Sci. Aging Knowl. Environ., 24 May 2006
Vol. 2006, Issue 9, p. pe14
[DOI: 10.1126/sageke.2006.9.pe14]

PERSPECTIVES

Aging at the Interface of Stem Cell Renewal, Apoptosis, Senescence, and Cancer

Almut Nebel, Elke Schaffitzel, and Maren Hertweck

The authors are at the Institute of Clinical Molecular Biology, University of Kiel, Germany (A.N.), the Bio 3, Bioinformatics and Molecular Genetics, University of Freiburg, Germany (E.S. and M.H.), and the Renal Division, University Hospital Freiburg, Germany (E.S.). E-mail: maren.hertweck{at}biologie.uni-freiburg.de

http://sageke.sciencemag.org/cgi/content/full/2006/9/pe14

Key Words: stem cells • systems biology • regulatory pathways and networks • epigenetic modifications

Introduction

From its launch in 2002, the "Functional Genomics of Ageing" conference series has established itself as one of the prominent events in the rapidly growing aging-related research field. This spring (29 March to 1 April 2006), the third conference was held in the ancient Palazzo Reale in Palermo, in the Mediterranean island of Sicily (Italy). The venue could not have been more appropriate for a meeting focusing on the role of stem cells in aging, cells that have the capacity to regenerate different tissues and organs. As a city, Palermo had to reinvent and renew itself several times throughout its eventful 3000-year history, in the wake of various conquests and occupations. As conference organizers Yousin Suh and Jan Vijg pointed out in their welcoming address, regeneration and rejuvenation have been recurrent themes throughout European art and culture, as highlighted, for instance, in Mary Shelley's classic novel "Frankenstein" or in the Greek mythological figure of Prometheus whose liver was eaten by an eagle, but renewed each day, thereby causing endless punishment.

In this historic setting, Bruno Gridelli, co-organizer of the conference and director of the Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT) in Palermo, set the stage for an exciting conference by outlining in his opening address the importance and potential of modern transplantation medicine. The huge gap that exists between the need for and the availability of organ transplants continues to grow. To counter the shortage of available organs, Gridelli suggested a number of measures, ranging from preventive medical procedures, to novel technologies for improving the use of cadaveric and living organs, to artificial organs and regenerative medicine. He called on clinicians and scientists to jointly pursue novel research avenues in the field of aging and stem cell research that may help reestablish tissue functions and support the regeneration of organs impaired by disease or injury.

Keynote lecturer George Martin (University of Washington in Seattle and University of California in Los Angeles, USA), a leading expert in the field of aging, presented his views on the genetics and epigenetics of altered proliferative homeostasis in aging and cancer. Aging mammalian cells are subjected to a huge onslaught of genetic aberrations and DNA damage that perturb proliferative homeostasis, leading to two opposite manifestations in tissues: atrophies, caused by the postmaturational failure to adequately replace effete somatic cells, and hyperplasias, caused by excessive proliferation of somatic cells. Very often, both are observed side by side in the same tissues and in virtually all of the major geriatric disorders, such as Alzheimer's disease, arteriosclerosis, and immunosenescence. In Martin's opinion, atrophy is the likely initial event in most of these phenotypes, followed by an increase in proliferation as a secondary, compensatory response that frequently gets out of hand. The genetic analysis of unusual susceptibility or resistance to such phenotypes could help to elucidate the mechanisms involved.

In this respect, advances in stem cell biology will provide critical understanding. Martin reminded the audience of the controversial immortal DNA strand hypothesis, originally conceived by John Cairns in 1975 (1), which suggests that stem cells actively retain the oldest DNA strand during asymmetric cell divisions. That DNA should, statistically speaking, contain fewer replication-induced errors than DNA copies resulting from additional rounds of replication. Martin asked if it could be possible that stem cells are protected by such "immortal" strands. Coincidentally, in a later session, Thomas Rando (Stanford University Medical Center, Stanford, USA) provided some of the first experimental data to support this idea (see below).

