Why do women live longer than men? A new theory published in Aging Cell
by Dr. Peter Lansdorp (pictured) implicates telomeres and embryonic telomerase levels.
Can you briefly explain the significance of sex differences in telomere length?
We have all heard of the fact that women, on average, live longer than men. Here is how I think it can be explained. How often blood and tissues can be replenished with new cells, is limited by the loss of telomere repeats at the end of chromosomes with each cell division. In the long run, loss of telomeric DNA causes failure of cell renewal and immune responses. Interestingly, such failures and the related mortality are correlated to the average length of telomere repeats in white blood cells. The “mitotic clock” in stem cells and immune cells results from suppression of telomerase activity, the enzyme that elongates telomeres and maintains telomere length in cells of the germline. Women have, on average, longer telomeres than men at birth and throughout life. In the paper, I propose that sex differences in average telomere length and average lifespan are linked and originate very early in development, even before the embryo is implanted.
How might embryonic dyskerin levels affect telomere length and lifespan?
What is dyskerin and how does it work? Telomerase is a ribonucleoprotein composed of proteins, including a reverse transcriptase and dyskerin, and telomerase RNA. Before associating with the reverse transcriptase, telomerase RNA transcripts associate with two copies of dyskerin, a protein encoded by the DKC1 gene on the X chromosome. Dyskerin is needed to properly fold telomerase RNA and prevent it from degradation. And here is the crux: it was previously shown that in females many genes, including DKC1, are expressed from both X chromosomes before one X chromosome is randomly inactivated in each and every cell. My theory predicts that higher dyskerin levels result in more effective capture and stabilization of telomerase RNA, higher levels of telomerase and longer telomeres in female compared to male embryos. Longer telomeres allow the mitotic clock to tick a few more times in female cells, delaying cell senescence and increasing lifespan.
If telomeres are so important in aging, why are not more people studying it?
Good question. There are several explanations. Loss of telomere repeats does not seem to play a major role in the aging of short-lived animals such as laboratory mice. This greatly complicates laboratory studies. Limited renewal of human cells furthermore does not go well with simple notions about the “self-renewal” of cells that are prevalent in the stem cell field and regenerative medicine. The field as a whole has also suffered from “fake news” about telomerase and telomere length. Creams to rejuvenate your skin or pills that will make you live longer by stimulating telomerase as well as consumer targeted advertisements to measure the length of your telomeres using sloppy assays have distracted from accurate findings and serious science. Finally, side effects of hypothetical therapies that target telomerase or telomeres are a concern. Rejuvenation of cells by stimulating telomerase increases the risk of developing cancer risk and inhibiting telomerase will accelerate aging. Obvious “win-win” opportunities in the telomere field are hard to find.
What are the next steps for research in this area?
Many questions remain. For example, are sex differences in lifespan observed in other species? If so, are such differences indeed linked to embryonic dyskerin and telomerase levels? Although trying to elongate telomeres in human beings is not advisable, since we need shortening to prevent cancer, tinkering with telomerase levels in selected cells in the laboratory is probably useful to increase their replicative potential for clinical use. This could have applications in regenerative medicine and immunotherapies such as CAR-T cell therapies. We need to figure out how to elongate telomeres in cells of interest effectively, at scale and in a way that is safe. To better understand the role of telomeres in human biology, we need to find better and cheaper ways to measure the length of telomere repeats in cells. Ideally, such measurements should look at single cells and measure the distribution as well as the average length of telomere repeats in all chromosomes. Lots of things to explore!
Dr. Peter Lansdorp is a Distinguished scientist at the Terry Fox Laboratory of the BC Cancer Agency in Vancouver, Canada. He is a fellow of the Royal Society of Canada and a Professor in Medical Genetics at the University of British Columbia. He is the co-founder of Repeat Diagnostics, a Vancouver based company specializing in clinical telomere length measurements. See more details about ongoing work in the Lansdorp laboratory.
