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LECTURE SUMMARY |
College of Biological Sciences, University of Minnesota, St. Paul.
Address correspondence to Huber R. Warner, PhD, Associate Dean for Research, College of Biological Sciences, University of Minnesota, St. Paul, MN 55108. E-mail: warne033{at}umn.edu
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This article briefly summarizes the Kent Award Lecture I gave at the annual meeting of The Gerontological Society of America held in Dallas, Texas, in November 2006. Cell death is a normal response of cells to cytotoxic damage due to both internal and external threats, and this cell loss is normally countered by proliferation of neighboring cells and/or replacement of these cells from progenitor cell pools. Maintaining tissue homeostasis is a critical challenge during aging, and this article describes a few aspects of the dynamic cell turnover that occurs continuously in vivo, with particular reference to the adverse effects of mutations that accelerate cell death through dysfunctional DNA metabolism, and how these events might contribute to aging in general.
Three early milestones in aging research were already well past by that time, but they have continued to set the stage for later progress. These included the demonstration that caloric restriction extends the life span of rodents and delays the onset of age-related disease (2), Harman's hypothesis that oxidative damage is a major risk factor (3), and Hayflick's demonstration that human fibroblasts have a finite life span in terms of number of population doublings when grown in culture (4). These three insights and observations formed the basis for much of the basic research funded by the NIA since 1984 in response to the series of mechanistic initiatives listed in Table 1.
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Four of these initiatives (1,3–5) have been robust elements of NIA's overall research agenda; in fact, the longevity assurance gene initiative, developed and managed by Anna McCormick of the NIA's Biology of Aging Program (BAP), has undoubtedly been the most successful initiative launched by the BAP in terms of recruiting new investigators into aging research and producing novel information about longevity regulation in animal models, including yeast, nematodes, fruit flies, and mice. Work funded by these initiatives identified a number of proteins with effects on longevity, including: (i) three proteins in the insulin-signaling pathway (5–7), (ii) protein deacetylases (8), (iii) growth hormone (9), (iv) a dicarboxylic acid transport protein (10), and various antioxidant enzymes, to name a few. These results were largely due to demonstrating either that mutations in certain genes or that overexpressing certain other genes, increased life span. Increasing life span has become the well-accepted standard for showing that any gene and its protein product play a role in longevity regulation (11). Nevertheless, it is possible that short-lived models, if carefully chosen, could be informative about aging mechanisms (12).
The initiative listed in Table 1 on cell death mechanisms has not been as successful in generating convincing evidence about the basic mechanisms of aging. Although cell death clearly plays a role in degenerative diseases characterized by net cell loss, for example, neurodegenerative diseases (13), whether and how cell death plays a more general role in aging is not so clear. Even though many have assumed that failure to continue to replace lost cells from stem cell pools could be a factor in aging, a demonstration that this is a general phenomenon is lacking. The purpose of this presentation at the 2006 meeting of The Gerontological Society of America was to summarize the current state of knowledge regarding this possibility.
DNA DAMAGE AND ITS IMPLICATIONS FOR AGING
Damage to both nuclear and mitochondrial DNA occurs continuously as has been documented by many investigators, especially by Dolle and his coworkers (14). However, it is not exactly clear how DNA damage promotes aging. Tissues differ with respect to their sensitivity to damage, but the impact of the damage apparently depends on the nature of the damage (Figure 1). Mutagenic damage such as transition and transversion mutations may lead to cancer, for example, by inactivating a tumor suppressor protein, whereas cytotoxic damage such as DNA cross-links can block DNA replication and/or transcription, thus inducing either cell senescence or apoptosis (here and elsewhere, apoptosis is used as a surrogate word to mean any form of programmed cell death). If such cell loss becomes excessive, it could well promote development of adverse age-related phenotypes (15). What kind of evidence exists to suggest that this scenario could be true besides the obvious loss of cells that contributes to Alzheimer's and other neurodegenerative diseases, ischemia, retinal degeneration, autoimmunity, etc.?
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Over the past few years, a number of mouse mutants has been generated that prematurely develop various age-related pathologies. Some of these mutants are listed in Table 2. All of these mutations not only affect some aspect of DNA metabolism, but also increase the vulnerability of cells to apoptosis. The common features of these models are that (i) they are short-lived, but not dramatically so except for the Lmna mutant; (ii) they develop aging-like phenotypes early, especially in mesenchymal tissues; and (iii) they have diminished growth rates. The critical questions are what is the timing mechanism, what causes the short stature, and why are the mesenchymal tissues particularly affected? Presumably, either something is accumulating or something is being lost with increasing age to influence the length of time until the organism fails and begins to show adverse aging-related phenotypes. One possibility is that what is failing is the ability of stem cell pools to continue to replace lost cells in the face of excessive apoptosis. If this is so, the root cause might be exhaustion of stem cell pools, dysfunction of the pools, or both.