Martin went on to say that epigenetic modifications occurring during the aging process may explain the remarkable extent of individual variation in longevity, observed in genetically identical model organisms (2). Random fluctuations in gene expression might very well have evolved as an adaptive strategy to cope with environmental changes, but they may also get us into trouble as we age.

Genetic Variation, Pathways, and Networks for Survival and Longevity

The processes underlying aging are particularly suited to investigation by a systems biology approach--which looks at whole cells and tissues rather than focusing on specific genes and molecules--as they are multiple, complex, highly interactive, and often stochastic in nature. Tom Kirkwood (University of Newcastle upon Tyne, UK) opened the first of three "Biology of Ageing Sessions" by providing a detailed overview of the application of systems biology to studying the mechanisms of aging. According to his presentation, these mechanisms appear to be part of a network influenced by mostly random damage and genetically specified pathways. These pathways, mainly devoted to somatic maintenance and repair, play an important part in controlling life expectancy and ensuring longevity. How is survival at the cellular level influenced by biological "care takers" and "gate keepers?" This question was addressed in the fascinating talk given by Judith Campisi (Lawrence Berkeley National Laboratory in Berkeley, USA). Her particular focus was on senescence, an irreversible state of arrested growth and altered gene and cell function that, like apoptosis, is a potent mechanism for suppressing tumor development in mammals (see "Dangerous Liaisons" and "More Than a Sum of Our Cells"). There is increasing evidence that the senescence response may be an example of antagonistic pleiotropy; that is, natural selection favored genes conferring short-term benefits to the organism at a young age at the cost of deterioration when the organism is older (see Campisi Perspective). Senescence appears to protect against cancer early in life, but the accumulation of dysfunctional senescent cells later in life can cause aging phenotypes and, ironically, tumors (see "Faustian Bargain" and "Led Astray").

How might senescent cells contribute to aging and/or age-related diseases? Campisi showed that, in addition to permanent arrest of cell division, the senescence response is characterized by changes in gene expression of a large number of factors that can (i) promote the proliferation of neighboring normal cells, (ii) strongly alter the microenvironment, and (iii) inhibit adult stem cell renewal.

Nir Barzilai (Albert Einstein College of Medicine, Bronx, USA) discussed new results from a recently published study on genetic factors that may influence longevity. His group genotyped several hundred Ashkenazi Jewish centenarians, their offspring, and age-matched Ashkenazi controls (3). They identified alleles in three genes coding for cholesterol ester transfer protein (CETP), apo-lipoprotein C-3 (APOC3) and adiponectin (ADIPOQ) that increase in frequency in individuals between the ages of 60 and 110 years. Because the three genes are involved in lipoprotein metabolism, the genetic variants more prevalent in centenarians may protect against cardiovascular disease or the metabolic syndrome and thus enable their carriers to attain exceptional life expectancy. In addition, Barzilai argued for the existence of a buffering mechanism by which a beneficial "longevity gene" may compensate for the deleterious effect of an "aging gene."

The potential usefulness of centenarian studies to identify genes involved in human aging and longevity was further addressed by two other speakers: Calogero Caruso of the University of Palermo and Claudio Franceschi of the University of Bologna, also in Italy. According to Caruso, elderly individuals are characterized by a pro-inflammatory status that can, in conjunction with a particular genetic background, lead to the onset of age-related diseases such as Alzheimer's disease and atherosclerosis. The analysis of polymorphisms in genes that are key players in innate immunity (like TLR4 and COX/LOX) revealed that variants associated with a pro-inflammatory response are underrepresented in long-lived individuals and controls, relative to patients affected by Alzheimer's disease or atherosclerosis.

Claudio Franceschi summarized the major changes identified in human nuclear and mitochondrial genomes associated with aging and longevity. In his view, antagonistic pleiotropy is likely to be much more common and complex than previously thought. This idea is supported by two examples: (i) the same allele of a candidate gene can have different effects at different ages, becoming particularly important to survival in centenarians and (ii) homozygosity at various loci seems prevalent at old age, whereas heterozygosity is more frequent and apparently more essential earlier in life (in other words, individuals who live longer have more homozygous alleles). Moreover, Franceschi suggested that longevity genes are highly connected (forming hubs in genetic networks of aging) and evolutionarily conserved. Alleles of genes that limit life expectancy are ancestral genes from which beneficial alleles (primarily found in long-lived individuals) are derived.

Stem Cell Integrity and Maintenance

The second "Biology of Ageing" session focused on mechanisms that regulate cell integrity and maintenance. Simple model organisms, such as the unicellular yeast Saccharomyces cerevisiae, play a primary role in the identification of proteins and pathways that regulate the aging process in eukaryotes. Recent findings suggest that these pathways may have been partially conserved throughout evolution.

A key regulator of life span in yeast is the sirtuin (Sir2) gene. This gene encodes a conserved NAD+-dependent protein deacetylase that modulates life span in yeast, worms, and flies, and stress response in mammals. Valter Longo of the University of Southern California, USA, discussed new results from studies on chronological aging of nondividing cell populations (4). Lack of Sir2 and calorie restriction and/or mutations in the yeast Akt/SGK homolog Sch9 or components of the Ras pathways cause a dramatic life span extension, as well as a reduction in age-dependent DNA mutations and an increase in stress resistance. The latter effects may depend on the increased expression of genes involved in DNA repair mechanisms, stress resistance, metabolism, and sporulation, as identified by microarray expression analysis. However, Sir2 and Sch9 regulate different sets of genes. These results suggest that Sir2 inhibits entry into an extreme life-span extension phase, which is induced in yeast by starvation or by loss of Sch9 or Ras activity. Increased stress resistance and improved DNA protection and repair are major features of this extreme life-span phase.

Since the discovery that Sir2 regulates longevity in yeast, several groups have been interested in finding molecules that can alter the activity of sirtuins. David Sinclair (Harvard Medical School, USA) presented a new class of plant molecules, the so-called STACs (Sirtuin-activating molecules), that can activate Sir2 and promote longevity and stress resistance by mimicking calorie restriction in all animals tested so far, including yeast, Caenorhabditis elegans, Drosophila, and fish. One explanation for the observation that a plant molecule elicits effects in diverse animals is the "xenohormesis hypothesis," the idea that organisms have evolved mechanisms to respond to stress-signaling molecules produced by other species. In this way, organisms can be prepared for a deteriorating environment and a loss of food supply. Furthermore, in mouse models STACs can prevent cancer, diabetes, and neurodegeneration. Thus, the development of Sirtuin-activating drugs may be a promising therapeutical strategy to achieve the benefits of calorie restriction and prevent age-related diseases.

Sir2 and insulin/insulin-like growth factor 1 are the major pathways that impinge on aging in lower organisms. Laura Bordone of the Massachusetts Institute of Technology, Cambridge, USA, investigated a possible link between the two pathways in mammals. One of the major physiological regulatory pathways in response to high amounts of glucose is the induction of insulin secretion in pancreatic beta cells. Bordone discovered a new level of insulin regulation in which Sirt1, the mammalian ortholog of Sir2, functions as a positive modulator in response to increased amounts of glucose. Sirt1 represses expression of UCP2, which belongs to a family of mitochondrial inner membrane proteins (see "Uncoupling Insulin"). In cells with reduced Sirt1, insulin secretion is blunted as a result of increased amounts of UCP2, which reduces the synthesis of ATP during respiration. Thus, by controlling UCP2, Sirt1 regulates the amplitude of insulin induction by glucose. This mechanism may serve to regulate insulin production with respect to food intake.

