Posttraumatic stress disorder (PTSD) may increase biomarkers of the aging process and of medical conditions, such heart disease, associated with advanced age and lead to premature death, a new literature review reveals.

These findings reinforce the idea that PTSD is not just a mental illness, said senior study author Dilip Jeste, MD, distinguished professor of psychiatry and neurosciences and director, Center on Healthy Aging and Senior Care, University of California, San Diego (UCSD).

"It provides some tantalizing evidence ― it's preliminary and needs to be confirmed and all those caveats ― suggesting that if you treat PTSD early, properly, and well, and patients do recover, their outcome prognosis may be improved. So it's conceivable that you can actually stop the process of accelerated aging."

The review was published online May 7 in the American Journal of Geriatric Psychiatry.

Link to Specific Medical Conditions

Investigators searched PubMed, PsychINFO and PILOTS databases for relevant articles from 2000 to 2014, a period after the 9/11 attacks and the wars in Iraq and Afghanistan, when public and scientific interest in PTSD was intensifying. They selected 64 studies for inclusion in the review.

Outcomes of the studies fell into three categories: biomarkers of senescence, or "biological aging," including leukocyte telomere length (LTL), blood proinflammatory indices, and oxidative stress; comorbid medical conditions associated with aging, such as hypertension, cardiovascular disease, metabolic syndrome, diabetes, gastrointestinal ulcer disease, and dementia; and mortality.

The review included 22 studies of senescence-related biomarkers with sufficient information to calculate pooled effect sizes, including six reports on LTL in PTSD. All six of these studies reported shorter LTL among people with PTSD compared with groups who did not have PTSD.

Sixteen of the 22 studies were reports on proinflammatory indices, including C-reactive protein, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis actor alpha (TNF-α). Overall, there were positive effect sizes indicating an increase in the biomarker among people with PTSD relative to the comparison group.

The effect sizes varied but were strongest for LTL (.76) and for some proinflammatory markers, especially IL-6 (.78) and TNF-α (.81), said Dr Jeste.

The nature of the relationship between PTSD and these senescentlike changes is not known. Some experts suggest that shorter LTL may be a risk factor for PTSD, whereas others believe that LTL may be shortened as a result of the traumatic event.

Results from five studies of PTSD and oxidative measures were "mixed at best," say the authors. They note that given the limited availability of studies with overlapping methods of outcome measures and the small samples sizes within several of the available studies, "it seems premature to draw firm conclusions."

Researchers looked at 30 studies of the association between PTSD and one or more potentially fatal medical conditions known to increase in incidence with normal aging and to worsen with stress.

They determined that studies most consistently showed an association between PTSD and an increased incidence of cardiovascular disease, gastrointestinal ulcers, and dementia. The studies provided moderate support for an association with type 2 diabetes mellitus and less support for a relationship with hypertension.

"The association of PTSD with such distinct medical conditions, which nevertheless share an association with aging, supports an accelerated aging model of PTSD," the authors write.

Domino Effect

As for mortality, the researchers found 10 relevant studies, nine conducted in military veterans and one in veterans and World War II survivors in a community sample in the Netherlands.

Overall, the pooled hazard ratio (weighted by sample size) was 1.29 (95% confidence interval [CI], 1.11 - 1.5; P < .001), indicating a 29% increased risk for mortality in those with PTSD, corresponding to a small to medium effect size.

The authors describe these observations about the biology of PTSD as "premature senescence."

PTSD is unique in that, unlike schizophrenia, depression, and bipolar disorder, it is relatively simple to pinpoint when the condition started, said study coauthor Barton Palmer, PhD, a research psychologist in the San Diego Veterans Administration and professor of psychiatry at the UCSD.

Dr Barton Palmer

"In schizophrenia, there's evidence that some of the subtle abnormalities preceded the onset of the disorder by decades, whereas in PTSD, people appear to be doing normally until this unusual, traumatic event, so it allows us to gage the starting point with much more precision," said Dr Palmer.

This makes the findings of the review all the more surprising, said Dr Jeste.

"We didn't think that something like PTSD, which starts so acutely as a result of a specific trauma, can lead to something that is progressive," he said. "It's like a domino effect," in which a process is set in motion and then accelerates, he added.

