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MEETING REPORT |
1 International Longevity Center-USA, New York.
2 University of Idaho, Moscow.
3 Albert Einstein College of Medicine, New York.
4 Sequenom, Inc., San Diego, California.
5 University of Connecticut Health Center, Farmington.
6 University of California, Los Angeles.
7 National Institute on Aging, Bethesda, Maryland.
8 Boston Medical Center, Massachusetts.
9 University of Maryland School of Medicine, Baltimore.
10 Ellison Medical Foundation, Bethesda, Maryland.
AN early indication that not only environmental and behavioral factors but also genes can influence the rate of aging of individuals within a species comes from the identification of long-lived strains of fruit flies (1,2). A more recent indication was the observation that, among breeds of dogs, longevity inversely correlates with body size (3,4). Both of these observations suggest the existence of genes that can affect longevity. Such genes have been variously called longevity assurance genes, longevity enabling genes, longevity-associated genes, longevity genes, or gerontogenes. In this report we will use the term "longevity genes." Because longevity genes may mean different things to different people, it is important to sort out the nuances of different kinds of genes at the beginning. Longevity genes may manifest themselves in a variety of ways, including the following:
Whereas the over-expression or ablation of almost any gene may decrease life expectancy, the intention here is to focus on genetic changes that increase life expectancy or shorten life expectancy, if they do so with indications of premature aging. We suggest that these genes be sorted into distinct theoretical categories. Seven categories are described below with comments, where appropriate, about the nature and quantity of human genes that might be found in these categories. [Since this workshop, George Martin has published 2 review articles that also review classes of gene action with respect to longevity (5,6).]
Categories of Longevity Genes
Although the genes of primary interest for understanding aging are the ones that increase life expectancy when either over-expressed or mutated, other genes may be informative about a variety of age-related changes that influence life expectancy in other ways. It is important to recognize that there are only a few traits in the invertebrate systems that can be used as a measure of organismic aging. Thus, the best measure of retarded aging in invertebrate systems is usually increased life expectancy.
Genes That "Cause" Aging
This hypothetical category includes genes that evolved to bring about the aging process. Most gerontologists believe there are no such genes in most species, including humans, because a gene that promotes aging would most likely decrease reproductive fitness and therefore would be subject to negative selection.
Genes That Alter Longevity Because They Modulate the Risk of Early Life Pathology and Disease
Genes that cause or increase the risk of pathology or disease may lead to a dramatic diminution of life span but may not provide important insights into aging. Therefore, while there may be a large number of such genes, they should be considered to be longevity genes only if it can be shown that mutant alleles accelerate multiple aspects of aging. In humans, there are probably a good many genes that affect the risk of early life pathology and disease. Examples include tumor-suppressor genes such as RB and BRCA1, the Hutchinson-Gilford gene, and a whole host of mutated genes responsible for the so-called inborn errors of metabolism. Few, if any, of these should be considered to be true longevity genes (7).
Genes That Affect What Kind of Old Individual You Are
There are thousands, perhaps tens of thousands, of these genes in mice and humans. Such genes might be more difficult to identify in invertebrates because death is not currently associated with well-characterized pathology. The differences in these genes among humans help to determine which and how soon individuals will become gray or bald or develop specific pathologies such as osteoporosis, macular degeneration, or Alzheimer's disease.
Genes That Extend Life Expectancy or Maximum Life Span
Such genes are being increasingly found in model systems, especially in nematodes and fruit flies, and examples in mice are starting to appear. Some of these genes affect processes such as response to growth hormone, insulin-like signaling, and response to stress; genes of this type influence life expectancy in a wide range of organisms. These longevity genes may also influence aging per se by regulating pathways that modulate the rate of aging, but data showing this are scarce. The best documented example is the Snell (Pit1dw) dwarf mutant mouse (8), which is not only long-lived but also shows delayed development of both age-sensitive immunological changes (cellular aging) and collagen cross-linking (extracellular aging), as well as deceleration of both lethal illness and incidental pathology such as arthritic changes. Alleles of this sort exist in humans, but they are harder to demonstrate in this long-lived species than in short-lived animal models. The best way to identify these genes may be to first identify them in invertebrate and mammalian models.
Naturally Occurring Alleles and Allele Combinations That Alter Life Expectancy Because They Affect Aging
If there are any polymorphic genetic loci that influence the aging rate within a species, they probably include a large number with very small effects and at least a few with detectably large effects, as demonstrated by Miller and colleagues (9) and Jackson and colleagues (10) in mice. It is hoped that mice such as these will be particularly useful for asking questions about alleles of genes that differentially influence the rate of aging.
