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Searching for Human Longevity Genes

The Future History of Gerontology in the Post-genomic Era

^a Department of Medicine, Divisions of Geriatrics and Endocrinology, and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
^b Division of Endocrinology, Diabetes, and Nutrition, University of Maryland, and the Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore

Nir Barzilai, Divisions of Geriatrics and Endocrinology, Department of Medicine, Belfer Building 701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 E-mail: barzilai{at}aecom.yu.edu.

Decision Editor: John E. Morley, MB, BCh

	Abstract

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
Over the last 30 years, a number of genetic and environmental factors that lead to decreased length of life have been identified. Unfortunately, much less progress has been achieved in identifying genes associated with longevity that protect from common diseases or slow the aging process. Recent compelling evidence supports a role for important genetic and environmental interactions on longevity in lower organisms. Although less is known in humans, commonality in molecular and biological processes, evolutionary arguments, and epidemiological data would strongly suggest that similar mechanisms also apply. The completion of the Human Genome Project and the rapid innovations in technology will make possible the identification of human longevity-assurance genes. This article reviews such evidence, its implications for the identification of human longevity-assurance genes, and the significance of finding longevity genes to human health and disease.

	Evidence for a Genetic Basis to Life Span in Cells and Lower Organisms

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
Cells placed in culture undergo a defined number of replications before senescing ⁽¹⁾. Large numbers of genes are involved in controlling the destiny of the cell to either replication or senescence ⁽²⁾⁽³⁾. Cell senescence may be determined by telomeres and by enzymes controlling their length ⁽⁴⁾. However, transgenic manipulation in mice decreased telomere length but did not elicit a full spectrum of classic pathophysiological symptoms of aging. After transgenic manipulation of telomerase, age-dependent telomere shortening and the accompanying genetic instability was associated with only a very moderate decrease in life span and a reduced ability to respond to the stress produced by wound healing and hematopoietic ablation ⁽⁵⁾. Taken together with the fact that cell division is minimal in major organs such as muscle, heart, and brain, it is possible that regulation of telomere length plays a contributing role in longevity but is not likely to be a major determinant of life span.

Another attractive theory is that oxidative damage and production of free radicals are associated with aging and its phenotype ⁽⁶⁾. In support of the free-radical hypothesis, longevity in mice was moderately enhanced by preventing oxidative-induced apoptosis through deletion of the p66^shc protein ⁽⁷⁾. On the other hand, ubiquitous overexpression of CuZn superoxide dismutase, the major enzyme that metabolizes free radicals, was not sufficient to extend life span in trangenic mice ⁽⁸⁾.

A more dramatic extension of life span (Table 1 ) has been achieved in lower species (with <10% of the number of human genes), such as nematodes (Caenorhabditis elegans) and flies (Drosophila). One of the most remarkable life extensions (three- to fivefold increase) was achieved by genetically altering the primitive insulin-signaling pathway (daf-2 and daf-16) of the nematode ⁽²⁾⁽⁹⁾. A less well-defined genetic mutation (Methuselah) was induced in Drosophila ⁽¹⁰⁾, which increased life span by 35% and enhanced resistance to various forms of stress. The modulation of stress response by a signal transduction pathway in the latter study suggests that stress modulates life span. However, data in lower organisms should be cautiously applied to humans because of the complexity of human systems, associated with many more genes, and because life span and causes of death in humans are different than those in lower species. For example, mutations in homologs of the nematode insulin-signaling pathways have been described in humans suffering from obesity and diabetes. Thus, these mutations may have created a kind of obese (thrifty) phenotype that was beneficial to extend life span in the nematode, but is not beneficial to humans living in times of nutrient excess. These examples highlight the need to determine the relevance of mutations in lower species to humans, who are different in their much longer life span, genetic complexity, and specific causes of death. However, longevity induced by genetic manipulations on lower organisms provides strong support for the concept that genes can control life span and that cellular and metabolic pathways may mediate this phenotype.

	Caloric Restriction Increases Maximal Life Span: Evidence for Interaction Between Genes and the Environment

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

Increasing evidence suggests that altered metabolic pathways, in particular those related to energy metabolism and regulation of fat mass, may play a major role in modulating life span ⁽¹¹⁾. Mirroring ad libitum fed animals, increased fat mass in humans is commonly accompanied by insulin resistance, a condition associated with the development of type 2 diabetes mellitus, hyperlipidemia, hypertension, atherosclerosis, and increased mortality. Insulin resistance is usually accompanied by hyperinsulinemia and abnormalities in glucose homeostasis that may increase the rate of oxidative damage and the formation of advanced glycation end products, which, in turn, may result in cellular dysfunction and accelerated senescence.

