is therefore important because the Also, pleiotropic antagonism forms the basis for the reproductive cell lineage, or germ line, must be main- development of many age-related diseases. The examples tained at a level that preserves viability across the genera- for the mechanism of pleiotropic antagonism include tions, whereas the soma needs only to support the sur- amongst other, atherosclerosis, benign and malignant vival of a single generation. Thus, the key feature of the prostate hypertrophy, Alzheimer’s disease and the recip- disposable soma theory is its emphasis on the optimal rocal relationship between cellular senescence and can- balance between somatic maintenance and repair versus cer [for more details see 30]. Also, it is worth mentioning reproduction. The theory also suggests that multiple ‘paradoxical antagonistic pleiotropy’ which refers to the kinds of damage will accumulate in parallel within cells, setting of bad alleles with deleterious effect early in life as the same logic limits the investment in each of wide but which have beneficial late effects. One quoted ex- range of maintenance and repair functions. To conclude, ample is the allele at the plasminogen activator inibitor-1 the disposable soma theory closes the gap between mech- locus which is found augmented in centenarians al- anistic and evolutionary theories of aging by suggesting though, paradoxically, it is a predictor of recurrent myo- that aging results from progressive accumulation of mo- cardial infarctions in young people. Thus, paradoxi- lecular and cellular damage, as a direct consequence of cal antagonistic pleiotropy stands in contradiction to the evolved limitations in the genetic settings of maintenance ‘pay later’ proposal that genes are beneficial only at ear- and repair functions [12, 36]. lier ages but harmful at later ages. Antagonistic Pleiotropy Theory versus Mutation Evolutionary Theory of Aging and Research on Accumulation Theory Aging – Contradictions Exist What are the main differences between these 2 evolu- tionary theories of aging? In short, the main difference One of the most intriguing phenotypes in the biology between the 2 theories is that in the mutation accumula- of aging is that there are animals that appear not to age. tion theory, genes with negative effects at old age accu- In fact, these animals (e.g. female turtles) may increase mulate passively from one generation to the next, while both survivorship and reproductive output with age. in the antagonistic pleiotropy theory these genes are ac- These observations, which suggest some species may not tively kept in the gene pool by selection. However, it age, are contradictory to classical evolutionary models of should be noted that both theories are widely accepted as aging which predict that all species eventually age. applicable. Also, they are not mutually exclusive and both In addition, evolutionary theory was interpreted by evo- evolutionary mechanisms may operate at the same time lutionary biologists in a way that the search for single-. gene mutations or life-extending interventions with Evolutionary Theories of Aging Gerontology 2009;55:205–216 209 large positive effects on lifespan was considered a com- SGK-1, 3 downstream targets of DAF-2 [39, 44, 45]. The pletely futile task. However, the discovery of different major target of insulin-like signaling is the FOXO tran- single-gene mutants with profoundly extended longevity scription factor, DAF-16, whose mammalian orthologs was ultimately made. For example, a single-gene muta- are FOXO1, FOXO3a and FOXO4. tion (daf-2) more than doubles the lifespan of nematodes, Recently, Selman et al. offered evidence for life- keeping them active, fully fertile (contrary to predictions span extension and delayed age-related biomarkers in in- of the disposable soma theory) and having normal meta- sulin receptor substrate (IRS) 1 null mice. The authors bolic rates. measured the life span of mice lacking either IRS 1 or 2, Rapid progress in human genomics raises the prospect the major intracellular effectors of the insulin/insulin- of significantly increasing our knowledge of the determi- like growth factor-1 signaling receptors. Their provision- nants of human longevity. In the extensive search con- al results indicate that female Irs1–/– mice are long-lived. Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 ducted over the last 3 decades for genes that affect aging Furthermore, they displayed resistance to a range of age- in model organisms like yeast (Saccharomyces cerevisiae), sensitive markers of aging including skin, bone, immune nematode worms (C. elegans), and fruit flies (D. melano- and motor dysfunction. In contrast, Irs2–/– mice were gaster), many genes have been identified that alter the rate short-lived, whereas Irs1+/– and Irs2+/– mice of both sexes of aging, as measured both by lifespan and Gompertzian showed normal life spans. Thus, IRS1 signaling, an evo- increase in age-related mortality, but none has been found lutionarily conserved pathway regulating mammalian that abolishes the aging process altogether. Aging lifespan, may be a point of intervention for therapies with should not be viewed as programmed, but instead as the the potential to delay age-related processes. result of the accumulation of somatic damage, owing to limited investments in maintenance and repair. Is Nuclear