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Tyner and coworkers (16) and Dumble and coworkers (17) reported isolating a p53 mouse mutant with intriguing properties. The p53+/m protein tetramer is hyperactive and delays cancer incidence, but the mice are somewhat short-lived (80% of normal) despite the reduced cancer load. These mice also develop age-associated organ atrophy coupled with reduced regenerative responses, suggesting that the hyperactive p53 protein may be inhibiting stem cell proliferation in their niches while promoting apoptosis in the peripheral tissues. The age-related phenotypes include early osteoporosis, poor wound healing, dermal thinning, muscle atrophy, and reduced subcutaneous adipose tissue. These mutant mice also have reduced hematopoietic stem cell populations.
MUTATIONS IN THE XPD GENE
De Boer and coworkers (18) generated a mouse with a mutation in the XPD gene that codes for a DNA helicase involved in both transcription and DNA repair. These mice are somewhat deficient in DNA repair, but severely compromised in transcription, presumably due to stalled transcription complexes that promote apoptosis. They are short-lived and also develop age-related phenotypes comparable to those in the p53+/m mice. In particular, the nature of the premature osteoporosis has been examined by Raman microscopy showing that the bone mineral content in these mice is reduced, although the bone matrix content is normal (19), which is consistent with the lower osteogenic potential seen with increasing age in humans.
OTHER PRO-AGING MUTATIONS
Mutations in other genes that promote early death in mice, with accompanying typical age-related phenotypes, include p63 (20), Ku86 (21), PolgA (22), and Lmna (23) (coding for a p53-like protein, an enzyme required for double-strand break repair, mitochondrial DNA polymerase, and a nuclear envelope protein, respectively; Table 2). The p63 mutant mice are not cancer-prone but die prematurely, resembling the phenotype of the p53+/m mice. Although the PolgA mice synthesize mitochondrial DNA, the synthesis is error-prone so these mice accumulate mutations, but not due to increased oxidative stress, although the cells are prone to apoptosis (24). The Lmna mice resemble the human phenotypes of Hutchinson-Gilford syndrome (HGS), and their cells are subject to premature apoptosis as are cells from HGS patients (25). Thus, the common features of these mutants are vulnerability to cell death, premature development of aging-related phenotypes in mesenchymal tissues, and reduced life spans, and all of the defects affect some aspect of DNA metabolism. Whether cell replacement potential is compromised has not been directly studied in any of these systems, but the phenotypes suggest it could well be another common feature.
STEM CELL REPLACEMENT POTENTIAL AND AGING
Whereas replacement of lost cells with progenitors from stem cell pools may be difficult to measure directly, decreasing growth rate and organ atrophy with increasing age suggest that this could be a problem in at least some of the prematurely aging mouse models. A recent burst of articles related to p16INK4a expression suggests that this may also be a factor during normal aging (26–29). Aging causes an increase in p16INK4a, a potent tumor suppressor that promotes longevity by suppressing the development of cancer (26), but also induces cell senescence. However, this may have a cost in terms of suppressing stem/progenitor cell proliferation, thereby reducing tissue regeneration and repair and reducing longevity. This is a typical example of antagonistic pleiotropy in which a function that is beneficial early in life may become detrimental later in life. Manipulating the expression of p16INK4a in mice shows that increasing expression decreases brain neurogenesis (27) and pancreatic islet regeneration after exposure to a beta-cell toxin (28), whereas the absence of p16INK4a improves the repopulating potential of hematopoietic stem cells (29) and improves the stress tolerance of cells. Beausejour and Campisi (26) point out that, although this raises the possibility of treating aging-related diseases with inhibitors of p16INK4a activity or expression of the gene, the strategy would be risky because p16INK4a-deficient mice die early from cancer.
In a comprehensive review, Sethe and coworkers (30) summarized what is currently known about aging of mesenchymal stem cells (30). They concluded that there is evidence to suggest aging-related changes in quantity of stem cells, as well as changes in their ability to regenerate and differentiate. For example, researchers have concluded that the chondrogenic potential of stem cells in culture declines with age (31), whereas hair graying has been attributed to selective apoptosis of melanocyte stem cells, but not of differentiated melanocytes in the niche (32). In contrast, muscle differentiation programs are qualitatively compromised in Lmna-defective myoblasts, resulting in impaired myogenic potential (33).