These obesity-associated metabolic abnormalities have been shown to respond to weight loss, similar to the effects of caloric restriction in rodents, suggesting that increased fat mass, particularly visceral fat, may be pathogenic. Increased fat is also associated with the secretion of a variety of fat-derived peptides, including leptin, tumor necrosis factor , plasminogen activator inhibitor 1 (PAI-1), and angiotensinogen, among others, which may explain the link between metabolic pathways and longevity. Leptin modulates many of the neuroendocrine changes commonly observed in caloric restriction models ⁽¹³⁾. Furthermore, leptin modulates hepatic and peripheral insulin action as well as regulates body fat distribution ⁽¹⁴⁾. Some of these peripheral actions were shown to be mediated by the ß3-adrenoceptor system ⁽¹⁴⁾. Interestingly, a common mutation in the ß3-adrenoceptor has been shown to be associated with insulin-resistance-syndrome–related traits, including increased body mass index, visceral obesity, insulin resistance and/or hyperinsulinemia, increased blood pressure, and an earlier onset of diabetes ^(15)(16)(17). Indeed, we found that elderly male Pima Indians who are homozygous for the Trp64Arg ß3-adrenoceptor variant are underrepresented in the population, suggesting early mortality ⁽¹⁶⁾.

It is important to note that most calorically restricted animal models are genetically homogeneous. Thus, any common manipulation will induce similar results in all individuals of the group. On the other hand, humans are genetically heterogeneous, and, therefore, individual responses to environmental manipulations (e.g., food and physical activity) will depend greatly on genetic background. Thus, variation in life span in humans may occur through a complex interaction between the environment and genetically determined biological responses. Some of these genetically determined biological responses may involve similar pathways to those affected by caloric restriction in animals.

	Longevity as an Inherited Trait in Humans

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
Although most studies agree that genetics influence longevity in humans, the magnitude of this effect is debated. A study ⁽¹⁸⁾ of children of nonagenarians suggested a strong relation between genetic influences and longevity, as did a study ⁽¹⁹⁾ that compared the life span of adopted children with that of their adoptive and biological parents. Studies of twins reared together and twins reared apart suggested, at most, a small genetic influence on longevity. In one study ⁽²⁰⁾, genetic factors explained no more than 30% of the variance in longevity, and, in the other study ⁽²¹⁾, this variance was less. Of note, these twin studies did not analyze the oldest-old survivors, nor did they compare the longer-living with the shorter-living subjects. In fact, a strong relationship between genetics and longevity was demonstrated when centenarians were included ^(18)(19). This suggests that genetic influences on longevity are greatest in the oldest-old adults. Indeed, a recent study by Perls and colleagues ⁽²²⁾ demonstrated that the siblings of centenarians are three to four times more likely to survive to the 10th decade of life compared with siblings of noncentenarians (Fig. 1). In addition, the immediate ancestors of Jeanne Calment from France, who died at the age of 123, recently were shown to be 10 times more likely to reach age 80 than was the ancestral cohort ⁽²³⁾. These studies support the concept that longevity is a familial trait likely to be inherited and points to extreme age as the phenotype for an initial approach in identifying chromosomal regions that harbor longevity-assurance genes.

View larger version (12K): [in this window] [in a new window]   Figure 1. Inheritance associated with exceptional longevity: risk ratio of survival for siblings of centenarians compared with siblings of subjects from the centenarian cohort who died at age 73 years. Adopted from Perls and colleagues (22).

	Genes and Longevity in Humans

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

Werner syndrome is an interesting disease that is highly relevant to aging. This is a rare autosomal recessive disorder characterized by the premature development of the aging phenotype, as well as a large number of age-related diseases, and is due to a mutation of a helicase gene ⁽³⁰⁾. This gene is important for the maintenance of cellular function through DNA repair. Potentially, gene variants that slow DNA damage or enhance DNA repair may slow aging and decrease aging-related diseases. These data provide compelling evidence that variation in genes that slow aging processes and that protect from aging-related diseases exist, and influence, aging and aging-related traits.

	Centenarians and the Search for Longevity Genes

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
Because longevity is familial, it is likely to be at least in part genetically determined. The data also suggest that the strongest genetic determinants of longevity exist in the oldest-old adults. For example, age-related increases in frequencies of certain HLA-DR alleles ⁽²⁶⁾, and in the frequency of a variant of PAI-1 ⁽²⁷⁾, were found in centenarians. When age is plotted against the log of mortality rate, it gives a straight line as the mortality rate increased exponentially with age ⁽²⁴⁾. Moreover, according to data from the National Center for Health statistics and the U.S. Bureau of the Census, the log of mortality rate falls below the expected at the ages of 95 to 100 years, suggesting that mortality rate is no longer increasing exponentially in this age group ^(31)(32). This observation is further supported in a study ⁽³³⁾ based on death certificates of nine million people who died over the age of 85. In that study, the mortality rate reached a plateau by the age of 95 years and, by the age of 100 years, it actually decreased. Although the mortality rate from cancers increases by approximately 10% per decade, it actually decreases after the age of 90 years. Moreover, after the age of 90 years, the mortality rate from all cancers decreases by more than 20% ^{(31)(32)(33)(34)} and from prostatic cancer by approximately 40%. Thus, those who have achieved an age of 95 years or older seem to be biologically unique; they have escaped disease-related mortality and also have the biological make-up for successful aging. Interestingly, because the ratio of women to men at age 100 is 5 to 1, the female phenotype contributes to longevity independently of other genetic characteristics. Thus, based on biological distinctions, differences in mortality patterns, and the marked decrease in cancer, centenarians are likely to possess the strongest genetic determinants of longevity.