Candidate Genes Assumed to Influence the Rate of Aging Because of the Function of the Proteins Coded by These Genes [Also Termed "Longevity Assurance Genes"]
Examples of candidate genes include genes coding for proteins that either repair or prevent damage to cellular components. Under some conditions, naturally occurring alleles of such genes could alter the rate of aging. A possible specific example for this category is the gene for methionine sulfoxide reductase (11,12). If such genes exist in mice, it is expected that similar genes will usually influence longevity in humans. Human examples might include genes for DNA repair and antioxidant defense systems.
Genes That Influence Life Expectancy Differences Among Species
These are the real longevity genes of interest and should explain the wide differences in the rate of aging among diverse species such as nematodes, fruit flies, mice, and humans. They should also explain why similarly sized rodents and birds (e.g., rats, pigeons) and different species of rodents or fish (e.g., mice vs naked mole rats) sometimes have anomalous life expectancies. No genes in this category have yet been unequivocally identified, but it is posited that these genes will regulate the pace of multiple developmental and degenerative processes, much as caloric restriction appears to do, but to a much greater extent (13).
Lessons From Invertebrate Model Systems
Nematodes (Caenorhabditis elegans)
age-1 was the first single gene mutation shown to extend life expectancy in any organism (14,15). This was followed by the demonstration by Kenyon and colleagues (16) and Larsen and colleagues (17) that Caenorhabditis elegans daf-2 and daf-23 mutants are also long lived. Subsequently, age-1 and daf-23 were shown to be the same genetic locus based on their failure to complement (18,19) and to code for a protein with homology to the enzyme phosphatidylinositol 3-kinase (19). These results were quickly followed by the identification of other C. elegans mutations and manipulations that increase life expectancy, including mutations that alter the mitochondria or the ability to eat, laser ablation of specific cells, changes in food composition, or drug administration.
Thus, regulation of life expectancy of C. elegans can be influenced by at least 3 important pathways or processes: insulin-like signaling, stress resistance, and metabolic rate. These processes overlap to some extent, and all have putative mammalian parallels.
Fruit Flies (Drosophila melanogaster)
The discovery that nematode mutants with an attenuated insulin-like signaling pathway have increased life expectancy spurred attempts to determine whether the same would be true in fruit flies. Support for this point of view has been obtained (20), but it is not clear why some effects are much greater in females than in males (21).
Research on fruit flies has identified several new longevity genes. In the mutant called Indy (I'm not dead yet), partial decreases in this transporter protein significantly increase life expectancy without a significant change in either reproduction or physical activity. The Indy mutation is a partial loss-of-function mutation, suggesting that normal levels of this protein are not optimal for life expectancy. This mutation is particularly interesting because of its possible relevance to the mechanistic basis of caloric restriction. Rogina and colleagues (22) suggest that "these mutations may create a metabolic state that mimics caloric restriction, which has been shown to extend life-span." Another way to extend life expectancy is to over-express the hsp70 gene, which codes for a heat-shock protein (23). Such proteins are assumed to increase survival by preventing denaturation of proteins in response to stress.
Another longevity gene is the methuselah (mth) gene that codes for a putative transmembrane signal transduction protein whose specific role in vivo is unknown, although these mutants have increased resistance to stress (24). Over-expression of the gene coding for methionine sulfoxide reductase in fruit flies increases life expectancy (12), providing another example of the relationship between stress resistance and longevity.
In summary, regulation of life expectancy in fruit flies may be influenced by attenuation of the insulin-like signaling pathway and/or metabolic rate and is associated with stress resistance, all of which mirror the findings with nematodes.
Lessons From a Mammalian Model System
Because of their more complex anatomy, and our better knowledge of their physiology and metabolism, mice provide a very useful model system for a bridge between invertebrates and humans. At least 4 distinct genes (Pit1dw, Prop1df, Ghr, Ghrhrlit) have been identified in which loss-of-function mutations lead to dwarfism and increased mean and maximum longevity. These all affect either the production of growth hormone or the ability to respond to it, and the first 3 have been shown to reduce the levels of circulating IGF-1 (insulin-like growth factor-1), insulin, and body temperature (25). All of these dwarf mice live longer than normal, in agreement with results found in nematodes and fruit flies. Of considerable interest is the observation that caloric restriction further increases the life expectancy of Prop1df dwarf mice (26), suggesting that the mechanism by which these two pathways influence the rate of aging may be at least partially distinct.
Only 2 other genetic alterations that increase mouse life expectancy have been identified. These include a genetic intervention that appears to mimic caloric restriction (27) and a mutation in the p66shc gene (28). Over-expression of the gene coding for the urokinase type of plasminogen activator in the hypothalamus apparently down-regulates appetite, leading to lower food intake and smaller body size. The p66shc mutation occurs in a gene that codes for a protein that regulates cell death in response to oxidative stress with decreasing insulin-signaling. [Since this workshop, 2 other genetically altered long-lived mouse mutants have been described (29,30).]
Many genetically altered mice have been generated to determine whether enzymes involved in either preventing or repairing damage to cellular components (such as proteins, DNA, and membranes) play critical roles in aging. Foremost among these are DNA repair enzymes and antioxidant enzymes. Some of these genetic manipulations are of limited interest because the mice die very young, and thus it is unlikely that studying such mice will provide much information about normal aging. However, some short-lived models may be informative. An interesting short-lived mutant mouse model was reported recently by Tyner and colleagues (31). This heterozygous mouse carries 1 normal allele of the p53 gene and 1 truncated but still active allele of p53. Although these mice are very cancer resistant, they also develop age-related pathologies (e.g., osteoporosis, loss of subcutaneous fat, reduced rate of wound healing, muscle atrophy) and die about 20% sooner than usual. Another interesting but very short-lived mutant is the klotho mouse, which exhibits a similar syndrome resembling human aging (e.g., osteoporosis, atherosclerosis, skin atrophy) and dies by 10 weeks of age (32). The klotho gene is homologous to a gene for a putative membrane protein with ß-glucosidase activity. Humans with polymorphisms in this gene are known, and homozygous individuals with 2 variant alleles of this gene are underrepresented in the older population (33).
In summary, putative parallels have been observed among nematodes, fruit flies, and mice, assuming that the growth hormone-related mutations act by reducing insulin-like signaling in mice. At least some of nematode, fruit fly, and mouse mutations may mimic changes induced in mice by caloric restriction.
Transition From Animal Models to Humans
Major questions arising from these studies with animal models are:
One example of the difficulty encountered comparing the effect of natural human mutations with targeted mouse mutations is provided by the growth hormone receptor gene (GHR). Humans lacking growth hormone receptor function are known, and these Laron syndrome patients are characterized by short stature, facial dysmorphism, obesity, low serum glucose and IGF-1, and delayed puberty (34). More than 220 cases have been reported so far, but these represent at least 25 different mutations (partial gene deletions and nonsense and missense point mutations), so there are also various phenotypes (35). Furthermore, longevity data on these human cases appear to be scarce. The oldest patient with Laron syndrome in the Israeli cohort is only 70 years old. However, fragmentary information for the "Little People" of Krk with mutations in the PROP1 gene suggest that these individuals may be long lived (25,36); at least 1 patient lived for 91 years. Thus, while either complete growth hormone deficiency or the inability to respond to growth hormone might not be the optimal strategy for manipulating life expectancy and aging in humans, it is at least possible that moderate depression of circulating growth hormone and IGF-1 levels at early ages might lead to lower risk of age-related diseases at older ages. Such a preventive strategy would most likely involve direct manipulation of the IGF-1 signaling pathway by nongenetic interventions. However, although decreased insulin-like signaling appears to increase life expectancy in invertebrates, similar mutations in humans might cause insulin resistance, which would be life shortening (e.g., rare patients with leprechaunism and type A syndrome of insulin resistance due to insulin receptor mutations). It is not clear at this time how to resolve this interspecies dichotomy.
Success in identifying human longevity genes will require the recruitment of centenarians and their long-lived siblings and/or long-lived multigenerational families for genetic analysis. Candidate genes can be selected for study based on the results of studies with animal models. Association analysis can then be used to identify genes that are either more or less common in long-lived individuals; this approach has already identified APOE (apolipoprotein E) gene alleles as risk factors for both aging and Alzheimer's disease (37). Identification of human longevity genes will be greatly facilitated by the knowledge gained from the Human Genome Project.
The value of understanding the genetic basis of aging and longevity is to increase the potential for rational drug discovery related to reducing the incidence and/or delaying the onset of age-related disease. Thus, emphasis should be placed on research leading to the discovery of useful drug interventions to improve the health of older people and to prevent disability.
Acknowledgments
This report is based on an interdisciplinary workshop cosponsored by the International Longevity Center-USA, American Federation for Aging Research, Ellison Medical Foundation, Glenn Foundation for Medical Research, Institute for the Study of Aging, and Canyon Ranch Health Resort.
Address correspondence to Robert N. Butler, MD, ILC-USA, 60 East 86th Street, New York, NY 10028. E-mail (c/o): milagrosm{at}ilcusa.org
Footnotes
James R. Smith,, PhD, Decision Editor
Received January 27, 2003
Accepted May 2, 2003
References
This article has been cited by other articles:
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  A. M. Berzlanovich, W. Keil, T. Waldhoer, E. Sim, P. Fasching, and B. Fazeny-Dorner Do Centenarians Die Healthy? An Autopsy Study J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2005; 60(7): 862 - 865. [Abstract] [Full Text] [PDF]
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