Genetics: Longevity Assurance

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Researchers have identified numerous longevity genes, variants of which predispose individuals to a longer life span than the average for a species (see Table 1). These gene variants, or alleles, may occur spontaneously in a fraction of the natural population (e.g., human apoE2) or they be created by researchers in laboratory organisms (e.g., mouse p66shc). A subset of longevity genes extends life span when additional copies are introduced (e.g., worm sir-2, yeast RAS2 ). The term longevity assurance gene, often used synonymously with longevity gene, should not be confused with premature aging (i.e., progeroid) genes, variants of which apparently accelerate aspects of the aging process (e.g., mouse klotho, human WRN ). Longevity genes have been subdivided into two classes. Private longevity genes increase longevity only in certain lineages, populations, or species, whereas public longevity genes are evolutionarily conserved and increase the longevity in a diverse group of species (Martin et al., 1996).

Why do longevity genes exist?

In the 1970s the prevailing view was that aging was the end point of a developmental program that served to remove older individuals from the population. This prompted a search for so-called death genes that dictated the aging process. However, today most scientists believe that there is no selection for aging and that aging is merely a by-product of natural selection. This new paradigm raises a question: If aging provides no selective advantage, how did longevity genes evolve? The answer lies in the distinction between aging and longevity. Although aging is generally believed to be an essentially random process, longevity is evolutionarily adaptive.

This idea was first formulated in the disposable soma theory (Kirkwood and Holliday, 1979), which is based on the premise that all biological activities come at a price. If an organism devotes resources to one activity, those resources are no longer available for other activities. Due to the competing priorities of reproduction, organisms can not afford to allocate the necessary amount of resources to body (i.e., somatic) maintenance to ensure indefinite survival. It follows that a species with a relatively high probability of being killed by extrinsic forces (e.g., starvation, disease, predation, and accidents) will have evolved to invest heavily in reproduction, so that its members develop rapidly and reproduce at a young age (Kirkwood et al., 2000).

Striking the optimum balance between reproduction and survival is as important for species as it is for individuals. During an individual's lifetime the environment is likely to change and, along with it, the optimal balance between reproduction and somatic maintenance. The majority of longevity genes appear to have evolved to boost somatic maintenance during harsh times and to increase growth and reproduction during good times.

An important corollary of the disposable soma theory is that the causes of aging should be primarily species-specific (i.e., private), whereas longevity assurance mechanisms should be evolutionarily conserved (i.e., public). This prediction has been supported by abundant experimental evidence. For example, a major cause of aging in baker's yeast is the accumulation of circular DNA molecules. In contrast, aging in nematode worms is apparently due to the accumulation of cellular damage caused by reactive oxygen species. Despite their having obviously different aging mechanisms, researchers have recently identified at least two public longevity genes that function in both organisms, SIR2/ sir2-1 and SCH9/akt-1 (Kenyon, 2001). Such findings highlight the potential for experimental organisms to provide clues about human longevity, even if their causes of aging are seemingly unrelated.

Human longevity genes

Although the study of longevity genes in humans is still in its infancy, there is overwhelming evidence that the human life span has a significant heritable component (Caurnil and Kirkwood, 2001). Studies of twins have suggested that genetics accounts for up to 30 percent of the variance in human longevity. An even stronger relationship between genetics and longevity was observed by analyzing the genetics of centenarians and their families. In one study, the siblings of centenarians were three to four times more likely to reach age 100 than were siblings of non-centenarians. Another study showed that the immediate ancestors of Jeanne Calment of France (who died at the age of 122, after breaking the record for human life span) were ten times more likely to reach age 80 than was the ancestral cohort (Robine and Allard, 1998).

Examination of the frequency of known gene variants in very old individuals has led to identification of five putative human longevity genes. A major problem in the identification of human longevity genes is that different studies often reach different conclusions. Scientists generally agree that the genes for apolipoprotein E (apoE ), angiotensin-converting enzyme (ACE ), and histocompatibility locus antigen (HLA-DR ) are genuine longevity genes (see Table 1). Genes for superoxide dismutase 2 (SOD2) and tyrosine hydroxylase (TH) have also been implicated in longevity. Human genes whose association with longevity is debated include those for cytochrome P-450, certain blood coagulation factors, and homocysteine methylation (MTHFR ). In 2001, Thomas Perls, Luis Kunkel, and colleagues reported the identification in one family of a region on human chromosome IV that predisposes for exceptional longevity (Puca et al., 2001). However, the individual gene or genes responsible have not yet been identified.

