June 26, 2005
Late Conceiving Mothers Have Unique Genetic Profiles

Genetic profile of women who can start pregnancies in their late 40s provide clues about why some people age more slowly than others.

Copenhagen, Denmark: Women who have a special genetic profile can conceive spontaneously after the age of 45 years, a scientist said at the 21st annual conference of the European Society of Human Reproduction and Embryology today (Tuesday 21 June 2005). Dr. Neri Laufer, from the Haddassah University Hospital, Jerusalem, Israel, told the conference that his team's work to identify a specific gene expression profile linked to later fertility would help understanding of the ageing process, as well as enabling the development of better treatments for infertility in older patients.

Dr. Laufer and colleagues studied a large group of 250 women over 45 who conceived spontaneously. Women are generally not fertile after this age due to ageing of the ovaries, so the scientists thought that there might be some special factor that was allowing these women to conceive. "Mostly they had had a large number of children and also a low miscarriage rate", he said "and these two factors indicated to us that they had a natural ability to escape the ageing process of the ovaries. We decided to see if we could find any differences in gene expression between 8 such women and another 6 women of the same age group who had finished their families at the age of 30."

Using gene chip technology, the scientists found that blood samples from the 8 women had a unique pattern of gene expression that did not exist in the control group. The two main groups of genes expressed in these women were involved in apoptosis (cell death) and in DNA repair mechanisms. "These women appear to differ from the normal population due to a unique genetic predisposition that protects them from the DNA damage and cellular ageing that helps age the ovary", said Dr. Laufer. "What we do not yet know is whether this reproductive success is linked with potential longevity." The women were all Ashkenazi Jews but Dr. Laufer's team does not believe that the gene profile is unique to this group. "We already have preliminary results demonstrating similar results from another group", he said. The team intends to study women from different ethnic, and hence genetic, groups and study their genetic fingerprints against those of the first group.

One wonders whether the apoptosis genes were regulated to make cell death more or less likely in the late conceiving women. Did their ovary cells manage to avoid death and therefore hang around longer to reproduce? Or did their bad ovary cells more reliably die and thereby eliminate their harmful influence on neighboring cells? Some biologists theorize that senescent cells and other old damaged cells release free radicals and other chemicals into their environment that damage neighboring cells. So a greater ability to commit cell suicide might provide a net benefit in the reproductive tract.

These women who have babies later in life who also have repair enzymes unregulated probably have longer average life expectancies. Study of the genetic differences between them and women whose repair enzymes are highly expressed could lead to discovery of genetic variations which upregulate repair enzymes and proteins and RNA fragments which are involved in repair upregulation.

While women who have babies at late ages might have longer life expectancies there is a more obvious group to investigate for life extending genetic variations: really old people. A comparison of gene expression profiles between 90+ year olds and these late reproducing women might yield some insights into which gene expression profiles are most valuable for longevity. Also, really old women could be asked what age they gave birth to their last child.

As DNA sequencing technologies continue to drop in price the rate of search for genetic variations which influence longevity will accelerate. This will lead to identification of proteins that regulate repair and other processes that influence longevity. Any proteins that are involved in DNA repair enzyme regulation would be obvious targets for pharmaceutical development. However, drugs that increase longevity are still a distant prospect for a few reasons.

First off, The development of a drug that upregulates repair would be a tough challenge. Ideally the drug would work in all the cells of the body. A long half life would be desirable in order for it to be able to build up in all cells. Such a drug would probably have to be taken for decades in order to provide a large benefit for longevity. So it would need to be very non-toxic with low incidence of side effects.

Second, proving that a supposedly life extending drug will be efficacious is an extremely difficult task. Clinical trials on 30, 40, or 50 year olds that last a few years can't demonstrate what the effect of a drug will be if taken for decades. If a clinical trial was held for decades it would cost too much, the patent on the drug would expire while the trial was on-going, and, well, we'd all be too old (or dead) by the time the benefit was proven. So, er, who cares?

Third, the US Food and Drug Administration and similar regulatory agencies in other countries are set up to approve drugs that treat or prevent specific diseases. These agencies do not treat aging as a disease. A life extending drug would need to provide some measurable benefit on the incidence of diseases in shorter time frames. While cholesterol lowering drugs and blood pressure lowering drugs extend life they do so by changing metabolisms for purposes that very directly reduce the risk of well characterized diseases. What quickly measurable benefit would up-regulation of DNA repair enzymes bring? Can anyone think of anything? I can't off the top of my head.

While I'd happily take drugs which slow the rate of aging I'm expecting to see treatments that repair and reverse aging before drugs that slow the general rate of aging. The push to develop, for example, stem cell therapies is so great that I expect many useful stem cell therapies to come to market in the next 10 years and probably two or three times more in the following 5 years and again in the following 5 years. But I do not expect any general aging deceleration drug to hit the market in the next 10 years and I'm not certain about the prospects for such drugs in the following 10 years.

Share |      Randall Parker, 2005 June 26 09:49 AM  Aging Studies

Lei said at June 26, 2005 11:00 AM:

quickly measurable benefit would up-regulation of DNA repair enzymes bring

I guess since most DNA repair defects result in cancer, any clinical trials would require some long-term follow-ups. Progeria is one example in which it might be possible to see a noticeable improvement after treatment with a drug to up-regulate DNA repair.

There's a list of human diseases with DNA-repair defects here: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=iga.table.2780.

Louise Krekic said at April 29, 2010 6:52 PM:

I dont believe that mothers who concieve later in life are any different. I know many such women who actualy lived shorter. My mom had two of us at 23 and 25 and she is still living at 87. She even has some health problems like slight diabetes and a broken hip. I think the women who live in a fast lane and mature fast are the ones that die fast. They usually have kids early and they drink, smoke and party. The reason why the late conceiving mothers live longer is that they live a different lifestyle of caring for young children after 4o. They are simply prolonging the life by living healthier until the later years.

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