The mechanisms by which calorie restriction extends replicative life span in yeast were discussed in detail by Brian Kennedy (University of Washington, USA). Large-scale genetic screens for longevity phenotypes using strains deleted for individual genes identified components of the TOR, PKA, and Sch9/Akt/SGK pathways. All three kinases regulate multiple cellular processes in response to nutrients. Calorie restriction typically increases life span in yeast, but failed to do so in the long-lived TOR-lacking mutant, suggesting that calorie restriction signals through TOR. Kennedy proposed a model whereby calorie restriction leads to reduced activity of nutrient-responsive kinases, thereby connecting cellular energetics to replicative life span.

Embryonic stem (ES) cells and germ cells need to maintain genomic integrity; high levels of DNA damage are not tolerable because these cells must retain the capacity to differentiate into multiple cell types. Peter Stambrook at the University of Cincinnati Medical Center, USA, compared the genome stability of somatic cells and stem cells. In adult somatic cells, mutations occur at high frequencies and accumulate with age; as a result, these mutations may manifest as somatic disease such as cancer. In contrast, the degree of DNA damage in ES cells occurs less frequently than in somatic cells. Thus, ES cells contain additional mechanisms to protect the integrity of their genome. One possible protective mechanism is the apoptosis of cells that have accumulated a mutational burden. Consistent with this hypothesis, mouse ES cells lack a G1 checkpoint and are hypersensitive to DNA damage.

Hair graying is one of the most obvious signs of aging in humans. Emi Nishimura (Dana-Farber Cancer Institute, Boston, USA) discussed the mechanisms of stem cell maintenance and their involvement in the process of hair graying (5) (see "Gray Matters"). Using transgenic mice (in which pigment-producing melanocytes were marked with an easily detectable protein) and aging human hair follicles, she demonstrated that hair graying is caused by defects in the self-maintenance of melanocyte stem cells. The process is accelerated by a deficiency in Bcl2, which causes apoptosis of melanocyte stem cells but not of differentiated melanocytes, within the stem cell niche (the lower permanent portion of the hair follicle) at their entry in the dormant state. In addition, the physiological aging of melanocyte stem cells is associated with ectopic pigmentation or differentiation within the niche. This process is accelerated by mutations in the melanocyte master transcriptional regulator Mitf.

Maintenance of genome integrity has emerged as a major factor for determining longevity and cell viability. The genome is continuously exposed to DNA-damaging reagents. To protect their genetic information, organisms evolved a complex network of DNA repair systems. In his keynote lecture, Jan Hoeijmakers of Rotterdam University, the Netherlands, discussed the use of mouse models with defects in genome maintenance to obtain insights into human DNA repair-deficiency syndromes and to understand the molecular basis of aging. Mice with a partial defect in nucleotide excision repair (XpdTTD-deficient mice) exhibit a strong premature aging phenotype, but they are only moderately cancer prone. Complete repair deficiency in mice aggravates many premature aging symptoms. The correlation between the severity of DNA repair defects and phenotypic manifestations provides strong evidence for the "DNA damage" theory of aging. Hoeijmaker proposed that endogenous oxidative lesions compromise protein biosynthesis and trigger senescence and apoptosis. Moreover, enhanced levels of DNA mutagenesis as a consequence of defects in genome maintenance correlate with increased carcinogenesis.

In Werner syndrome, patients prematurely display many physical characteristics of human aging. Whereas it remains to be seen whether similar processes underlie normal and premature aging, Werner syndrome provides a useful model for the study of aging. Vilhelm Bohr (National Institute on Aging, Baltimore, USA) is studying pathways critical for DNA metabolism and genomic stability in Werner syndrome. He has found that the Werner syndrome protein is involved in base excision repair and thus contributes to the maintenance of genome integrity. Furthermore, the protein has a critical role in telomere processing.

