Danith H. Ly [1], David J. Lockhart [2], Richard A. Lerner [1*], and Peter G. Schultz [1,2*], "Mitotic Misregulation and Human Aging," Science, Vol. 287, No. 5462, pp. 2486-92 (March 31, 2000).


Messenger RNA levels were measured in actively dividing fibroblasts isolated from young, middle-age, and old-age humans, and humans with progeria, a rare genetic disorder characterized by accelerated aging. Genes whose expression is associated with age-related phenotypes and diseases were identified. The data also suggest that an underlying mechanism of the aging process involves increasing errors in the mitotic machinery of dividing cells in the post-reproductive stage of life. We propose that this dysfunction leads to chromosomal pathologies that result in misregulation of genes involved in the aging process.
1. Department of Chemistry and the Skaggs Institute for Chemical Biology; The Scripps Research Institute; 10550 North Torrey Pines Road; La Jolla, CA 92037; USA.

2. Genomics Institute of the Novartis Research Foundation; 3115 Merryfield Row; San Diego, CA 92121; USA.
* To whom correspondence should be addressed.
URL: /www.scripps.edu/chem/lerner

Research: Genetic Errors Cause Aging
Paul Recer,
AP Science Writer

4:12 PM ET 03/30/00; Washington, D.C. (AP) -- Hair turning gray? Skin wrinkling? Muscles weaker? The inevitable signs of aging may be caused by a failure of quality control in your chromosomes and genes, a new study says. Dr. Richard A. Lerner and his team at the Scripps Research Institute in La Jolla, California compared the effects of aging on 6,000 genes and found that 61 key genes (1 percent) went through dramatic changes from the ages [9 - 90]. It is these changes, he said in an interview, that cause the dramatic symptoms of aging. "There are checkpoint genes that have to do with quality control in a cell," said Lerner. "These genes decide after a cell divides if it is good enough to live or not [apoptosis]." When the checkpoint genes fail, mistakes in DNA are perpetuated because the flawed cells then make new cells with the same genetic flaws, or worse. This cascade of genetic goofs can eventually cause a loss of function that may include the typical symptoms of aging. Thus, said Lerner, it is the "mismanagement" of these checkpoint genes "that is responsible for aging." Lerner said the study, appearing Friday in the journal Science, "eventually could lead to finding ways of controlling the aging process. But, for now, the work just gives science a new understanding of why all people suffer from what he called a common disease -- aging." [Editor's Note: Not all physicians agree that "aging" is a disease; some doctors prefer to think of it as a natural process. However, we -- of the GRG -- know this "natural" process for what it is -- a disease. Indeed, giving "aging" a proper label is important. It is critical to our deciding whether or not to try to intervene, given the opportunity. And interventional knowledge is of a different sort than observational knowledge. By comparison, it is hard won knowledge. And we wish to formally thank the Scripts Institute and Novartis Genomics for sponsoring this study and getting us on track.]

"This is an extremely interesting piece of work,'' said Dr. Leonard Guarente, a researcher of aging at the Massachusetts Institute of Technology, "but it is not a breakthrough. It just gives a hint" of a possible aging process, and "a suggestion of an area that should be looked into." Guarente said that the study used only laboratory cell lines and that further research is needed to show that the changes found in the laboratory work actually occur in living human beings. Until that is done, he said, nothing has been proven by the research.

Specifics of the California Study

Lerner and his colleagues used a gene analysis system called microarrays to monitor the activity levels of 6,000 genes in differently-aged cells. They used cells donated from the tissue of patients as young as 9 and as old as 90 yo, along with cells from patients with progeria [ Hutchison Gilford Syndrome], a disorder of highly-accelerated aging and premature death. The cells were put into four groups: (1) the normal young, (2) the normal middle-aged, (3) the normal old, and the (4) progeria children. Lerner said the researchers found a consistent pattern of growing impairment in specific genes when comparing the cells of the young, middle-aged, and old. The impairment found in the progeria cells, he said, closely matched those in the very old. It is a normal function of the body to replace old cells with new cells. This is done by the process of division [mitosis] -- an old cell divides and creates two new [daughter] cells. Each cell gets full [identical] copies of the [46] chromosomes from the old [mother] cell. But Lerner said his study suggests "the aging process involves mistakes [mutations] in the transfer of chromosomes and genes from old cells to new cells, and the failure of quality-control genes to find and fix these mistakes [defective repair enzymes] or to [completely] eliminate the bad cells [apoptosis]. Some of the changes cause genes to stop working, while other changes cause an increased activity ["up regulation," secondary to the loss of inhibitory regulation]. This shows that as we get older, altered gene expression results in the production of cells with diminished function," he said.

"[Gerontic] genes linked to the common physical manifestations of aging -- gray hair, wrinkled skin, reduced function of some organs -- are all sensitive to changes in their structure," said Lerner. "For instance," he said, "quality control among bone marrow [stem] cells can become so flawed that it perpetuates bad genes, even to the extent that whole chromosomes may be missing in cells. By the time one is 90, a huge percentage of one's cells in the bone marrow may have missing chromosomes," said Lerner. [Editor's Note: Hello! That's a show-stopper, isn't it?] "This could help explain such things the brittle bones common among the aged," he said. The researcher said his findings, if verified by other scientists, put a new perspective on the process of aging and suggest that it shares some of the characteristics of cancer. "If you had asked before what aging is like and what cancer is like, people would have said that cancer is a disease of abnormal cell replication while aging is a disease in which cells wear out," said Lerner. However, "our study suggests that aging and cancer are really quite similar -- they are both caused by a failure of certain quality-control genes."

[ Editor's Questions: For further discussion, if Dr. Lerner or one of his co-authors agrees to be a future speaker to the LA-GRG at the UCLA Medical School given that their home base in San Diego is not too far away:

1. Why don't highly-proliferative germ cells -- spermatocytes -- undergo senescence at the same rate as epithelial cells? Or cancer for that matter, if these phenomena are really flip sides of the same coin? {There are testicular cancers derived from interstitial supporting cells (Sertoli or Leydig [testosterone-making] Cells), but they represent only 3 percent of the cases; germ-cell tumors are responsible for 97 percent of the cases. Are there such things as "transformed" mature spermatocyes (not seminomas, embryonal carcinoma, teratoma, or choriocarcinomas)? They would have to dedifferentiate themselves first, wouldn't they? Paradoxically, there may be some, but we can't know because they would get ejaculated and never successfully fertilize an egg to reveal their true nature. Speculation: Maybe spermatogenesis should be regarded as a healthy form of "cancer," since Sertoli cells have the characteristic metabolic chemistry of a cancer cell; it's just that they never form tumors nor do they find their way back into the blood stream (there exists a blood barrier), and therefore they don't "metastasize" to other organs like a typical malignancy. Also, if there weren't a certain natural mutation rate in both sperm and eggs (by making them completely impervious to cosmic radiation or whatever), there never would be a Darwinian evolution of the species, would there?} Does lack of senescence have something to with the continual synthesis of telomerase? Ejaculatory volume is known to decline with age, largely as a function of hormonal loss. The rate of morphological anomalies (dual-headed) in sperm rises with age, as does a gradual ( andropausal) decline in fertility with age, presumably secondary to a failure to "swim" as aggressively as sperm from younger men. On the other hand, there are so many checks and balances in the system (hoops for the sperm to jump through, so to speak) on the way to finding an egg ahead of potential competitors, that any sperm lucky enough to get near an egg is probably a "good" sperm. The documented rate of genetic anomalies with paternal age hardly compares with the rate for maternal age (e.g., the incidence of Down's Syndrome rises exponentially after age 35 for women, while the rate of congenital anomalies with paternal age is negligible [except for some very obscure conditions].) So what do sperm know that fibrocytes don't?

2. Why do oocytes, quietly tucked away in the ovaries -- waiting in the wings to be called for follicularization -- avoid mutational defects for so long (>30 years)? And why isn't there a linear increase in the rate of defects with age instead of an exponential rate at the end? So what do eggs know that fibrocytes don't?

3. The obvious next interventional experiment would have to do with stem cells (pleuripotent ESCs or Bone Marrow SCs]. What happens in tissue culture when stem cells are continuously added to the culture?

4. What happens when tissue samples are taken from aborted embryos or from living Super Centenarians (>110 years) by surgical biopsy to help flesh out the range of data points?

5. What are the critical-path limitations to getting more data in general? Is it the lack of volunteers or the cost of gene chips?

6. Given the work of Prolla and Weindruch in Madison, Wisconsin published in Science last August on mice, what took you so long? ;-)

Please feel free to continue this discussion in our Discussion Category on "Stem Cells." -- LSC]

On the Web:

1. Science: www.sciencemag.org ;

2. News from Science: www.eurekalert.org