Factor Kappa B a Signaling Mediator of Aging? Genetic studies in model organisms such as yeast, Molecular Genetic Studies of Aging and Longevity worms, flies and mice that have lead to lifespan extension suggest that longevity is subject to regulation. In addi- Insulin Signaling and Longevity tion, various system-wide interventions in old animals In most cases, the genes with major effects on longev- can reverse features of aging. To better understand these ity have been found to regulate central aspects of metab- processes, much effort has been put into the study of ag- olism, particularly with respect to organism energetic ing on a molecular level. In particular, genome-wide mi- balance, such as insulin/insulin-like growth factor-1 sig- croarray analysis of differently aged individual organ- naling. The studies of caloric restriction, mutant isms or tissues has been used to track the global expres- worms and flies as well as long lived mutant mice led to sion changes that occur during normal aging. Although recognition of the centrality of insulin-like signaling in these studies consistently implicate specific pathways in regulation of longevity in widely separated species of an- aging processes, there is little conservation between the imals. In that way, the daf-2 signaling pathway is part of individual genes that change. To circumvent this prob- an endocrine system that regulates longevity, metabolism lem, Adler et al. [48, 49] have recently developed a novel and development in C. elegans and is homologous to computational approach to discover transcription factors mammalian insulin and insulin-like growth factor-1 sig- that may be responsible for driving global expression naling pathway. Daf-2 encodes the worm homolog of changes with age. They developed a systematic approach the insulin/insulin-like growth factor-1 receptor. Signal- to identify combinatorial cis-regulatory motifs that drive ing from DAF-2 is mediated through the AGE-1 phos- age-dependent gene expression across different tissues phatidylinositol 3-kinase, PDK-1, and AKT-1/2 kinases to and organisms. Integrated analysis of 365 micro arrays antagonize DAF-16, orthologous to human FOXO, a spanning 9 tissue types predicted 14 motifs as major reg- forkhead transcription factor. In C. elegans, a conserved ulators of age-dependent gene expression in humans and insulin-like signaling pathway promotes wild type life- mice. The motif most strongly associated with aging was span, stress resistance and reproductive development that of the transcription factor nuclear factor kappa B. Adult lifespan and stress resistance were found to be (NF-␬B). Accordingly, the transcription factor NF-␬B increased by mutations in the DAF-2/insulin receptor- has been identified as a candidate activator of aging-re- like protein, AGE-1 (a homolog of the p110 catalytic sub- lated transcriptional changes in multiple human and unit of phosphoinositide 3-kinase) or in AKT-1, PDK-1 or mouse tissues. Inducible genetic blockade of NF-␬B for 2 210 Gerontology 2009;55:205–216 Ljubuncic/Reznick weeks in the epidermis of chronologically aged mice by with the yeast proteins Rpd3 (class I), Hda1 (class II) and adenovirus-mediated expression of dominantly active Sir2 (class III) serving as charter members of the 3 major I␬B␣ (Ad-I␬B␣) reverted the tissue characteristics and classes. global gene expression programs to those of young mice Class III deacetylases, the regulatory Sirtuins, which. Also, age-specific NF-␬B blockade and orthogonal are considered anti-aging proteins related to the yeast cell cycle interventions revealed that NF-␬B controls cell SIR2 and its mammalian ortholog SIRT1, are unique in cycle exit and gene expression signature of aging in paral- that they require nicotinamide adenine dinucleotide lel, but not sequential pathways. These results identify a (NAD) coenzyme as a cofactor which is involved with conserved network of regulatory pathways underlying many types of oxidation reactions. As such, Sirtuin activ- mammalian aging and show that NF-␬B is continually ity may be controlled by cellular [NAD]/[NADH] ratios required to enforce many features of aging in a tissue- and respond to changes in cellular metabolism. In- Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 specific manner. Thus, genetic blockade of NF-␬B in the creased Sir2 activity has been reported to enhance the skin of chronologically aged mice (⌬SP-p50-ER trans- lifespan of C. elegans and D. melanogaster [59, 60]. genic mice) reversed the global gene expression program and tissue characteristics to those of young mice, demon- Heat Shock Proteins and Longevity strating for the first time that disruption of a single gene The analysis of long lived mutant worms led to im- is sufficient to reverse features of aging, at least for the portant findings. For example, it was observed that the short-term. Age-associated genes whose expres- lifespan extending mutations have in common an in- sion was inhibited by NF-␬B blockade included those re- creased resistance to cellular damage caused by ultra- lated to chromatin/transcriptional regulation (RAD50, violet light, oxidizing agents and overheating. From that, SMC2L1, SMC6L1 and ATRX), protein modification/sig- it can be assumed that the increased resistance to such nal transduction (STK25, RAMP2 and HIP2), cell cycle/ types of injuries is the