Systems Biology of Aging

The third part of the "Advanced Genomics Session" focused on genome-wide analyses of aging pathways and system biology approaches for studying aging. A long-term goal of the so-called "interactome" (the entire cellular compendium of protein-protein interactions) modeling is to understand how global and local properties of complex macromolecular networks affect biological properties and how changes in such properties are implicated in human aging or human diseases. Denis Dupuy from the laboratory of Marc Vidal at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA, presented studies on the role of protein networks in the nematode C. elegans by generating interactome maps. In addition, the lab generated so-called "promoterome" maps, which reveal where (e.g., in what cells and tissues) and when (e.g., at what stage of development or under what conditions) the promoters of all genes are active. To generate such maps, the researchers created a library of constructs consisting of C. elegans promoters fused to the gene encoding the green fluorescent protein, microinjected these constructs into C. elegans, and monitored their expression. The integration of interactome and promoterome data, suggested Dupuy, may lead to tissue-specific signatures for all genes (6).

To gain a global perspective on which molecular pathways change with age, Stuart Kim (Stanford University Medical Center, USA) performed genome-wide expression analysis in different human tissues to determine how gene expression varies as a function of age. He presented a molecular portrait of the aging process in the kidney based on the expression analysis of 74 samples from patients of varying ages. More than 400 genes are differentially expressed in aging kidney; this expression profile differs from that of damaged tissue. Because the set of age-regulated genes in kidney overlaps in part with that of muscle and brain, Kim suggested a common signature for aging. Core mechanisms and pathways of the aging process include oxidative damage, fibrosis, and inefficient protein synthesis. Thus, the slight weakening of many pathways in old age may cumulatively cause substantial decline in cell function.

Hiroaki Kitano of the Systems Biology Institute, Tokyo, Japan, presented "biological robustness" as a fundamental and ubiquitously observed property of biological systems. Robustness enables a system to maintain its function despite external and internal perturbations. Traits that enhance robustness of the organism are often selected by evolution. Specific architectural features make a biological system robust, and these might be universal to any robust system capable of evolving. Basic mechanisms that provide robustness to the system are system control (e.g., negative and positive feedback), modularity, alternative mechanisms (e.g., "fail-safe mechanisms"), and decoupling. These mechanisms must be organized into a coherent architecture to be effective at the level of the organism. However, identification of the basic architecture of a robust system and the associated trade-offs will provide a better understanding of complex diseases. According to C. Franceschi, centenarians are an example of humans with increased robustness.

Organ Dysfunction and Regeneration

The morning session of the last day of the meeting was organized to illustrate the biology of aging in the context of organ dysfunction and regeneration in various model systems, including Drosophila, mouse, and human stem cells. Drosophila is the simplest genetically tractable model system with a heart (a simple tube in flies). It thus provides a unique opportunity to study the genetic control of aging in the heart, as discussed by Rolf Bodmer (Burnham Institute, La Jolla, USA). Using image-based heart-function assays, he found that the risk of flies' heart failure dramatically increased with age and that the heartbeat became progressively arrhythmic. Life span-affecting pathways including insulin and TOR signaling were shown also to regulate heart function. Flies with mutations in InR (insulin receptor), CHICO (insulin receptor substrate), and TOR (target of rapamycin) did not experience a decline in cardiac performance with age compared to wild type. Overexpression of components of the phosphatidylinositol 3' (PI3)-kinase signaling pathway, which is involved in muscle cell development, including InR, the PTEN tumor suppressor, or the FOXO forkhead transcription factor, improved cardiac performance (7). Bodmer concluded that insights into cardiac-specific aging mechanisms are likely to impact treatments of age-related cardiac malfunction and disease in humans.

The availability of invertebrate model systems greatly facilitates genetic analyses of aging, but the complexity of the molecular pathways involved in mammalian systems is much greater. Nadia Rosenthal (EMBL-Monterotondo, Rome, Italy) showed that modulating key signaling pathways in the adult mouse restores injured or degenerated tissues. Transgenic expression of a locally acting isoform of IGF-1 promotes efficient tissue repair of damaged skeletal and cardiac muscles and prevents muscle atrophy in heart failure. In skeletal muscles, IGF-1 suppresses NF{kappa}B signaling, thereby modulating muscle hypertrophy and muscle strength. Taken together, the data presented suggest that it is possible to recapture embryonic regenerative capacity in adult animals by modulating key signaling pathways.