	The Complexity in Identifying Longevity-Assurance Genes

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
The identification of gene variants for complex traits presents unique challenges. Candidate gene approaches, in which a gene is chosen based on function and the presumption that alteration in its function may affect the phenotype, have met with some success. There are limitations to such approaches. First, choosing the candidate gene requires a mechanistic knowledge of the underlying disease process, which is not known for most complex diseases. Second, the gene must be known and previously cloned. Third, once a candidate gene is chosen, it is often difficult to screen for sequence variation in all functional regions of the gene (e.g., regulatory regions), since they are usually not known. Finally, evaluation of a genetic variant, once found, requires large numbers of individuals (or families) with the trait of interest. Demonstrating association or linkage of a given polymorphism with the disease or trait may be very difficult, given the likelihood that the genetic variant will have a modest effect itself, because its phenotypic expression is likely to be dependent on other genes (genetic background), and that these will likely be environmental interactions.

In recent years, genes for several monogenic diseases (e.g., cystic fibrosis, Huntington's disease, hemochromotosis, Werner syndrome) have been identified through positional cloning ^(35)(36). This elegant approach makes no a priori assumptions about a specific gene or genes. Instead, hundreds of polymorphic markers, dispersed throughout the genome, are assayed in multiplex pedigrees to identify chromosomal regions that are inherited statistically more frequently in affected pedigree members than unaffected members; so-called linkage analysis, in which the log odds score is calculated. The markers showing linkage to the phenotype are likely to be in close proximity to genes that harbor the pathogenic mutation, which may be identified through physical mapping and/or positional cloning approaches. Although genomewide searches for complex diseases or traits hold great promise for a variety of age-related diseases, including hypertension, diabetes, osteoporosis, and Alzheimer's disease, difficulties due to the polygenic and heterogeneous nature of these disorders, and the contribution of environmental factors, are nontrivial. In addition to these difficulties, the identification of genetic loci influencing longevity presents unique challenges. For example, the definiition of longevity and its associated intermediate phenotypes is still being debated. Second, in the absence of detailed genealogies and longitudinal data, it is not possible to know definitively which individuals are or will be long-lived, and which are or will not be long-lived. Furthermore, subjects who died at early ages in accidents or war, or even of diseases due to enviromental and/or other genetic factors, may still have harbored longevity-assurance genes. Many of these problems may be minimized by the use of special founder populations, such as the Ashkenazi Jews and Amish, which are more genetically homogeneous ⁽³⁷⁾, and by use of statistical methods that are robust to these confounding influences.

	Perspective

Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 
Defining the environmental and genetic factors that influence longevity in humans will have profound medical implications. Identification of specific traits relevant to the aging phenotype and genes that promote longevity will provide important mechanistic insights into the molecular basis of aging. Furthermore, these studies will provide insights into how these genes exert their phenotypic influences. These insights may lead to interventions that can be used to promote survival in people who were not fortunate enough to inherit a genome predisposing them to longevity.

An extended life span must be accompanied by a good quality of life. Although aging processes may be biologically modulated in many tissues, longevity is also determined by escaping from common killing diseases: cardiovascular disease, cancer, and infection are the leading causes of death in adults. Thus, in addition to possibly finding genes that modulate the aging process, this research is also likely to identify genes that protect from these diseases. Consequently, the discovery of longevity-assurance genes will lead to fundamental understandings of the molecular basis of several important diseases. These insights may lead to novel preventive and treatment strategies for these diseases, which will have a profound impact on morbidity, mortality, and enhancing the quality of life in the elderly population. In practical terms, such discoveries also will have profound social and economic implications. For example, one study ⁽³⁸⁾ showed that medical costs in the last 2 years of life of a 60- to 70-year-old person dying of disease was approximately threefold greater than in persons dying after the age of 100. Furthermore, persons over the age of 100 had little or no medical expenses when they were between 60 to 70 years old. Thus, protection from diseases, as a preventive form of medicine, may be cost effective, once longevity is attained.

	Acknowledgments

 
Dr. Barzilai is a recipient of the Paul Beeson Physician Faculty Scholar in Aging Award and also received support for this study by grants from the American Federation of Aging Research, the National Institutes of Health (Grant R21AG16916), and the Albert Einstein College of Medicine (General Clinical Research Center Grant 1MO1RR12248). Dr. Shuldiner was also a recipient of the Paul Beeson Physician Faculty Scholar in Aging Award.

Received July 24, 2000

Accepted August 10, 2000

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Top Abstract Evidence for a Genetic... Caloric Restriction Increases... Longevity as an Inherited... Genes and Longevity in... Centenarians and the Search... The Complexity in Identifying... Perspective References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barzilai, N. Articles by Shuldiner, A. R. Search for Related Content PubMed PubMed Citation Articles by Barzilai, N. Articles by Shuldiner, A. R.