Although the review articles did not "fully tease this out," there are effective psychological interventions for PTSD, including cognitive-behavioral therapies that address avoidance and intrusive thoughts, added Dr Palmer.

"An open question is, if people receive those effective treatments, will they still show the accelerated aging?," he said. "It opens up the possibility, which warrants investigation, that there is more to be treated in PTSD. We need to think about this as a systemic disorder and not only in terms of the psychological aspects."

If these treatments can turn back the proverbial clock, PTSD patients may not have easy access to them, added Dr Palmer.

"Are they suffering with PTSD for years or decades before coming to recognition or getting treatment soon after being diagnosed? Whether timing matters is an unanswered question, and if it does matter, how do we more effectively make sure people get those treatments?"

No Approved Medications

Currently, there are no US Food and Drug Administration (FDA)–approved drugs for PTSD. According to Dr Jeste, some patients are prescribed an antipsychotic or antidepressant, but there is no evidence that these drugs work, and they can carry significant side effects. "Long-term use of these drugs is really not indicated," he said.

As for possible explanations linking PTSD with accelerated aging, it might be that people who are vulnerable to early senescence processes are also more likely to develop PTSD. It could also be that patients with PTSD engage in unhealthy habits and have increased suicidal behaviors because of their trauma.

Because the studies included in the review did not show causality or sequence of events, "we can't answer the question of whether it's susceptibility or something that happens afterward, like increase in smoking or drug abuse," said Dr Jeste.

Survivors of trauma may have earlier mortality because of complications from physical injures rather than PTSD.

Another possible mechanism linking PTSD to early senescence is inflammation. According to Dr Jeste, inflammation is probably the main underlying mechanism for the aging process in general. "In this review, proinflammatory markers seem to be elevated to a significant extent."

In response to stress, a number of other physical changes, including increased heart rate and blood pressure, kick in, but these effects typically "wear off," and the body returns to its normal homeostatic level. However, with PTSD, it is almost like having chronic stress, said Dr Jeste.

"All of the changes become chronic, and they persist, so that may lead to an increase in inflammation and to morbidity, for example, hypertension, gastrointestinal ulcer, and heart disease. These are all related to stress."

The current review is "a call for research," said Dr Jeste. He and his colleagues recommend that future studies focus on issues relating to premature vs accelerated senescence and to senescence-associated medical comorbidities.

Dr Dilip Jeste

They would also like to see more attention paid to the nature of inflammatory, oxidative cellular aging and allostatic processes that may be involved in PTSD and of the relevant trauma ― the type, intensity, recurrence, and developmental timing.

Threat to Organismal Integrity

Commenting on the findings for Medscape Medical News, John Krystal, MD, professor of translational research and of neurobiology and chair, Department of Psychiatry, Yale University School of Medicine, in New Haven, Connecticut, said the authors make an important point that "long-term, dysfunctional psychological stress is a threat to organismal integrity."

"In other words, there is a tendency to view stress and PTSD as presenting problems only in the psychological or social spheres of life. However, it has been clear for a long time that psychological stress activates many processes, including the inflammatory processes."

To the extent that PTSD accelerates age-related changes in the body, it could be viewed as contributing to premature senescence, but that begs the question of whether the negative effects of stress are "just generally bad for you or bad for you in a specifically age-related way," said Dr Krystal.

Senescence has been defined as the gradual deterioration of function after maturation. Dr Krystal noted that the study authors define premature senescence on the basis of biomarkers of senescence, senescence-associated medical comorbidities, and mortality rates.

"Perhaps this is not a precise way to define senescence. After all, telomeres can be lengthened as well as shortened, the levels of proinflammatory markers can be decreased, and interventions may treat stress-related morbidity and prevent mortality."

Dr Krystal added that, given the definition of senescence as deterioration occurring after maturation, it is difficult to integrate this new article with other studies pointing to similar types of negative effects in the developing organism, for example, alterations in the way that the brain develops or long-lasting perturbations of "stress response systems" in the body.

Funding for the review came, in part, from the Veterans Affairs San Diego Healthcare System Center of Excellence for Stress and Mental Health, the National Institutes of Health, the US Department of Defense, the UCSD Center for Healthy Aging, and the Sam and Rose Stein Institute for Research on Aging.

Am J Geriatr Psychiatry. Published online May 7, 2015. Abstract