There are many genes in humans whose variants reduce life expectancy (e.g., the tumor suppressor gene, MSH2 ). However, these are not true longevity variants because they are known only to reduce the life span, not to extend it. The apoE gene, involved in lipoprotein metabolism, has been found to affect longevity most consistently. At least five studies have detected the apoE -epsilon2 variant more frequently in centenarians than in the general population. Even so, it has been suggested that the apoE is a not a longevity gene, but that the apoE -epsilon4 variant causes premature death by promoting atherosclerosis (Gerdes et al., 2000). This matter, which remains to be resolved, illustrates another difficulty in classifying human longevity genes.

Longevity assurance genes in model organisms

Much of what is understood about longevity comes from studies in model organisms such as baker's yeast (Saccharomyces cerevisiae ), nematode worms (Caenorhabditis elegans ), and fruit flies (Drosophila melanogaster ). Genetic screens for long-lived mutants have identified numerous longevity genes, many of which function in a conserved signaling pathway that regulates somatic maintenance and survival in response to environmental stress. In many species, including C. elegans and yeast, this regulatory pathway appears to be responsible for the longevity associated with calorie restriction.

Baker's yeast. The aging process and its regulation are better understood for yeast than for any other organism except, perhaps, nematode worms. There are two ways to define longevity in budding yeast. The more common measure is replicative life span, which is the number of offspring, or daughter cells, that a mother cell produces before she dies. Chronological life span is the length of time a population of nondividing yeast cells remains viable when deprived of nutrients. More than twelve yeast longevity genes have been identified. Most of these affect replicative life span, including genes for a sugar-processing enzyme, hexokinase 1 (HXK1 ); cyclic adenosine monophosphate production (CDC25 ); and the silent information regulator 2 (SIR2 ) (Defossez et al., 2001). Variants of these genes extend life span up to twofold by mimicking the effect of low food supply.

Unlike other model organisms, the precise mechanism by which many yeast longevity genes extend life span is known. In 1997, David Sinclair and Leonard Guarente discovered that circular DNA molecules known as ERCs are a primary cause of yeast aging (Sinclair and Guarente, 1997). ERCs are excised from the ribosomal DNA (a highly repetitive region of the yeast genome) by homologous DNA recombination about midway through a yeast cell's life span. ERCs then replicate each cell cycle until they reach toxic quantities (about one thousand per cell). The variants of most longevity genes that extend replicative life span (e.g., HXK2, SIR2, CDC25, FOB1, and NPT1 ) do so by stabilizing the ribosomal DNA locus, thus delaying the formation of ERCs.

One of the most interesting yeast longevity genes is SIR2. In 1999, Guarente and colleagues discovered that cells with additional copies of SIR2 enjoy a life span extension of 30 percent (Kaeberlein et al., 1999). SIR2 binds at various regions of the genome, including the ribosomal DNA, where it suppresses the formation of ERCs. SIR2 has been shown to encode a type of enzyme known as histone deacetylase (HDAC). HDACs rearrange DNA into a more compact chromatin structure. SIR2 activity is dependent on the availability of a key metabolite, nicotinamide adenine dinucleotide, which may explain how metabolic activity is coupled to longevity in this organism.

Longevity genes that regulate chronological life span include the gene for adenylate cyclase (CYR1 ) and a protein kinase signaling protein (SCH9 ) (Longo, 1999). Deletion of either of these genes increases resistance to oxidants and extends life span by up to threefold. SCH9 is considered a public longevity gene because a related worm gene, akt-1, also regulates life span and stress resistance in that organism.

Nematode worms. In 1988, Thomas Johnson and colleagues isolated the longevity gene age-1 from the nematode worm C. elegans, the first from any species. Mutations in age-1 extend life span by about 50 percent. In 1993, Cynthia Kenyon and colleagues showed that worm life span could be doubled by mutating a gene called daf-2. More than ten longevity genes have now been identified in C. elegans (Braeckman et al., 2001).

