Lifespan is related to the rate of accumulation of genetic mutations

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Differences in the rate that genetic mutations accumulate in healthy young adults could help predict remaining lifespan in both sexes and the remaining years of fertility in women, according to University of Utah Health scientists.

Their study, believed to be the first of its kind, found that young adults who acquired fewer mutations over time lived about five years longer than those who acquired them more rapidly.

The researchers say the discovery could eventually lead to the development of interventions to slow the aging process.

“If the results from this small study are validated by other independent research, it would have tremendous implications,” says Lynn B. Jorde, Ph.D., chair of the Department of Human Genetics at U of U Health and a co-author of the study. “It would mean that we could possibly find ways to fix ourselves and live longer and better lives.”

The study appears online in the journal Scientific Reports.

Scientists have long known that DNA damage constantly occurs in the body. Typically, various mechanisms repair this damage and prevent potentially harmful mutations, according to lead and corresponding author Richard Cawthon, M.D., Ph.D., a U of U Health research associate professor of human genetics.

As we get older, these mechanisms become less efficient and more mutations accumulate. Older parents, for instance, tend to pass on more genetic mutations through their germline (egg and sperm) to their children than younger parents.

However, Cawthon and colleagues theorized that these mutations could be a biomarker for rates of aging and potentially predict lifespan in younger individuals as well as fertility in women.

The researchers sequenced DNA from 61 men and 61 women who were grandparents in 41 three-generational families. The families were part of the Centre d’Etude du Polymorphisme Humain (CEPH) consortium, which was central to many key investigations that have contributed toward a modern understanding of human genetics.

The researchers analyzed blood DNA sequences in trios consisting of pairs of grandparents from the first generation and one of their children from the second generation. That’s because germline mutations are passed on to their offspring.

Mutations found in the child’s blood DNA that were not present in either parent’s blood DNA were then inferred to have originated in the parents’ germlines. The researchers were then able to determine which parent each germline mutation came from, and, therefore, the number of such mutations each parent had accumulated in egg or sperm by the time of conception of the child.

Knowing that allowed the researchers to compare each first-generation parent to others of the same sex and estimate their rate of aging.

“So, compared to a 32-year-old man with 75 mutations, we would expect a 40-year-old with the same number of mutations to be aging more slowly,” Cawthon says.

“We’d expect him to die at an older age than the age at which the 32-year-old dies.”

The scientists found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens.

Some young adults acquired mutations at up to three times the rate of others. After adjusting for age, the researchers determined that individuals with the slowest rates of mutation accumulation were likely to live about five years longer than those who accumulated mutations more rapidly.

This is a difference comparable to the effects of smoking or lack of physical activity, Cawthon says.

Women with the highest mutation rates had significantly fewer live births than other women and were more likely to be younger when they gave birth to their last child. This suggests that the high rate of mutation was affecting their fertility.

“The ability to determine when aging starts, how long women can stay fertile, and how long people can live is an exciting possibility,” Cawthon says.

“If we can get to a point where we better understand what sort of developmental biology affecting mutation rates is happening during puberty, then we should be able to develop medical interventions to restore DNA repair and other homeostatic mechanisms back to what they were before puberty. If we could do that, it’s possible people could live and stay healthy much longer.”

In addition to Drs. Cawthon and Jorde, other U of U Health researchers involved in this study, titled “Germline Mutation Rates in Young Adults Predict Longevity and Reproductive Lifespan,” were H.D. Meeks, T.A. Sasani, K.R. Smith, L. Baird, M.M. Dixon, A.P. Peiffer, M.F. Leppert, and A.R. Quinlan. The research was conducted in conjunction with E. O’Brien and R. Kerber at the University of Louisville.

Funding: The study was funded by the National Institutes of Health, the University of Utah Program in Personalized Health, the National Center for Research Resources, the National Center for Advancing Translational Sciences, the Howard Hughes Medical Institute, the W.M. Keck Foundation, and the George S. and Delores Doré Eccles Foundation.


The world of modern biology is unified by genetics. Genetic approaches have the ability to transcend species and provide cross-links between fields for several reasons. First, is the fact that all species are evolutionarily related.

Thus, distinct species have similar gene function, and DNA sequence homology can be found between even distantly related species. Indeed, DNA sequence homology is used as a metric to determine evolutionary relationships among species.

Second, molecular genetic manipulation changes both the genotype and the phenotype of an organism. Such manipulations represent an extremely fine-scale tool for dissection of the underlying biochemistry, physiology, anatomy, and development of an individual species.

