The human genetic blueprint, or genome, consists of approximately 25,000 genes made up of approximately 3 billion letters (base pairs) of DNA. Small deviations in the base pairs naturally occur about once in every 1,000 letters of DNA code, generating small genetic variants. Scientists are finding that some of these variants (polymorphisms) are actually associated with particular traits or chance of developing a specific disease. People with a certain trait, for example, those living past age 100, may be more likely to have one variant of a gene, while people without the same trait may be more likely to have another variant. While it is very difficult to prove that a gene influences aging in humans, a relationship, or “association,” may be inferred based upon whether a genetic variant is found more frequently among successful agers, such as centenarians, compared with groups of people who have an average or short lifespan and health span.
Human Genetic Blueprint
Illustration adapted from Alzheimer's Disease: Unraveling the Mystery
The human genetic blueprint, or genome, consists of approximately 25,000 genes made up of approximately 3 billion letters (base pairs) of DNA. Base pair sequences: guanine (G) pairs with cytosine (C); adenine (A) pairs with thymine (T).
Several approaches are used to identify possible genes associated with longevity in humans. In the candidate gene approach, scientists look for genes in humans that serve similar functions in the body as genes already associated with aging in animal models, so-called “homologs” or “orthologs” to animal genes. For instance, after finding longevity genes involved in the insulin/IGF-1 pathway of animal models, researchers look for the comparable genes in the insulin/IGF-1 pathway of humans. Scientists then determine whether the genes are linked to longevity in humans by looking to see if a variant of the genes is prevalent among people who live healthy, long lives but not for people who have an average health span and lifespan.
In one NIA-funded project, researchers studied 30 genes associated with the insulin/IGF-1 pathway in humans to see if any variants of those genes were more common in women over 92 years old compared to women who were less than 80 years old. Variants of certain genes—like the FOXO3a gene—predominated among long-lived individuals, suggesting a possible role with longer lifespan. This finding provides evidence that, like in animal models, the insulin/IGF-1 pathway has a role in human aging. These genes may be important to future development of therapies to support healthy aging.
Another approach, the genome-wide association study, or GWAS, is particularly productive in finding genes involved in diseases and conditions associated with aging. In this approach, scientists scan the entire genome looking for variants that occur more often among a group with a particular health issue or trait. In one GWAS study, NIH-funded researchers identified genes possibly associated with high and low blood fat levels, cholesterol, and, therefore, risk for coronary artery disease. The data analyzed were collected from Sardinians, a small genetically alike population living off the coast of Italy in the Mediterranean, and from two other international studies. The findings revealed more than 25 genetic variants in 18 genes connected to cholesterol and lipid levels. Seven of the genes were not previously connected to cholesterol/lipid levels, suggesting that there are possibly other pathways associated with risk for coronary artery disease. Heart disease is a major health issue facing older people. Finding a way to eliminate or lower risk for heart disease could have important ramifications for reducing disability and death from this particular age-related condition.
Scientists are also currently using GWAS to find genes directly associated with aging and longevity. Because the GWAS approach does not require previous knowledge of the function of the gene or its potential relationship with longevity, it could possibly uncover genes involved in cellular processes and pathways that were not previously thought to play roles in aging. Since no single approach can precisely identify each and every gene involved in aging, scientists will use multiple methods, including a combination of the GWAS and candidate gene approaches to identify genes involved in aging.
As scientists continue to explore the genetics of aging, its complexity becomes increasingly evident. Further studies could illustrate the varying ways genes influence longevity. For example, some people who live to a very old age may have genes that better equip them to survive a disease; others may have genes that help them resist getting a disease in the first place. Some genes may accelerate the rate of aging, others may slow it down. Scientists investigating the genetics of aging do not foresee a “Eureka!” moment when one gene is discovered as the principal factor affecting health and lifespan. It is more likely that we will identify several combinations of many genes that affect aging, each to a small degree.
Most longevity genes identified thus far influence one of three pathways in a cell: insulin/IGF-1, sirtuins, or mTOR.
In the 1980s, scientists discovered the first gene shown to limit lifespan in roundworms, which they named age-1. Further investigation revealed that the effects of age-1 are involved with the insulin/IGF-1 pathway. When scientists “silenced” the age-1 gene’s activity, the insulin/IGF-1 pathway’s activity also decreased and the worms lived longer. Since then, many other genes associated with the insulin/IGF-1 pathway have been found to affect the lifespan of fruit flies and mice, strengthening the hypothesis that the insulin/IGF-1 pathway plays an important role in the aging process. More research is needed to determine if inhibiting this pathway could increase longevity in humans or create insulin-related health problems like diabetes. A recent report suggests that people with a mutation related to the insulin/IGF-1 pathway may have less risk of developing diabetes and cancer.
There is also a great deal of interest in the sirtuin pathway. Sirtuin genes are present in all species and regulate metabolism in the cell. They are crucial for cell activity and cell life. In the 1990s, scientists at the Massachusetts Institute of Technology found that inserting an extra copy of a sirtuin equivalent, called Sir2, increased the lifespan of yeast. Extension of lifespan has been replicated in other organisms, including flies and worms. However, studies in mice have yielded conflicting results.
The mTOR pathway—an abbreviation of “mammalian target of rapamycin”—plays a role in aging of yeast, worms, flies, and mice. This pathway controls the cell’s rate of protein synthesis, which is important for proper cell function. Researchers have found that inhibiting the pathway in mice genetically or pharmacologically (using rapamycin) leads to increased longevity and improved health span.
The Future of Aging Research: Epigenetics
An emerging area of research called “epigenetics” opens the door to a scientific blending of two worlds that for decades were thought of as totally separate—that is nature and nurture, or more specifically genetics and the environment. Epigenetics research looks at how your environment, over time, can affect how your genes work and influence your development, health, and aging.
At the center of this research is the epigenome—chemical modifications, or marks, on our DNA, or in proteins that interact with DNA, that tell it what to do, where to do it, and when to do it. The marks that make up the epigenome are affected by your lifestyle and environment and may change, for example, based on what you eat and drink, if you smoke, what medicines you take, and what pollutants you encounter. Changes in the epigenome can cause changes in gene activity. Most epigenetic changes are likely harmless, but some could trigger or exacerbate a disease or condition, such as your risk for age-related diseases. In some cases, scientists find that these epigenetic changes driven by the environment can be inherited by the offspring.
Identical, maternal twins are ideal for epigenetic research. At birth, twins have nearly the same genetic blueprint; however, over time, they may have fewer identical traits. Careful study of these changes may help scientists better understand environmental and lifestyle’s influence on genes.
Epigenetics might also explain variations in lifespan among laboratory mice that are genetically identical and seemingly raised in the exact same environment. Scientists theorize that the difference in their lifespans may result from a disparity in the amount of nurturing they received when very young. The mice with the shorter lifespan might have been less adept at feeding and, therefore, got less of their mother’s milk, or their mother may have licked them less, or they may have slept farther away from the center of the litter. Receiving less nurturing may have influenced their epigenetics, marking the genes that control aging.
As epigenetic research moves forward, scientists hope to answer three key questions: