November 30, 2004
Chronic Stress Accelerates Aging As Measured By Telomere Length

Stress shortens chromosome telomeres and short telomeres are bad things to have.

Increasing scientific evidence suggests that prolonged psychological stress takes its toll on the body, but the exact mechanisms by which stress influences disease processes have remained elusive. Now, scientists report that psychological stress may exact its toll, at least in part, by affecting molecules believed to play a key role in cellular aging and, possibly, disease development.

In the study, published in the November 30 issue of Proceedings of the National Academy of Sciences, the UCSF-led team determined that chronic stress, and the perception of life stress, each had a significant impact on three biological factors -- the length of telomeres, the activity of telomerase, and levels of oxidative stress -- in immune system cells known as peripheral blood mononucleocytes, in healthy premenopausal women.

Telomeres are DNA-protein complexes that cap the ends of chromosomes and promote genetic stability. Each time a cell divides, a portion of telomeric DNA dwindles away, and after many rounds of cell division, so much telomeric DNA has diminished that the aged cell stops dividing. Thus, telomeres play a critical role in determining the number of times a cell divides, its health, and its life span. These factors, in turn, affect the health of the tissues that cells form. Telomerase is an enzyme that replenishes a portion of telomeres with each round of cell division, and protects telomeres. Oxidative stress, which causes DNA damage, has been shown to hasten the shortening of telomeres in cell culture.

The results of the study -- which involved 58 women, ages 20-50, all of whom were biological mothers either of a chronically ill child (39 women, so-called "caregivers") or a healthy child (19 women, or "controls") -- were dramatic.

As expected, most women who cared for a chronically ill child reported that they were more stressed than women in the control group, though, as a group, their biological markers were not different from those of the controls. However, in one of the study's key findings, the duration of caregiving -- after controlling for the age of the women -- proved critical: The more years of care giving, the shorter the length of the telomeres, the lower the telomerase activity, and the greater the oxidative stress.

Moreover, the perception of being stressed correlated in both the caregiver and control groups with the biological markers. In fact, in the most stunning result, the telomeres of women with the highest perceived psychological stress -- across both groups -- had undergone the equivalent of approximately 10 years of additional aging, compared with the women across both groups who had the lowest perception of being stressed. The highest-stress group also had significantly decreased telomerase activity and higher oxidative stress than the lowest-stress group.

"The results were striking," says co-author Elizabeth Blackburn, PhD, Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at UCSF. "This is the first evidence that chronic psychological stress -- and how a person perceives stress -- may damp down telomerase and have a significant impact on the length of telomeres, suggesting that stress may modulate the rate of cellular aging."

The link from mind to body

"Numerous studies have solidly demonstrated a link between chronic psychological stress and indices of impaired health, including cardiovascular disease and weakened immune function," says lead author Elissa Epel, PhD, UCSF assistant professor of psychiatry. "The new findings suggest a cellular mechanism for how chronic stress may cause premature onset of disease. Anecdotal evidence and scientific evidence has have suggested that chronic stress can take years off your life; the implications of this study are that this is true at the cellular level. Chronic stress appears to have the potential to shorten the life of cells, at least immune cells."

While it is not yet clear how psychological stress impacts telomeres, the team suspects stress hormones may play a role.

The next investigative steps

A next step in the research will be determining if prolonged psychological stress has an impact on telomeres in other types of cells, such as cells of the lining of the cardiovascular system.

The scientists also plan to further examine the impact of prolonged psychological stress on immune system cells, which mount the body's healing response to wounds, and defenses against illness. When the immune system needs to rev up, it produces more defense cells, which requires high levels of the telomerase enzyme, in order to maintain telomere length, thus allowing for additional rounds of cell division. The current study suggests that, for people under chronic stress, the telomerase activity of their immune cells might be impaired.

These scientists are now going to conduct a longitudinal study (following the same group of subject for years while repeatedly testing them) to prove that stress really does accelerate aging as measured by telomere length.

For those of you asking "What are telomeres and why are they important?" here is the short version: Telomeres are caps on the ends of chromosomes. They are made up of a very simple repeating sequence of DNA. Every time a cell divides its telomere gets shortened. Eventually the telomere gets so short that somehow as a result the cell can no longer divide or can divide only slowly and with increasing genetic damage.

So how to telomeres get long in the first place if they normally get shorter in all cells that divide? Way back at some step in the creation of an embryo (sorry, I don't know when, maybe when eggs and sperm are made? Or right after fertilization? anyone biologists reading this who know?) the telomerase enzyme gets turned on to lengthen telomeres. After that most (though perhaps not all) cell types do not have active telomerase and when they divide they get progressively shorter telomeres. The shortening of the telomeres serves as one limit on how many times cells can divide.

My guess on the study reported above is that the mechanism of telomere shortening the researchers are observing is that stress causes certain classes of cells to divide more rapidly. Keep in mind that not all cells divide. For example, most nerve and heart cells are what are called post-mitotic. They no longer go through mitotic cell division. But skin cells and the various types of adult stem cells divide. One major cause of aging is that adult stem cell reservoirs throughout the body go through so many divisions that their telomeres get too short and they can't divide very well to provide cells to do repair.

Evidence has previously been found linking telomere length to mortality risk. The length of telomeres in endothelial progenitor cells (a type of adult stem cell) is linked to increased risk of cardiovascular disease. So those cells would be logical candidates to check for telomere length in women who have been under sustained stress.

You might think that lengthening telomeres would be a great way to rejuvenate cells. Well, like so many things in life, it depends. In order for cancer cells to become cancerous one of the mutations that helps them divide better is to turn on telomerase (an enzyme that lengthens telomeres) so that telomere length won't be an obstacle to the cancer's growth. A blanket lengthening of all the telomeres of all the cells in your body (say by a gene therapy yet to be developed) would probably substantially increase your risk of cancer. Of course, for someone who is about to die from some non-cancer disease telomere lengthening might increase their lifespan by enabling adult stem cells and other cells to divide and repair damaged tissue.

Telomere lengthening techniques usable in cell culture have been developed. But the use such techniques on adult stem cells removed from your body would probably best be done in combination with genetic testing and selection processes (still to be developed) that would assure these stem cells do not already have genetic mutations that increase the risk of the cells going cancerous. Aubrey de Grey proposes reseeding adult stem cell reservoirs with cells that have lengthened telomeres. Aubrey goes so far as to argue that the replacement stem cells should have their telomerase enzymes removed entirely in order to provide a limit to cancer cell replication. Evidence from mice shows that bone marrow stem cell replenishment reduces the risk of atherosclerosis.

My advice: Avoid stress. Also, support scientific research into rejuvenation. Your telomeres are getting shorter every day and that is not good. We need safe rejuvenation therapies to give us young adult stem cells and other cell types.

Share |      Randall Parker, 2004 November 30 03:52 PM  Aging Studies

Fly said at November 30, 2004 5:01 PM:

This article discusses the molecule nanog.

Scientists have identified a molecule that allows special cells from embryos, called stem cells, to multiply without limit.

Age-associated Characteristics of Murine Hematopoietic Stem Cells

“An important question that should be addressed is how HSCs become defective with time. It has been suggested that the length of telomeres limits a life-span of normal somatic cells (20) (21), including HSCs (13). Correlation of telomerase activity and self-renewal potential has been suggested for hematopoietic cells (22). Telomere length can be an indicator of replicative history for HSCs. However, aging in HSCs may be not related solely to shortening of telomeres, since, as shown in this study, aging preferentially affects the lymphoid differentiation potential of HSCs but does not affect their myeloid differentiation potential nor their self-renewal potential.”

This article looks at the regenerative ability of HSC’s. HSC’s from adult mice were used to reconstruct the blood stem cells of young mice. After the young mice aged, the HSC’s were again transplanted. The HSC’s retained their regenerative abilities through several generations.

There is evidence that telomerase is active in some stem cells. There is also evidence that chronic diseases can lead to stem cells with shortened telomeres and less regenerative ability.

Fly said at November 30, 2004 5:08 PM:

Whoops, I left off the link for the HSC's paper.

Fly said at November 30, 2004 5:14 PM:

Here’s a better reference.

Telomerase and its role in the biology of stem cells

“Telomerase is found in embryonic cells and adult male germline cells and in the proliferative cells of renewing tissues, e.g. haematopoietic stem cells and activated lymphocytes, basal cells of the epidermis and intestinal crypt cells. It is, however, missing from most normal human somatic cells which undergo telomere attrition with progressive rounds of cell division, ultimately reaching replicative senescence.”

Reason said at November 30, 2004 11:07 PM:

There's some recent discussion of telomeres w/ Aubrey de Grey and others here:

Fly said at December 1, 2004 12:50 PM:

Reason, thanks for the link to the discussion.

GENEarchy said at December 3, 2004 4:50 PM:

With technology progressing to the point of eventually enabling governments & others to read our minds, predict our behaviors & fashion our offspring into true genetic slaves/toys, i wonder how much drive & incentive there'll be for life-extending tech & research. Seems like suicide'll emerge to be a better opt than immortality. This a fabulous & interesting scienceblog, but we all know where all this is inevitably leading. Just a thought.

NuSapiens said at December 8, 2004 10:20 PM:

The effects of stress don't make sense for the individual, but they do make evolutionary sense at the population level. Here's my theory of why:

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