Because virtually any gene can be manipulated at will in many species, a dedicated approach can lead to an unraveling of the relationship between genotype and phenotype for almost any gene in these species.

In the study of longevity, genetic approaches can play a key role because the phenotype of longevity can be studied only at the whole-organism level; nevertheless, understanding at the molecular level could lead to accurate predictions of the dynamics of life-expectancy change.

The unraveling of this genotype/phenotype relationship in determining organismic life span has only just begun. Third, and most important, is the fact that genetics has the power to reveal causality by factors that are not dependent upon investigator prejudice.

Unlike a biochemical approach, which by its very nature must focus on one physiological system and on even one molecule or one part of that molecule (for example), a genetic approach can survey and identify alterations in any subsystem in the species in which the genetic alteration is detected (Botstein and Mauer, 1982).

It should be noted, however, that genetics alone has little hope of unraveling molecular mechanisms and that the strongest analysis results from the combined use of biochemistry, cell biology, and genetics.

I will first review the concept of genetic determination of life span and life expectancy and the concept of longevity-determining genes that we call ”gerontogenes.” Next, we will review relevant literature and experiments done in an effort to identify such gerontogenes.

This review will focus mostly on invertebrates because few experiments in vertebrates, notably the mouse, have tried to identify gerontogenes. We will speculate as to how these gerontogenes might be identified in other species, paying careful attention to the mapping of quantitative trait loci (QTLs).

This discussion will focus on identifying gerontogenes in nematodes and mice; much of the material has been selected from ongoing experiments in our own laboratory. Their subsequent extension to humans and/or the identification of gerontogenes directly in humans is the subject of another author.

Finally, we will review work from our laboratory on the genetic determination of mortality rates. Many recent reviews are available on the genetics of aging (Johnson et al., 1996; Fleming and Rose, 1996; Jazwinski, 1996; Lithgow, 1996; Martin et al., 1996; Nooden and Guiamét, 1996).

Concept Of Gerontogenes
The gene is the basic unit of inheritance; typically a gene makes a protein.

A gerontogene, then, makes a protein involved in aging and, more precisely, a protein involved in determining life span. Gerontogenes are defined functionally: they can be altered by mutation such that animals carrying them have a longer-than-normal life span. Vijg and Papaconstantinou (1990) suggested that gerontogenes might be separated into four distinct categories based upon their effects on life span and their evolutionary origin.

“Deleterious” and “pleiotropic” genes are predicted by the evolutionary theory of aging (Charlesworth, 1980; Rose, 1991) and have evolved as a result of mutation accumulation or pleiotropic gene action, respectively.

“Aging” genes that actively kill the organism are thought not to operate in organism senescence by evolutionary criteria; “longevity” genes promote survival, and presumably most genes that are fixed in an organism are of this type. “Longevity assurance gene,” a term used by Sacher (1978) and by D’mello et al. (1994), means essentially the same as the term gerontogene.

Methods For Identifying Gerontogenes
Five methods have been used to identify genes involved in aging, with variable success. These approaches mirror the approaches used to identify genes involved in other biological processes.

These approaches are:

(1) gene association,

(2) selective breeding,

(3) quantitative trait locus (QTL) mapping,

(4) induction of new mutations, and

(5) construction of transgenic stocks (Table 7-1 ).

TABLE 7-1Approaches Used to Identify Gerontogenes

Allelic associationMapping quantitative trait lociSelective breedingInduction of new mutationsConstruction of transgenic stocks

The first three approaches use genetic variation latent in the species studied. In the first approach, these genes are studied as found; this is the only approach useful for studying genes in humans because of constraints inherent in human studies.

The second approach involves selective breeding using the phenotype [or more recently the genotype, as in marker-assisted selection (Tanksley, 1993)] of interest to establish a strain in which genes leading to the desired phenotypic alterations (in this case increased longevity) have been differentially accumulated in one line as compared with another. Selected lines differing in traits of interest have been used by humans since the beginning of the agricultural era.

The third approach, QTL mapping, is a method for separating the overall polygenic effects of a selected line, for example, into individual components, providing estimated map positions and effect sizes for each QTL (Tanksley, 1993).

Approaches 4 and 5 differ from the former two approaches in that they do not rely on preexisting genetic variation and instead involve the creation of new mutations that then become the object of study.

Approach 4 involves the identification of mutants induced by mutagens; these mutants are identified solely on the basis of their effect on the phenotype of interest—i.e., longevity. The last approach targets genes of interest to test a specific hypothesis and to determine whether that gene is actually causally involved in aging.


Source:
University of Utah

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