The life cycle of C. elegans comprises four larval stages prior to the adult stage. In harsh conditions such as starvation or crowding, larvae often enter a developmentally arrested but resistant form called dauer. The majority of longevity genes in C. elegans encode components of an insulin-like growth factor (IGF-1) signaling pathway that regulates dauer development (see Table 1). Loss-of-function mutations in dauer formation (daf ) genes extend the life span by allowing worms to reach maturity and retain some of the traits of dauers, including resistance to heat and oxidative stress.

Not all longevity genes in C. elegans are associated with loss-of-function mutations. The C. elegans sir-2 gene is a relative of the yeast SIR2 longevity gene. In 2001, Tissenbaum and Guarente reported that additional copies of sir-2 extended life span in worms by 30 percent. This extension did not occur when the daf-16 gene was mutated, which suggests that sir-2 regulates the dauer pathway via daf-16. Sir-2 is now considered a significant public longevity gene whose relatives likely regulate longevity in a variety of organisms (Kenyon, 2001).

Certain variants of another C. elegans gene, clk-1, slow development and extend life span up to 50 percent (Wong et al., 1995). Worms engineered to possess longevity variants of both clk-1 and daf-2 live up to five times longer than normal. The clk-1 gene is implicated in the biosynthesis of coenzyme Q, a component of the mitochondrial electron transport chain. The electron transport chain is a primary source of free radicals that can damage DNA, lipids, and proteins. It was originally thought that clk-1 increased longevity by reducing free radicals, but recent findings suggest that increased longevity may be attributable to the increased expression of a catalase gene, ctl-1, that helps detoxify free radicals (Taub et al., 1999).

Fruit flies. The fruit fly Drosophila melanogaster has been used since the 1970s to study the relationship between genetics and longevity, but only recently has there been a concerted effort to identify individual longevity genes in this organism. During winter, Drosophila egg development is arrested by downregulating the production of juvenile hormone, which, like worm development, appears to be regulated by an insulin-like growth factor (IGF) signaling pathway (Gems and Partridge, 2001). Mutations in the insulin receptor substrate (IRS) gene, chico, and in the insulin/IGF-1 receptor (InR ) gene allow flies to live up to 80 percent longer than normal by apparently invoking diapausal survival mechanisms. In Drosophila, the insulin/IGF-1 pathway also regulates body size, and many long-lived mutants are small. It is not yet known how the other two Drosophila longevity genes, indy (I 'm n ot d ead y et) and methusela, extend life span.

Mice. Although large-scale genetic screens for long-lived mice have not been undertaken because of the cost and labor involved, some longevity mutants have identified in preexisting laboratory stocks of mice, some of which live 60 percent longer than normal mice (Bartke et al., 2001). Snell and Ames dwarf strains of mice are both long-lived and carry spontaneous mutations in the Pit-1 and Prop-1 genes, respectively, which are required for the proper development of pituitary cells that produce growth hormone, prolactin, and thyroid hormone, among others. Two other long-lived mouse strains have defects in growth hormone metabolism (i.e., little mice and mice with a targeted disruption of the growth homone receptor gene). All of these mice are small and have very low levels of insulin-like growth factor 1 (IGF-1), which has prompted speculation that an insulin/IGF-1 signaling pathway regulates body size and longevity in mice, as it does in flies.

In 1999, Pier Giuseppe Pelicci and colleagues reported that mice lacking the p66shc gene are not small but live one-third longer than normal animals (Migliaccio et al., 1999). p66shc encodes a signaling protein that promotes cell death after environmental stress and also seems to promote metabolic activities that generate free radicals.


The fact that similar pathways regulate longevity in organisms as diverse as flies and mice raises the possibility that humans also possess such a pathway. If they do, there will be an opportunity to develop small compounds that can alter this pathway and possibly delay the onset of age-associated diseases. The greatest obstacle to developing any drug that delays aging is the great length of time it will take to determine its efficacy. At least the discovery that single gene mutations can dramatically increase longevity makes it feasible that one day such drugs will be developed.

David A. Sinclair

See also Cellular Aging; Centenarians; Genetics: Gene Expression; Longevity: Selection; Molecular Therapy; Nutrition: Caloric Restriction; Roundworms: Caenorhabditis elegans ; Theories of Biological Aging: Disposable Soma; Yeast.


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Genetics: Longevity Assurance

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