link which may lead to longevity. growth control (DNAJC2 and IGFBP5) and mitochondria In that way, heat shock genes may be candidates for such (ALAS2, GSTK1, and PTE1). links because they become induced by a similarly wide It should also be noted that experiments have shown range of stresses not only in worm and fly cells but also that activation of NF-␬B can induce muscle atrophy , in human cells. Stress proteins, including the heat shock insulin resistance and neurotoxicity in Alzheimer’s proteins (HSPs), function in combating the stress-in- disease , 3 prevalent age-associated morbidities. Our duced damage. Experiments have shown that transgen- work in vitro has shown that NF-␬B activity increases in ic worms which are genetically engineered to have cer- cultured muscle cells exposed to pro-inflammatory reac- tain types of HSP upregulated, such as Hsp16 or Hsp70F, tive nitrogen species, which are increasingly generated live much longer [61, 62]. Moreover, transcriptional ac- during aging, and that peroxynitrite may induce alterna- tivator heat shock factor HSF-1, which regulates the tive activation of the NF-␬B classic pathway of activation heat-shock response, also influences aging in C. elegans.. In addition, in our in vivo work we have observed a Hsu et al. have shown that hsf-1 overexpression ex- distinctive biphasic pattern of NF-␬B activation in atro- tends lifespan. They found that HSF-1, like the tran- phic muscles of old rats [54, 55]. Interestingly, the human scription factor DAF-16, is required for daf-2-insulin/ NFKB1 gene maps within a genetic locus on chromosome IGF-1 receptor mutations to extend life-span. Accord- 4 that has been repeatedly associated with human longev- ingly, they suggested that this is because HSF-1 and ity. DAF-16 together activate expression of genes encoding small HSPs, which in turn promote longevity. Thus, Sirtuins-Anti-Aging Proteins the role of multiple transcription factors in extending Experiments in model organisms including yeast, lifespan in yeast and worms raises the possibility that worms, flies and mice reveal that several lifespan-related many transcriptional regulators can contribute to lon- genes act through similar evolutionarily conserved path- gevity. ways, of which the best characterized is the insulin/insu- lin-like growth factor 1 endocrine pathway. Among the Mitochondrial Electron Transport Chain Gene Set – genes that have been shown to regulate aging in different A Biomarker of Aging? species are the SIR2 family and its functional orthologs Most age-related expression changes are specific for a that make up a family of deacetylase enzymes termed Sir- given species, but genes in the electron transport chain tuins. Histone and protein deacetylases fall into 4 classes pathway, show common age regulation in species from Evolutionary Theories of Aging Gerontology 2009;55:205–216 211 worms to humans. It was found that the electron trans- complete theories, but rather a set of ideas that themselves port chain gene set was similarly age-regulated in worms, require further elaboration and validation. flies, mice and humans by showing about a 2-fold de- In addition, evolutionary biologists do not expect any crease in the overall level of expression in old age for all single theory to provide all the answers, but rather see the 4 species. Zahn et al. found that genes involved in the process of aging as involving a combination of theoretical electron transport chain show common age regulation in causes. Consequently, the ongoing research will deter- all 4 species, indicating that these genes may be excep- mine through a systems biology approach the degree to tionally good markers of aging. which each theory contributes to the actual process of ag- Most of the electron transport chain genes are located ing. in the nuclear DNA and encode components of mito- The emerging view from the genomics experiments is chondrial enzyme complexes that are the primary source that the aging process is quite different in mice and hu- Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 of generation of free radicals in the cell. Oxidative dam- mans, emphasizing the need for research using human age from the mitochondrial free radicals may accumulate samples to uncover aging mechanisms relevant to hu- with time and thereby decrease overall cell function and man longevity. A small number of age-related changes in ultimately limit an organism’s lifespan. The lifespans expression are conserved across species. These aging of worms and humans differ by approximately 2,000-fold pathways may be linked to functions in young adults or (2 weeks vs. 80 years), and the slope of age-related chang- may be unavoidable consequences of growing old. Iden- es in expression for this pathway scales with lifespan such tification of these pathways is crucial because they high- that old worms and old humans showed a similar overall light specific aging pathways that can be dissected in decrease in expression levels. Although indicating that model organisms to elucidate general principles of aging genes may be exceptionally good markers of aging, Zahn. et al. saw no overall correlation of age regulation be- Development of functional genomics tools has made it tween mice and humans, thus suggesting that aging pro- possible to define the aging process by performing ge- cesses in mice and humans in