Age-related defects in stem cells can limit proper tissue maintenance and, thus, contribute to a shortened life span. Three presentations focused on the role of stem cells in the biology of aging. In muscles, the ability of human progenitor cells to maintain, repair, or replace injured tissue is critical to avoiding muscle loss. Aged muscles have less regenerative potential than young muscles. Thomas Rando (Stanford University Medical Center, Stanford, USA) showed that about half of primary muscle stem cells undergo asymmetric segregation of the DNA template strands during mitosis. The cells that maintain their stem-like properties retain the DNA template, which is the older and, thus, more reliable DNA strand, whereas the stem cell progenies obtain the DNA copies. Rando also suggested that age-related impairment of muscle regeneration is not due to an irreversible depletion of stem cells but may in fact be amenable to systemic treatment to promote more effective tissue repair and maintenance.

Gerald de Haan (University Medical Center Groningen, Groningen, The Netherlands) reviewed mechanisms and molecules involved in the aging of hematopoietic stem cells. He suggested that stabilization of the chromatin structure by overexpression of a novel factor (Ezh2) preserves hematopoietic stem cell potential after replicative stress induced by serial transplantation of bone marrow cells. However, repression of stem cell senescence leads to preleukemic myeloproliferation. In summary, de Haan identified the gene Ezh2 (enhancer of zeste homolog 2) as a key player in balancing senescence and self-renewal pathways in stem cells.

Margaret Goodell (Baylor College of Medicine, Houston, USA) demonstrated that hematopoietic stem cells of aged mice are functionally defective, as indicated by limited tissue maintenance, but that aged mice have a greater number of such cells than do young mice. Expression analyses point to a broad dysregulation of the expression in several gene clusters rather than mutations in a small subset of aging-specific genes. Instead, these broad epigenetic changes may drive both functional attenuation and increased disposition to cancer with age.

High-Content Technologies

For the last session of the meeting, the organizers collected a fascinating set of experts to discuss new and advanced technologies to study aging on a genome-wide or systems level. Whereas these technologies have been primarily applied to the study of cancer and other diseases, the same principles apply to the study of aging.

Thomas Werner from Genomatix Software GmbH (Munich, Germany) summarized the logic behind advanced DNA microarray strategies and the advantages they provide over more traditional molecular biology techniques. Thomas Joos (Natural and Medical Sciences Institute, Reutlingen, Germany) established protein microarray-based systems that are capable of detecting marker proteins directly from biopsy material of tumor patients. The development of miniaturized and multiplexed immunoassays, which allow the measurement of several dozen different analytes from limiting amounts of samples, may evolve into a key technology for the characterization of complex samples. Yoshinobu Baba (Nagoya University, Nagoya, Japan) described recent developments in nanotechnologies based on the nanofabrication, molecular nanotechnology, and nanomaterials that can be applied to studying aging. He demonstrated how these technologies help to develop novel methods to analyze different biomolecules, including DNA, RNA, and proteins for applications in genomics and proteomics. He ended his talk by demonstrating how quantum dot anti-CD conjugates is a powerful tool to diagnose cancer in the early state, as well as for cancer therapy by provoking apoptosis in cancer cells (8).

Conclusion

Palermo is a unique place for a meeting of a "young" scientific discipline such as aging research. Sicily is where Archimedes initiated modern mathematics and physics and where Empedokles died while exploring the inside of the Aetna crater. Palermo was the capital of the medieval Norman kingdom where ancient Greek heritage, rational Arab science, and northern European curiosity met one another. Every participant at the conference could not help but be touched by this vivid historical background, which made the conference all the more enjoyable. We enjoyed the lively discussions during the scientific sessions and the well-attended poster sessions and anticipate future meetings of the growing aging-related research family.


May 24, 2006
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Citation: A. Nebel, E. Schaffitzel, M. Hertweck, Aging at the Interface of Stem Cell Renewal, Apoptosis, Senescence, and Cancer. Sci. Aging Knowl. Environ. 2006 (9), pe14 (2006).








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