The above results emphasize the general need to devise stem cell therapies for age-related diseases characterized by cell loss to replace these lost cells with either endogenous adult stem cells or exogenously supplied stem cells. Some success has been achieved from both approaches. Conboy and Rando (34) increased the regenerative potential of satellite cells by inducing Notch activity; they also demonstrated that young mice contain a circulating factor that activates old satellite cells. Sun and Bartke (35) showed that increased insulin-like growth factor I (IGF-I) in brain improves neurogenesis from endogenous precursors, apparently by reducing apoptosis. In contrast, LaBarge and Blau (36) used bone marrow–derived cells to generate muscle fiber in response to injury, and Orlic and coworkers (37) also used bone marrow cells to replace cells lost due to cardiac infarct damage. Success has even been reported using heterologous cord-blood cells to treat children with Hurler's syndrome, a progressive deterioration of the central nervous system due to accumulation of mucopolysaccharide (38); this success was achieved without doing whole-body irradiation to destroy existing bone marrow cells. These results prompted the NIA to issue a program announcement in 2005 to encourage attempts to test stem cell therapy in mouse models of premature aging like those listed in Table 2.
HUMAN PROGEROID SYNDROMES
The above results raise the question of whether compromised cell replacement has a causal role in human progeroid syndromes. This seems like a possibility in childhood progeria, that is, HGS. Fibroblasts from HGS patients are prone to apoptosis (25), and growth failure then begins to manifest itself in the children in year 2. Halaschek-Wiener and Brooks-Wilson (39) have argued for such an interpretation of the pattern of segmental pathologies associated with HGS, in the absence of increased cancer risk. In general, the tissues most affected are those for which stem cells are required for regeneration or repair of ongoing damage (e.g., subcutaneous adipose tissue and bones), tissues undergoing mechanical stress (e.g., the vascular system and joints), and tissues required to support continuous growth (e.g., hair follicles and nails), whereas cataracts and neurodegenerative pathologies are not observed in HGS children.
Werner's syndrome (WS) is characterized by both growth failure and increased cancer risk. Patients with WS lack a DNA helicase that plays many roles, including a critical structural role in optimizing DNA repair (40). It is possible that these individuals suffer from both pathways indicated in Figure 1; genome instability leading to cancer, but also some compromised DNA metabolism leading to increased apoptosis. Moderately increased apoptosis might account for the much later onset of symptoms in WS patients, that is, in the late teens versus second year of life for WS and HGS, respectively. In contrast, Bloom's syndrome (BS) patients, who also lack a DNA helicase, are born small and remain small throughout their short life of about 20 years. Although cells from BS patients are very prone to p53-dependent apoptosis due to stalled replication forks (41), they do not develop typical age-related phenotypes, indicating that apoptosis alone is not sufficient to cause these phenotypes.
CONCLUSIONS
The results discussed above suggest that we need to know much more about whether and why cell replacement potential decreases with increasing age, and if so, how this contributes to the various phenotypes that are routinely associated with aging in humans. Even more importantly, we need to understand why individuals within a population age differently, as only then will we understand how to delay the onset of such aging phenotypes that occur in some individuals, but not others. It appears that progeroid mouse mutants may provide an opportunity to more easily study these phenotypes in models where dramatic changes occur, in contrast to the almost imperceptible changes that occur with time during normal aging in humans. Although we will not know whether the events that occur in rapidly aging mice perfectly mimic aging-related changes in humans, it is likely that useful insights will be gained that may prove useful in understanding human aging (12), and for developing strategies that may be useful in maintaining cognitive and physical functioning into late life in humans.
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I sincerely thank the National Institute on Aging (NIA) for the opportunity to work in the area of biogerontology during my tenure there from 1984 to 2005, Dr. Richard L. Sprott for his support and mentoring from 1984 to 2000, my other coworkers at the NIA during the period from 1984 to 2005, and The Gerontological Society of America for the 2005 Kent Award honoring my achievements in this field while I was an employee of the NIA.
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Decision Editor: Estela E. Medrano, PhD
Received April 19, 2007
Accepted June 25, 2007
References
This article has been cited by other articles:
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  H. R. Warner Research on Hutchinson-Gilford Progeria Syndrome J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 775 - 776. [Full Text] [PDF]
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L. B. Gordon, C. J. Harling-Berg, and F. G. Rothman Highlights of the 2007 Progeria Research Foundation Scientific Workshop: Progress in Translational Science J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2008; 63(8): 777 - 787. [Full Text] [PDF]
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