general may be fundamen- nome-wide scans for transcriptional differences between tally different. the young and the old using gene array technology assess- ment. Global screens for age regulation have been per- formed for worms and flies, as well as many tissues in Evolutionary Theories in the Light of Genomic mice and humans. A series of recent works has compared Studies age-related expression profiles in worms, mice, flies and humans. For worms and flies, DNA microarrays have Clearly, the experiments in which the single gene been used on whole animals over the entire lifespan to knock-outs were shown to delay aging in animals are profile transcriptional changes of aging. Recently, contradictory to the evolutionary theory of aging. Also, Zahn et al. have used data from AGEMAP (Atlas of some genetic manipulations can delay aging without af- Gene Expression in Mouse Aging Project), which is a fecting reproduction , which also contradicts the evo- large database of expression changes as a function of age lutionary theory of aging. Therefore, evolutionary biolo- in 16 mouse tissues. They found great heterogeneity in gists are presented with the task of reconciling these new the amount of transcriptional change with age in differ- discoveries, including the single-gene life-extending mu- ent tissues. Some tissues displayed large transcriptional tations, with the evolutionary theory of aging. differences in old mice, suggesting that these tissues may Nevertheless, the evolutionary theory of aging offers a contribute strongly to organism decline. Other tissues theoretical framework that explains many observations. showed few or no changes in expression with age, indicat- The theory offers some indications as to the evolutionary ing strong levels of homeostasis throughout life. Based on mechanisms and the events leading to the evolution of ag- the pattern of age related transcriptional changes, they ing, although it does not offer a complete picture on the found that tissues could be classified into 1 of 3 aging evolution of aging across different species. According to processes: (1) a pattern common to neural tissues; (2) a Gavrilov and Gavrilova , evolutionary theories of ag- pattern for vascular tissues, and (3) a pattern for steroid- ing are useful when they open new opportunities for re- responsive tissues. They observed that different tissues search by suggesting testable predictions, but they should age in a coordinated fashion in individual mice, such that never be used to impose limitations on aging studies. This certain mice exhibit rapid aging, whereas others exhibit is because the evolutionary theories of aging are not in fact slow aging for multiple tissues. 212 Gerontology 2009;55:205–216 Ljubuncic/Reznick  Transcriptional profiles for aging contain quantitative gle gene. Because these diseases display different aspects data on age-related changes in expression for a large frac- of aging, but never every aspect, they are often called tion of the genome. Genes that show age-related tran- ‘segmental progeroid syndrome’, a term introduced by scriptional differences in multiple species are exception- George Martin [74, 75]. Thus, the molecular basis of ally interesting as biomarkers for age. Their age-related Hutchinson-Gilford syndrome and the details of muta- decline scales with lifespan, such that age-related chang- tions of the WRN locus may contribute to our under- es occur relatively quickly in short-lived animals but standing of the coordinated appearance of the changes slowly in long-lived ones. By contrast, genes that show age which are general phenomena of the process of normal regulation in mice but not humans may help identify aging. pathways and mechanisms that account for the much Other areas in biogerontology research that may fur- longer lifespan of humans. ther contribute to our better understanding of evolution Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 of aging can include research works on control of protein synthesis, validation of biomarkers of aging, understand- Challenges for Future Research in Biogerontology ing the biochemistry of longevity, comparative biology studies and research in the fields of gerontologic pathol- Modern biogerontology is characterized by several ogy. For example, both the rate of synthesis and rate of major and important discoveries which include: degradation of most proteins is slower in tissues of old (1) Lifespan extension (in rodents) by caloric restric- rodents and humans, which extends time for the occur- tion, provided that protein, vitamins and micronutrients rence of different protein modifications and intramolec- are sufficiently available to prevent malnutrition. ular rearrangements that may ultimately lead to creation (2) The occurrence of stress-resistance of long-lived of atypical protein forms and have pathological conse- mutant worm strains. quences. Also, the shortening of telomeres, the special- (3) The existence of single gene mutants which extend ized nucleoprotein structures at the ends of chromo- mouse longevity. somes, can cause changes in expression of genes nearest (4) The role of insulin and insulin-like signals in mod- the telomere, known as the telomere position effect. As a ulating aging rates in widely separated species and ani- result, the telomere position effect can result in the age- mals. related expression and/or over-expression of genes near a These experimental findings have paved the way for telomere that is dependent on both distance from the evolutionary approaches to make a substantial contribu- telomere and individual chromosomal telomere length. tion to the biology of aging and, ultimately, to medicine In that way, telomere shortening in mitotic somatic cells. For example, Partridge and Gems have recently may contribute to and cause their senescence, accelerate given emphasis to the fact that a largely parallel body of the senescence of neighboring mitotic and postmitotic work in biogerontology has produced descriptions of the cells, and underlie organism aging. Accordingly, it has phenotypes of aging and experimental analysis of their been suggested that if telomere shortening could be mechanistic basis. There have also been some interac- slowed or prevented in dividing cells in vivo, this could tions between these 2 approaches: for example, the phe- lead to an increase in replicative lifespan, which may en- nomenon of cellular senescence, which can result in the able these cells to carry out their normal cellular func- presence of useless or even damaging cells in the divid- tions for a longer period of time. Another area of ing tissues of older humans, can be understood as a side- particular interest is stem cells research. The embryonic effect of a mechanism for preventing cancer. Simi- stem cells can differentiate into various cell types. Stem larly, several of the neurodegenerative diseases of aging, cells from adult tissues also maintain such a potential, if such as Huntington’s and Alzheimer’s, might arise as a transplanted into the target organ, or cultured in the result of the inadequacy of energetically expensive cel- presence of relevant cytokines and growth factors. In ad- lular defense mechanisms. Also, work on progeria, dition, studies on centenarians revealed that their periph- or Hutchinson-Gilford Progeria Syndrome which is eral blood also contains circulating stem cells, albeit at a caused by a mutation in the LMNA gene on chromosome lower proportion compared to the young adults. 1 as well as Werner’s syndrome, in which patients have However, one of the issues to be solved is the limited ca- inherited 2 copies of the null allele at the WRN locus on pacity of the stem cells from mature tissues to replicate chromosome 8 suggest that the occurrence of age-associ- sequentially, as in most of the normal cell types. The ated changes can happen as a result of mutation in a sin- aging of tissue-specific stem cell and progenitor cell com- Evolutionary Theories of Aging Gerontology 2009;55:205–216 213 partments is believed to be central to the decline of tissue humans with exceptional longevity. In another study, and organ integrity and function in the elderly, and the gender-specific and functionally significant insulin-like question of whether or not stem cell aging is accompa- growth factor I receptor mutations were described in fe- nied by increased cellular senescence remains an impor- male centenarians. Moreover, an additional advanta- tant unresolved issue. Finally, we propose further fo- geous finding that the CETP-VV genotype was protective cus on research elucidating the biochemical and molecu- in neutralizing the deleterious effects of the lipoprotein(a) lar basis for longevity in very old people because data gene leads to the proposal that, in fact, long-lived from studies on human longevity showed that nonage- people can have just as many deleterious aging genotypes narians and centenarians were healthier than originally as the rest of the population and that their protective lon- predicted on the basis of classical studies on human ag- gevity genotype (‘buffering genes’ hypothesis) would ing. It thus led to research on the genetics of the healthy protect them from the harmful effects of the others. Downloaded from http://karger.com/ger/article-pdf/55/2/205/2835177/000200772.pdf by Universidade de Sao Paulo - USP + SIBI user on 28 June 2024 very old people in which, for example, it was demonstrat- Thus, studies of genotypic frequencies among different ed that subjects with exceptional longevity and their off- age groups can elucidate the genetic determinants and spring have significantly greater high-density lipoprotein pathways responsible for longevity. levels and particle sizes and lower levels of low-density lipoprotein, which reflect their general health and cogni- tive function performance. Also, there was the find- Acknowledgments ing of a markedly higher frequency of a functional cho- This report is supported by the Krol Foundation of Barnegat, lesteryl ester transfer protein (CETP) variant (homozy- N.J., USA, and a grant from the Technion Vice President for Re- gosity for the 405 valine) in these people, which is the first search. example of a phenotype and an associated genotype in References 1 Weismann A: Essays Upon Heredity. Ox- 11 Weismann A: Essays Upon Heredity and 20 Curtsinger JW, Fukui HH, Townsend DR, ford, Clarendon Press, 1891. Kindred Biological Problems. Oxford, Clar- Vaupel JW: Demography of genotypes: fail- 2 Weismann A: Über die Dauer des Lebens. endon Press, 1889. ure of the limited life-span paradigm in Dro- Fisher, Jena, 1882. 12 Kirkwood TB: Evolution of ageing. Nature sophila melanogaster. 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